Acute cryoglobulinemic vasculitis following rituximab infusion for waldenström macroglobulinemia

Introduction

Waldenström macroglobulinemia (WM) is an indolent B-cell lymphoproliferative disorder characterized by lymphoplasmacytic lymphoma in the bone marrow and an immunoglobulin M (IgM) monoclonal gammopathy in the blood. The symptoms of WM are varied and are caused by the proliferation of plasma cells and the accumulation of paraproteins in the serum, which may cause “B” symptoms, hyperviscosity syndrome requiring plasmapheresis, cryoglobulinemia, and neuropathy. Symptomatic WM is typically treated with chemotherapy in conjugation with rituximab, or with bruton kinase inhibitors. A paradoxical increase in serum IgM following rituximab initiation for WM has been reported and can result in hyperviscosity symptoms.¹ Rituximab has also been observed to cause flares in autoimmune conditions and cryoglobulinemic vasculitis (CV).²

Cryoglobulinemia as a sequela of WM is caused by the accumulation of paraproteins in the serum, most often IgM kappa. WM is associated with both type I and type II cryoglobulinemia. In WM-associated type II cryoglobulinemia, the monoclonal IgM exhibits rheumatoid factor activity and serves as an autoantibody for polyclonal IgG. Clinically, WM-associated type II cryoglobulinemia presents as palpable purpura that can become necrotic. Skin biopsy of lesions demonstrates leukocytoclastic vasculitis, and direct immunofluorescence microscopy often reveals deposits of IgM, IgG, and/or C3 complement.

This case report highlights a case of CV in the setting of WM that manifested after treatment with rituximab.

Case report

A 68-year-old man with a past medical history of WM presented with palpable purpuric papules with erythema and edema on the bilateral ankles and feet that he first noticed after his second round of treatment with bendamustine and rituximab. The patient was diagnosed with WM 3 years prior to presentation and had recently initiated therapy with bendamustine (90 mg/m² on days 1 and 2 of each cycle) and rituximab (375 mg/m² on day 1 of each cycle) repeated every 4 weeks after developing constitutional symptoms and neuropathy.

Of note, the patient developed tumor lysis syndrome during his first cycle of treatment and was started on allopurinol. The patient was hospitalized after his first cycle of chemotherapy for acute kidney injury, suspected sepsis, and atrial fibrillation, and was treated with antibiotics and intravenous fluids. A diffuse morbilliform eruption and eosinophilia developed during hospitalization, suspicious for DRESS (Drug reaction with eosinophilia and systemic symptoms) syndrome, and allopurinol was discontinued. The rash and eosinophilia resolved with systemic and topical corticosteroids prior to his second cycle of bendamustine and rituximab.

Two days following the second cycle of treatment, the patient developed palpable purpuric papules with erythema and associated edema on the bilateral ankles and feet (Fig 1). The rash began on his toes and feet and progressed proximally to both legs and eventually to his thighs. The lesions were not painful to palpation. The patient had no associated symptoms besides mild joint pain in his feet. Complete blood count, comprehensive metabolic panel, and urinalysis showed no sign of other organ involvement.

Fig 1.

A-C, Palpable purpuric papules and plaques on the feet and legs with associated edema.

Biopsy of 2 lesions demonstrated a perivascular mixed dermal infiltrate associated with vascular fibrin deposition, consistent with leukocytoclastic vasculitis (Fig 2). Direct immunofluorescence showed deposition of multiple Igs (IgG, IgM, and IgA) and complement within the superficial and upper dermal blood vessels (Fig 3) with a differential diagnosis including CV and vasculitis associated with connective tissue disease. Serum testing yielded elevated rheumatoid factor, low complement (C4), and positive cryoglobulins (immunofixation confirmed monoclonal IgM kappa), together with negative antineutrophil cytoplasmic antibodies and antinuclear antibodies. A diagnosis of type II (mixed) CV was made based on the combination of clinical and histopathologic findings of leukocytoclastic vasculitis, a mixture of a IgM, IgG, and IgA in and around dermal blood vessels, positive serum IgM monoclonal cryoglobulins, elevated rheumatoid factor, and low C3.

Fig 2.

A-C, Punch biopsy from left lateral distal calf showing perivascular mixed dermal infiltrate (neutrophil-predominant) associated with vascular fibrin deposition.

Fig 3.

A-C, Direct immunofluorescence showing deposition of multiple immunoglobulins and complement within superficial and upper dermal blood vessels with associated destruction marked by abundant perivascular fibrinogen. (A, B and C, Hematoxylin-eosin stain; original magnifications: A, IgM 200×, B, IgG 200×, and C, fibrinogen 200×).

The rash resolved after treatment with a short course of oral corticosteroids. Treatment for WM was continued with rituximab and bendamustine without recurrence of vasculitis. Further testing showed no presence of serum cryoglobulins 1 month after the initial presentation.

Discussion

This case report presents a patient with WM with no previous history of cryoglobulinemia who developed type II CV after treatment with rituximab. This case highlights the possibility of isolated cutaneous manifestations of rituximab-associated cryoglobulinemia.

Rituximab has been observed to cause flares in patients with known CV. A retrospective study by Sy-Go et al² demonstrated that 22% of patients with CV demonstrated a disease flare following treatment with rituximab. Clinical manifestations most often involved the skin, kidneys, and peripheral nerves. This study also found that CV flares are most likely to occur in patients with underlying B-cell lymphoproliferative disorders. This flare in cryoglobulinemia parallels the observed phenomenon of a paradoxical increase in serum IgM in 30% to 70% individuals with WM early in treatment with rituximab.¹

Although the clinical manifestations of CV following rituximab administration can be dramatic, this should not be considered a failure of treatment. Previous case reports have demonstrated that despite an initial increase in cryoglobulin levels following rituximab therapy, levels quickly fall and normalize, leading to disease remission.³ A similar outcome was seen in our patient, who responded rapidly to a prednisone taper and had negative cryoglobulins 1 month after initial presentation.

Shaikh et al⁴ described a similar patient with a new diagnosis of CV following rituximab administration, who developed renal failure that was reversed with plasmapheresis. It was advised that cryoglobulins should be measured before treatment with rituximab to establish a baseline. Recent guidelines have also recommended that, given the paradoxical rise in IgM seen following rituximab therapy, rituximab to be delayed if IgM levels are above 40 g/dL.⁵ The patient described in this case had an IgM level of 561 g/L prior to treatment.

Plasmapheresis is recommended in the treatment of WM when symptomatic hyperviscosity develops. To avoid the worsening of symptoms that accompany a flare in IgM and/or cryoglobulins, it has been proposed to perform plasmapheresis prior to rituximab administration if serum viscosity is above 3.5 cp or IgM level is >50 g/L. The flare phenomenon has also become less common with the employment of combination regimens that utilize chemotherapy prior to rituximab.⁶

In conclusion, this case highlights an example of CV presenting after treatment of WM with rituximab, demonstrating the importance of monitoring for cutaneous side effects, especially in the setting of high initial serum IgM.

Conflicts of interest

None disclosed.