Mixed Cryoglobulinemia in the Setting of Monoclonal B-Cell Lymphocytosis and Monoclonal Gammopathy of Unknown Significance: A Case Report

Introduction

Cryoglobulinemia refers to the presence of cryoglobulins in the blood and is classified into 3 categories [1]. Type I comprises monoclonal immunoglobulins (IgM or IgG) and is associated with monoclonal gammopathies and B-cell lineage monoclonal lymphoproliferative disorders. Type II and type III cryoglobulinemias (mixed) contain both isotypes of polyclonal cryoglobulins and tend to occur in conditions of persistent immune stimulation and polyclonal B-cell proliferation, such as chronic viral infections and autoimmune disorders [2]. Cryoglobulinemic vasculitis is a clinical syndrome that stems from the deposition of cryoglobulin-containing immune complexes into small- to medium-sized vessels, usually in the skin, kidneys and peripheral nerves. While HCV infection remains the dominant cause of cryoglobulinemic vasculitis in much of the world, non-infectious causes, such as autoimmune diseases and lymphoproliferative disorders, have grown in prevalence and importance and pose new diagnostic and management challenges.

Two commonly recognized non-infectious causes of cryoglobulinemic vasculitis are monoclonal gammopathy of undetermined significance (MGUS) and myeloma [3]. MGUS is a premalignant condition characterized by the presence of a monoclonal protein in the serum at a level of <3 g/dL, with <10% clonal plasma cells infiltrates in the bone marrow and absence of end-organ damage [4]. While generally thought to be asymptomatic, certain secondary manifestations of the disease have been recognized, including cryoglobulinemia and cold agglutinin disease, which are both associated with IgM MGUS [5, 6], and associated immunoglobulin deposit-mediated glomerulonephritis, termed monoclonal gammopathy of renal significance (MGRS) [7].

Monoclonal B-cell lymphocytosis (MBL) describes a small, but detectable B-cell lineage-derived proliferation disorder of malignant potential [8], a subcategory of the monotypic lymphoproliferative disorders of undetermined significance (MLDUS), which is characterized by the presence of a small monoclonal subpopulation of B lymphocytes (<5000 cells/uL) in the peripheral blood of patients in the absence of B symptoms and any other typical feature of a lymphoproliferative disorder [9]. MGUS can be related to a concurrent MBL, but not all patients with MBL produce monoclonal proteins. MGUS and MBL/MLDUS are often found incidentally and are generally managed with close monitoring for progression to plasma cell dyscrasias and aggressive lymphoproliferative disorders, respectively [10–12].

In our case, non-infectious mixed cryoglobulinemic vasculitis, as well MBL with small MGUS, were present in our patient. This presentation highlights the diagnostic challenges that a complex hematologic and rheumatologic history can pose, especially for a new diagnosis of cryoglobulinemic vasculitis. Furthermore, it raises the question of whether, and to what extent, these comorbidities might have contributed to our patient’s rapidly progressive clinical picture.

Case Report

We present the case of an 82-year-old woman with a past medical history of hypertension, hypothyroidism, and osteoarthritis, and a 2-year history of hypocomplementemic urticarial vasculitis (HUV), stable on omalizumab, as well as a monoclonal B-cell lymphocytosis (MBL) with small monoclonal gammopathy of undetermined significance (MGUS) on active surveillance, who presented to a tertiary care center with pleuritic chest pain, fatigue, and generalized weakness.

On presentation, she was afebrile, tachycardic to 105/min, hypertensive to 151/81 mmHg, and saturating 99% on room air. A physical exam was remarkable for worsening of her known urticarial vasculitis skin rash on the bilateral lower extremities.

Initial laboratory investigations were notable for acute kidney injury (AKI) with creatinine of 1.6 mg/dL and a blood urea nitrogen of 37 mg/dL (baseline kidney parameters were within normal limits), and a new finding of microhematuria with dysmorphic red blood cells without proteinuria, bacteriuria, or pyuria on urinalysis. A complete blood count showed a new mild normocytic anemia with a hemoglobin of 11.3 g/dL. Electrolytes were within normal limits and there was a stable troponin elevation at 0.04 ng/mL, consistent with type II myocardial injury, and EKG showed normal sinus rhythm without abnormalities.

