POEMS syndrome with atypical presentation: A rare case

ABSTRACT

POEMS is an uncommon paraneoplastic plasma cell disorder known with the expansion of polyneuropathy, organomegaly, endocrine abnormalities, M-band, and skin changes. We report a patient presenting with monoarthritis and weight loss for 5 months, who was treated empirically for tuberculous arthritis and later developed debilitating axonal polyneuropathy due to delayed diagnosis. POEMS/Plasma cell dyscrasias rarely involve joints, and this case highlights this unique presentation of POEMS syndrome. Bone biopsy from the affected joint revealed the diagnosis. Chronic large-joint monoarthritis with systemic symptoms, mimicking tuberculous arthritis, and polyneuropathy is a unique combination—so clinicians should consider an underlying plasma cell dyscrasia/POEMS to avoid delayed diagnosis.

Introduction

POEMS syndrome is a rare (prevalence 0.3/100000), male predominant (median age 54 years, range 21–84 years) multisystem paraneoplastic disorder due to an underlying plasma cell dyscrasia, classically presenting with progressive peripheral neuropathy and systemic features.[1,2] Joint involvement is uncommon; large-joint monoarthritis is rarely reported and may mimic septic arthritis, amyloid arthropathy, or rheumatoid arthritis. In endemic regions, chronic monoarthritis with constitutional symptoms is often presumed to be tuberculous arthritis delaying recognition of the plasma cell disorder. This case highlights monoarthritis as an early, atypical manifestation preceding neuropathy and underscores the need for tissue diagnosis and evaluation for monoclonal protein/vascular endothelial growth factor (VEGF) when multisystem clues are present.

Case Details

A 37-year-old male presented with pain in the left hip, low-grade fever, anorexia, and weight loss for 9 months. He developed tingling sensations and weakness in his legs, which progressed from feet to knees and fingers over 4 months. He could not rise from a squatting position and developed difficulty retaining slippers on walking for 1 month. There was no history of cranial nerve innervated muscle weakness, sicca symptoms, renal impairment, or substance abuse. He was taking isoniazid, rifampicin, ethambutol, pyrazinamide, and pyridoxine for 5 months for a provisional diagnosis left hip tuberculosis before consulting us.

On examination, he had exfoliation of skin on anterior shins and hyperpigmentation of hands, legs, and feet [Figure 1a]. He had 3–4 cm, firm, mobile, nontender left inguinal lymph nodes. Movement at the left hip was painful and restricted. The left hip area was tender to deep palpation. There was symmetrical atrophy of leg muscles. The Medical Research Council (MRC) grade of power at the right hip and both knee joint was grade 2/5. Ankle had grade 0/5 power. Mild hand grip weakness was present. All deep tendon jerks were not elicitable. There was graded sensory loss for pinprick/temperature sensations in stocking distribution below knee joints and glove distribution below wrist joints. Vibration sense was reduced below knee joints. Fine touch sensations were lost below ankle joints, and proprioception was lost in both great toes. Autonomic functions were normal. There were no thickened/tender nerves.

Figure 1.

(a) Hyperpigmentation of dorsum of feet, toes, and legs. (b) X-ray of left hip joint: Irregular radiolucent area involving the medial aspect of femoral head and neck showing cortical erosions (arrow) in the femur neck and sclerosis of acetabulum (arrowhead). (c) Fat-suppressed T2-weighted MRI showed synovial thickening, joint effusion (arrow), edema in adjacent muscle with bony destruction in the medial part of femoral head/neck. (d) Contrast T1 magnetic resonance imaging left hip showed small homogeneous enhancing collection (arrow) in the left gluteus medius muscles. (e) Sections of biopsy from the metaphyseal lesion of femur neck show diffuse sheets of infiltration by abnormal plasma cells (arrow) with large eccentric nuclei, coarse chromatin, and moderate cytoplasm (Hematoxylin and Eosin stain 20x). (f), (g) PET CT scan showing lytic lesion in left femur head (arrow) and ala of sacrum (arrowhead) with FDG avid metabolically active lesion in corresponding area (star)

Question 1: How will you approach to a case of hip arthritis, constitutional symptoms, and sensorimotor quadriparesis?

