Recalcitrant cutaneous vasculitis - A surrogate marker of smoldering multiple myeloma

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A 55-year-old woman presented with recurrent episodes of palpable purpura and erythematous plaques on her limbs and trunk for 6 years. She also had painful ulcers with haemorrhagic crusts that healed with scars, along with intermittent abdominal pain, fever and joint pain. She had no history of chronic cough, weight loss or bone pain. Previous treatments with steroids, azathioprine, cyclophosphamide and rituximab led to only partial improvement followed by relapse.

Her general physical examination was unremarkable. Cutaneous examination showed multiple erythematous tender papules, urticarial plaques and purpuric lesions that had ulcerated to form superficial to deep non-healing ulcers (2.5 cm to 4 cm) with necrotic slough, distributed on the dorsum of both hands [Figure 1] and feet [Figure 2]. Multiple scars from previously healed ulcers were noted on the upper and lower limbs. There were no nodules or livedoid erythema. Histopathological examination revealed leukocytoclastic vasculitis (LCV) [Figure 3] and direct immunofluorescence for IgG, IgM, IgA and C3 was negative. A clinical diagnosis of LCV was made and she was treated with cyclosporine 100 mg (3-4 mg/kg) twice daily along with indomethacin 75mg/day, leading to partial improvement followed by relapse. Later, two intravenous immunoglobulin (IVIG) infusions monthly led to cessation of new lesions and healed existing ulcers.

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Figure 1:

Multiple well-defined ulcers with central necrotic crusts on the dorsum of both hands.

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Figure 2:

Multiple ulcers on the dorsum of the feet with a large ulcer showing central black eschar on the great toe.

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Figure 3:

Histopathology showing features of leukocytoclastic vasculitis involving dermal vessels: fibrinoid necrosis (black arrow), neutrophilic infiltration (yellow arrow), leukocytoclasia (red arrow) and extravasated erythrocytes (blue arrow) (Haemotoxylin and eosin, 400x).

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Laboratory investigations showed normocytic normochromic anemia, increased erythrocyte sedimentation rate (ESR) and C-reactive protein. Antinuclear antibody, anti-double-stranded DNA, anti-smith, antineutrophil cytoplasmic antibodies, cryoglobulins, rheumatoid factor, lupus anticoagulant, antiphospholipid antibody, HIV, hepatitis B and C were found to be negative. Serum creatinine, blood urea, urinalysis and serum calcium levels were within normal limits. Urine and stool for occult blood, carcinoembryonic antigen, mammography and Papanicolaou smear were normal. Immunoelectrophoresis demonstrated monoclonal IgA gammopathy, kappa light chains, an elevated kappa/lambda ratio and M band. IgG, IgM and lambda light chain were normal. Bone marrow aspirate and biopsy showed increased plasma cells >10%. There was no evidence of osteolysis in radiographs of the skull and spine. Based on these findings, a diagnosis of smouldering multiple myeloma (SMM) was made. The delayed diagnosis was due to financial constraints, incomplete evaluation at previously treated centres and lack of access to specialised tests such as serum electrophoresis and bone marrow biopsy.

The patient was referred to the haematology department and is under regular follow-up every three months for disease monitoring.

Our patient was initially managed with hydroxychloroquine, aspirin and pentoxifylline without significant improvement. Cyclosporine was added, leading to a partial response. However, due to financial constraints, cyclosporine was gradually tapered and discontinued and colchicine therapy was started subsequently. IVIG could not be administered due to unavailability and cost. Subsequently, she was treated with a rituximab infusion which resulted in appreciable improvement in her symptoms.

Vasculitis may be primary (autoimmune) or secondary to infections, drugs, malignancies or autoinflammatory diseases, though its association with myeloproliferative disorders is rare. Cutaneous involvement in multiple myeloma is uncommon and may occur directly via plasma cell infiltration or indirectly through inflammatory or metabolic changes, presenting as amyloidosis, cryoglobulinemia, plasmacytoma, LCV or other dermatoses.^1,2

LCV is a rare paraneoplastic manifestation of multiple myeloma which may manifest before diagnosis of malignancy and in our patient, LCV manifested several years before smoldering multiple myeloma was identified. As per our knowledge, only 22 cases of vasculitis associated with multiple myeloma have been reported so far.³

Patients with malignancy-associated cutaneous vasculitis are usually older and present with recurrent, treatment-resistant lesions. Constitutional symptoms and haematologic abnormalities like cytopenias, anaemia and elevated ESR are common, while usual triggers like infections or drugs are absent. Associated malignancies include haematologic neoplasms such as lymphoma, leukaemia and multiple myeloma and solid tumours like lung, colorectal, renal, prostate, breast, uterine, ovarian and hepatic carcinomas.^4,5

SMM has ≥10% clonal plasma cells or serum protein ≥3 g/dL, while active multiple myeloma (MM) shows these findings along with CRAB (hypercalcemia, renal failure, anaemia, bone lesions) or SLiM (≥60% plasma cells, light chain ratio ≥100, MRI bone lesion) features. SMM carries a high risk of progression to active MM, about 10% per year for the first 5 years, decreasing thereafter. Management of SMM involves close observation with regular monitoring every 2–3 months initially, then every 4–6 months if stable. Standard regimens for MM include combinations such as lenalidomide with dexamethasone (Rd), bortezomib, lenalidomide and dexamethasone (VRd) or bortezomib, cyclophosphamide and dexamethasone (VCd).^6,7

Our patient had long-standing, recurrent LCV unresponsive to multiple immunosuppressive treatments. Its persistent, resistant course and exclusion of other causes prompted us to investigate an underlying neoplasm.

In conclusion, recalcitrant vasculitis should raise the suspicion of underlying malignancy, warranting evaluation and screening.