Given her pleuritic chest pain, a chest CT with contrast was obtained upon admission to rule out pulmonary embolism. The CT demonstrated bibasilar compression atelectasis in the setting of small bilateral pleural effusions with some anterolateral septal thickening and reactive-appearing mediastinal adenopathy (Figure 1). Echocardiography showed normal left-ventricular systolic and diastolic function, but diffuse visceral pericardial thickening with a small pericardial effusion. The combination of AKI with hematuria concerning for glomerulonephritis, worsening chronic leukocytoclastic skin rash, and polyserositis with pleural and pericardial involvement raised a concern for progression of the previous urticarial, skin-limited vasculitis to systemic vasculitis [13].

In consultation with rheumatology, a biopsy was obtained to assess for new vasculitic involvement of the kidneys. The biopsy, however, showed diffuse glomerulonephritis with focal membranoproliferative features and mainly monoclonal IgG1 and IgM kappa deposits, consistent with a proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and cryoglobulinemic glomerulonephritis. Further laboratory investigations revealed a positive antinuclear antibody titer of 1: 320 with homogeneous pattern via indirect immunofluorescence and negative extractable nuclear antigen antibody panel, and cryoglobulinemia with a cryocrit of 3%, as well as a newly decreased IgG and increased IgM. Positive rheumatoid factor activity, decreased C3, and undetectable C4 levels had been present in prior evaluations undertaken for her skin vasculitis. Taken together, these findings were consistent with cryoglobulinemic vasculitis. Cryoglobulin typing demonstrated a mixed picture with monoclonal IgM kappa and polyclonal IgG components, consistent with type II cryoglobulinemia. During our investigation, a skin biopsy was repeated, which showed leukocytoclastic vasculitis unchanged from findings in prior skin biopsies. This finding can be seen in both cryoglobulinemic and hypocomplementemic urticarial vasculitis.

To evaluate for possible underlying causes of cryoglobulinemia, the patient was tested for HIV and hepatitis B and C, which were all negative. Given her previous history of MBL with associated small MGUS, we wondered whether this had caused her cryoglobulinemia. She therefore underwent a repeat bone marrow biopsy, which demonstrated stability of her previously known biclonal MBL (Figure 2). Monoclonal B-cell populations showed kappa restriction with CLL/SLL-like immunophenotypes, totaling 0.54% (0.46% and 0.08%, respectively) of the total bone marrow white blood cell count (Figure 3). In respect of her MGUS, no information was available regarding the subtype of the paraproteinemia and whether it was IgG, IgM, or IgA.

During her hospital stay, she contracted SARS-CoV-2 infection, detected by the diagnostic workup. Her SARS-CoV-2 infection was associated with mild hypoxia requiring oxygen supplementation with 1 to 2 L/min via nasal cannula, and she completed a 5-day course of Remdesivir, with improvement in her symptoms. After completion of diagnostics and COVID-19 treatment, she was started on pulse-dose steroids and B-cell-directed therapy with Rituximab for her cryoglobulinemic vasculitis. Despite improvement in kidney function and skin rash, she developed rapidly progressive hypoxemic respiratory failure 5 days after initiation of treatment, with escalation in oxygen requirements from nasal cannula to maximal settings of heated high-flow support within 36 hours. Chest imaging at the time was significant for bilateral hazy opacities extending on all lung fields, as well as large bilateral pleural effusions (Figure 4). As further escalation of care with invasive measures, such as bronchoscopy, plasmapheresis, intubation, and mechanical ventilation, did not align with her goals of care, she decided on a comfort-based approach and died within 24 hours, about 3 weeks after admission.