Reply: Glove-stocking sensory loss, hyporeflexia, and graded weakness favor length-dependent (dying-back) axonal sensory–motor polyneuropathy. The presence of left hip arthritis, accompanied by fever, weight loss, skin changes, and enlarged lymph nodes, indicates multisystem involvement, and a history of 9 months suggests a chronic process. The etiological possibilities include infective causes, systemic inflammation, and malignancy.

Considering a multisystem involvement, a list of causes that can produce arthritis, neuropathy, and constitutional symptoms are detailed in Table 1.

Table 1.

Differential diagnosis of arthritis and peripheral neuropathy

Diseases	Pattern of joint involvement	Associated features	Present Case: Points in favour	Present Case: Points against
Tuberculosis	Large joint – hip, knee, sacroiliac joint, shoulder	Fever, weight loss, night sweats	Monoarthritis hip joint, Constitutional symptoms	Neuropathy. May only be seen with isoniazid or nutritional.
Fungal (candida, aspergillus etc.)	Large joint (weight bearing) – knee	Immunosuppressed hosts, intravenous drug user, prolonged antibiotics, neutropenia Prosthetic implant	Monoarthritis Polyneuropathy	No immunocompromised state
Lyme Disease	Recurrent, episodic synovitis, Pauci-articular – knee joint, hip joint Can be migratory or polyarticular	Fever during arthritis episode, cutaneous changes	Arthritis with polyneuropathy	No pauciarticular or polyarticular involvement. No cutaneous changes of Lyme disease
Sarcoidosis	Oligoarticular or polyarticular large joint involvement, Rarely monoarticular	Significant cutaneous features plus Lofgren syndrome – (erythema nodosum and hilar lymphadenopathy)	Large joint arthritis with peripheral neuropathy	No oligo or poly articular involvement No erythema nodosum
Non-Hodgkin’s lymphoma	Monoarticular – knee, symptoms of inflammatory arthritis, limited range of motion	Systemic Class B symptoms, Lymphadenopathy	Monoarticular involvement, Polyneuropathy, constitutional symptom, Lymphadenopathy	None
Malignant cell histiocytosis	Axial skeleton preferably skull, spine and pelvis, infrequent joint involvement	Lymph node, skin or gastrointestinal symptoms	Arthritis Polyneuropathy Lymphadenopathy	Appendicular involvement No skin or gastrointestinal symptoms
Plasma cell dyscrasia	Bone involvement common, joint involvement rare.	CRAB features, skin changes, organomegaly, endocrinopathy	Bone involvement. Polyneuropathy Skin changes Lymphadenopathy	Appendicular joint involvement Absence of CRAB features
Amyloid arthropathy	Shoulder, wrists, hands and knees, shoulder pad sign, preserved joint space	Autonomic dysfunction, painful peripheral neuropathy, signs of systemic amyloidosis	Polyneuropathy with articular involvement	Absence of dysautonomia, allodynia, signs of systemic amyloidosis

Tuberculosis produces constitutional symptoms and large-joint arthritis. However, tuberculosis rarely produces neuropathy. Isoniazid does not produce motor neuropathy. Lyme disease, fungal infection, and syphilis are rare causes of arthritis. Syphilis may produce polyarticular arthritis. Lyme disease (chronic persistent stage) may produce oligoarticular arthritis, peripheral neuropathy, and cutaneous changes. However, it involves knee/elbow joints. Lymes disease is uncommon in the North Indian plains. Fungal arthritis is uncommon in immunocompetent hosts. Sarcoidosis may produce oligoarticular or polyarticular arthritis, erythema nodosum, and bilateral hilar lymphadenopathy (Lofgren syndrome). Non-Hodgkins’s lymphoma, plasma cell dyscrasia, and malignant cell histiocytosis also cause arthritis and peripheral neuropathy.