Discussion

This case is an excellent example of the diagnostic and therapeutic challenges of non-infectious type II (mixed) cryoglobulinemic vasculitis in patients with intricate hematologic and rheumatic medical histories. As the incidence and prevalence of infectious-related mixed cryoglobulinemia is decreasing, this highlights the need to validate more precise and accessible diagnostic modalities and treatment protocols for non-HCV-related type II cryoglobulinemia.

Firstly, confirming the diagnosis of mixed cryoglobulinemia in our patient was not straightforward given that both a flare of her pre-existing HUV and a newly arising cryoglobulinemic vasculitis would present very similarly from both a laboratory and clinical perspective. Additionally, while our patient’s positive cryocrit was an indicator, this does not suffice by itself for a diagnosis, and the uncertainty whether this was a truly new finding given the inherent difficulty to reliably detect cryoglobulins using standard laboratory methods must be considered as well [14]. Further laboratory testing, namely our patient’s low complement levels and positive rheumatoid factor, are nonspecific findings in cryoglobulinemic vasculitis and other vasculitides and preceded her clinical deterioration. In respect to her clinical picture, both a progression of HUV as well as cryoglobulinemic vasculitis would affect the skin, the renal vasculature, and glomeruli [15–17]. Moreover, the finding of leukocytoclastic vasculitis is common between these 2 disease processes, rendering the skin biopsy results in our patient inconclusive [18, 19]. Ultimately, what proved to be instrumental to differentiate between these 2 conditions in our case was the renal biopsy, which cemented the diagnosis of cryoglobulinemic glomerulonephritis and associated mixed cryoglobulinemic vasculitis.

Identifying the etiology of our patient’s cryoglobulinemic vasculitis was equally challenging. Our patient’s non-corroborative infectious and autoimmune workup ruled out the classic culprits for mixed cryoglobulinemia and raised the question of whether her underlying hematologic or rheumatologic conditions could be the drivers of disease in her case.

While MGUS has a well-established association with type 1 cryoglobulinemic glomerulonephritis, MGUS-associated mixed cryoglobulinemic vasculitis is a less commonly reported and studied finding [20–24]. Thus, it remains unclear under what circumstances a monoclonal proliferative disorder like MGUS can cause a polyclonal, mixed cryoglobulinemia instead of a monoclonal type I cryoglobulinemia.

Furthermore, while there are no published reports suggesting a connection between MBL and non-infectious-related mixed cryoglobulinemic vasculitis, it is worth examining if and how the presence of MBL in our patient might have influenced the phenotype of her cryoglobulinemic vasculitis [25]. While the relationship between MBL and cryoglobulinemia has not been thoroughly examined before, there are reports attempting to characterize the association between clonal hematopoiesis and autoimmune disorders [26] However, remains unclear whether the prolonged inflammatory state of chronic infections and autoimmune conditions drive mutagenesis in white blood cell lines, or if, conversely, monoclonal cells lines foster autoimmune activation and autoantibody formation. For example, studies have found expansion of T cell clones in rheumatoid arthritis patients, which are thought to precede the development of large granular lymphocyte leukemia in these patients, but there are other hypotheses regarding T cell clones’ causative involvement in the dysregulation of immune response to self-antigens, thereby leading to development of rheumatoid arthritis [22,23].

While previously well controlled, it is also worth considering whether our patient’s pre-existing, skin-limited, hypocomplementemic vasculitis (HUV) was involved in the later manifestation of the systemic cryoglobulinemic vasculitis with multiorgan compromise. While these 2 vasculitides can co-exist, they are usually in association with a systemic autoimmune condition, which was not found in our patient [27]. Little is known on whether HUV can be a predisposing factor or a culprit for other autoimmune vasculitides, such as cryoglobulinemia, or rather simply a sign of a predisposition towards autoimmune conditions in the patient.

While examining the etiology behind our patient’s acute presentation, we also need to recognize that the simultaneous occurrence of MBL with MGUS, HUV, and mixed cryoglobulinemic vasculitis in our patient could be purely coincidental and that none of these conditions are related to each other. However, one might hypothesize that both the autoimmune disorder as well as the clonal lymphocyte populations can result from a generalized inability of the immune system to eliminate lymphocytes with autoreactive and clonal potential [28,29].