Case Details (Continued)

Blood investigations revealed platelet counts of 6.20 × 10^5/mm³ (normal range 1.5 × 10^5/mm³ to 4.5 × 10^5/mm³) and serum sodium of 127 mEq/L, with normal renal and liver function tests, vitamin B12, and folate levels. Serological testing for HIV, hepatitis B and C, syphilis (VDRL), and ANA, ENA screen, and ACE levels were unremarkable. Nerve conduction studies showed reduced compound muscle action potentials (CMAPs) and sensory nerve action potentials (SNAPs) in the median and ulnar nerves, with unrecordable signals in the common peroneal, posterior tibial, and sural nerves. Imaging studies revealed the following: X-ray of the left hip: Cortical erosions of the femoral head and neck with marginal sclerosis [Figure 1b]. MRI of the left hip: Homogeneously enhancing lesion with bony destruction in the left femoral head/neck and acetabulum, marginal sclerosis, synovial thickening, joint effusion, and muscle edema [Figure 1c and d]. Further testing demonstrated cerebrospinal fluid (CSF) findings of elevated protein (87 mg/dL), normal glucose levels (67 mg/dL), and a total leukocyte count of 5/mm³ (all lymphocytes). Serum protein electrophoresis, immunofixation, and free light chain assay revealed an M-band (0.5 g/dL) with IgG lambda monoclonal protein and a reduced kappa/lambda ratio. The skeletal bone survey was otherwise normal.

Question 2: Since the patient showed non-IgM gammopathy, which gammopathy can present with peripheral neuropathy and arthritis?

Reply: Non-IgM gammopathy and peripheral neuropathy are caused by multiple myeloma, POEMS syndrome, and AL amyloidosis.[3] However, they rarely present with arthritis.

Case Details (Continued)

A bone biopsy from femur head revealed sheets of atypical plasma cells [Figure 1e]. The bone and joint tissue were negative for any bacterial growth. Gene Xpert test was negative. Ziehl Neelsen stain was negative for acid-fast bacilli.

Bone marrow biopsy revealed normal plasma cells. A whole-body PET scan showed solitary lytic and hypermetabolic lesion in head/neck of left femur and left sacrum ala [Figure 1f and g], hypermetabolic cervical, axillary, mediastinal, abdominal, and pelvic lymph nodes. Other investigations revealed low serum cortisol, impaired glycemic control, hypothyroidism, and very high vascular endothelial growth factor (VEGF), 5368.5 pg/ml (62–710 pg/ml).

The presence of a localized plasma cell dyscrasia, positive M-band, and the absence of hypercalcemia, renal dysfunction, and anemia among the CRAB features fulfilled criteria for solitary plasmacytoma.

Question 3: With a negative tissue biopsy of left hip articular tissue for infective/inflammatory cause and femur head showing atypical plasma cells, what could be the possible mechanism of hip joint arthritis?

Left hip arthropathy was secondary to plasmacytoma of intra-articular femur head that produced secondary joint involvement in the form of synovial thickening and joint effusion.

With evidence of solitary lytic/sclerotic lesion and constitutional symptoms, a possibility of POEMS syndrome was considered. Diagnostic criteria for POEMS syndrome require the presence of peripheral neuropathy and monoclonal plasma cell proliferative disorder (mandatory criteria). It also requires the presence of at least one of three following major criteria: sclerotic bone lesion, elevated VGEF levels, and Castleman’s disease, and the presence of one of the following six minor criteria: organomegaly (hepatomegaly or splenomegaly or lymphadenopathy), endocrinopathy, extravascular volume overload, skin changes, papilledema, and thrombocytosis/polycythemia.[4] The presence of solitary plasmacytoma and peripheral neuropathy fulfilled the mandatory criteria. The sclerotic/lytic bone lesions and raised VEGF levels fulfilled major criteria, and skin changes, lymphadenopathy, thrombocytosis, hypothyroidism, and low cortisol levels fulfilled the minor criteria for POEMS syndrome.

Question 4: POEMS syndrome is associated with which plasma cell dyscrasia and how to differentiate those?

Reply: POEMS syndrome may be associated with multiple myeloma (≥60% clonal plasma cells in bone marrow), monoclonal gammopathy of unknown significance (MGUS, <10% clonal plasma cells in bone marrow), and solitary plasmacytoma.[4] PET scan may help in the diagnosis of solitary plasmacytoma.

Case Details (Continued)

The patient received local radiotherapy for left femur plasmacytoma along with thyroxine and corticosteroids supplementation. At 6 months, the patient had persistent elevated VEGF levels (3489.9 pg/ml), a positive M-band, and a metabolically active left femur head lesion on a repeat PET scan. Considering a highly active disease and failure of primary therapy, the patient received chemotherapy with the KRD regimen (carfilzomib, dexamethasone, and lenalidomide), followed by autologous stem cell transplantation (ASCT) that produced complete recovery of sensory symptoms and improved power in legs, M-band was undetectable, and VEGF levels normalized. PET scan indicated a metabolically inactive solitary lytic lesion in the femoral head/neck consistent with a complete metabolic response.

Question 5: What is the pattern of peripheral neuropathy in POEMS syndrome and other paraproteinemic conditions?

Reply: POEMS syndrome predominantly produces demyelinating polyneuropathy. However, severe axonal neuropathy due to axonal loss at nerve trunks due to narrowing of endoneurial blood vessels caused by abnormal endothelial cell activation due to VEGF and hypoxia-induced factor 1a (HIF 1a).[3,4,5] Peripheral neuropathy affects 5% to 20% individuals with multiple myeloma. Bortezomib/thalidomide treatment also produces sensory neuropathy. AL amyloidosis is characterized by painful neuropathy with autonomic dysfunction [Figure 2].

Figure 2.

Approach to a patient with paraproteinemia and peripheral neuropathy

Question 6: What is the pattern of joint disease in POEMS syndrome?

Reply: Joint involvement is not well-known with POEMS syndrome. Magnus Levy first noted arthropathy among patients of multiple myeloma.[6] This was described with various names as “Myelomose Arthrop- athie,” “dysprotidaemic joint disease,” “pseudorheumatoid arthritis,” and so on by other authors.[7] Monoarticular arthritis in plasma cell dyscrasias is often considered as septic arthritis caused by encapsulated bacteria (Streptococcus pneumoniae and Hemophilus Influenzae). Arthropathy is known with primary amyloidosis that affects shoulders, wrists, and hands and shows characteristic shoulder-pad sign, preserved joint spaces, cystic lesions with/without surrounding sclerosis, and soft-tissue nodular deposits on imaging. Congo red staining of synovial fluid reveals apple-green birefringent intracellular/extracellular amyloid deposits.[8] Inflammatory arthritis is rarely described in Waldenström macroglobulinemia and secondary amyloidosis.[9,10]

Question 7: What is the pattern of bone involvement in POEMS?

Reply: Bony lesions in POEMS syndrome are mostly densely sclerotic, some are lytic with sclerotic rim, and some show mixed soap bubble appearance.[4,11] Osteolytic lesions with diffuse osteopenia/pathological fractures are seen in multiple myeloma and MGUS.

Question 8: What is the treatment approach in POEMS syndrome?

Reply: Involved-field radiotherapy is usually curative for isolated plasmacytoma. For systemic disease (involvement of the bone marrow), there is a shift from a lenalidomide/dexamethasone-based regime to more proteasome inhibitor and autologous stem cell transplantation because of a higher response rate and prolonged survival.[12,13,14]

Conclusion

This case highlights that chronic large-joint monoarthritis with constitutional symptoms can be an early manifestation of POEMS syndrome and may be misdiagnosed as tuberculous or other infective/inflammatory arthritis, resulting in delayed recognition of the underlying plasma cell dyscrasia. Clinicians should consider POEMS when monoarthritis is accompanied by multisystem clues and/or evolving peripheral neuropathy and should have a low threshold for targeted bone/joint biopsy and evaluation for monoclonal protein and VEGF. To the best of our knowledge, this is the first report of POEMS syndrome presenting initially with monoarthritis preceding polyneuropathy.

Declaration of patient consent

The authors declare that appropriate patient consent has been obtained.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.