While these are all certainly compelling hypotheses, with the currently available knowledge it is not possible to ascertain a clear connection in our case, ultimately emphasizing the need for further mechanistic studies in this area.

A last point regarding our patient’s clinical presentation relates to her rapid, progressive respiratory failure at the end of her life. One condition high in our differential was cryoglobulin-associated pulmonary hemorrhage. This rare and devastating complication occurs when the cryoglobulinemic vasculitis involves the vasculature in the alveolar space, and carries a grave prognosis with high mortality rates [3,30,31]. Indeed, our findings of extensive bilateral hazy opacities over all lung fields and large bilateral pleural effusions on chest X-ray are compatible with pleuritic and pulmonary vasculitis involvement. However, the patient had already started high-dose steroid and Rituximab treatment when she developed pulmonary symptoms, and her other cryoglobulinemia-related symptoms in the skin and kidneys had been improving, making the hypothesis of cryoglobulinemia-associated pulmonary hemorrhage less consistent. Alternatively, an escalation of her COVID pneumonia could be considered, but it had been responding well to targeted treatment and had already resolved by the time of her respiratory failure. Moreover, repeat respiratory viral panels performed during her deterioration did not show a new or additional infection. Invasive diagnostic modalities, such as bronchoscopy, were not utilized because she declined additional invasive testing. In conclusion, given the unsatisfactory response to empiric treatment and the inability to employ more invasive testing, the cause of our patient’s respiratory deterioration also remains speculative.

If a non-infectious cryoglobulinemic vasculitis coexists with and is thought to be driven by an overt malignancy, appropriate oncologic treatment is indicated to manage the vasculitis [3]. However, there is scarce information regarding the management of cryoglobulinemia in the context of pre-existing premalignant conditions such as MGUS and MLDUS, especially if they co-exist and when it is challenging to determine whether these should be targeted specifically as potential drivers of mixed cryoglobulinemia. If no complicating factors are present, there is a consensus that patients with MLDUS and/or MGUS should never be subjected to cytotoxic or immunosuppressive therapies and should instead undergo active surveillance of their disease [32]. If, however, an association between non-infectious mixed cryoglobulinemia and a known MLDUS is suspected, experts agree that immunosuppressive and cytotoxic therapies, typically with B-cell-targeting agents, are reasonable initial treatment approaches [3]. Although steroids are a common component of lymphoma treatment regimens, this is not always straightforward, as there have been a few case reports in which administering high-potency immunosuppressants exacerbated a hematologic disorder. The underlying mechanism is not completely understood, but is thought to be similar to the development of immunodeficiency-associated lymphoproliferative disorders [28,33–35]. Our patient received high-dose corticosteroids due to renal involvement of her cryoglobulinemic vasculitis, but she did not undergo an additional biopsy to evaluate any possible response of the MGUS and/or MBL.

Conclusions

We present a noteworthy and educational case of a non-infectious mixed cryoglobulinemic vasculitis arising in the setting of 2 premalignant hematologic disorders. Our case underscores the complexity of diagnosing and managing cryoglobulinemia in patients with prior autoimmune and hematologic conditions and emphasizes the importance of tissue pathology in differential diagnosis. In our patient, for example, a kidney biopsy was essential to rule out other vasculitis syndromes. However, these invasive and resource-intensive diagnostic modalities are not always available to clinicians due to both patient-specific (eg, unwillingness to undergo invasive procedures) and healthcare setting-related limitations (eg, absence of experienced clinicians). Therefore, there is a compelling need to identify more specific and widely accessible bedside biomarkers for cryoglobulinemia. Research in this area would enable a more thorough understanding of the pathophysiology of non-infectious mixed cryoglobulinemia, especially when occurring in the context of premalignant B-cell conditions, thereby laying the groundwork for more effective disease stratification and targeted therapies with the potential to enhance patient outcomes.