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Abstract

Type II cryoglobulinemia is a rare disorder characterized by abnormal immunoglobulins (Igs) precipitating in the blood at low temperatures and redissolving upon warming. Sjogren's disease (SjD) is an autoimmune disorder involving secretory gland malfunction that leads to persistent dryness of the mouth and eyes. Here, we report the case of a 61-year-old woman with a 7-year history of SjD who was diagnosed with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). However, her complicated clinical features could not be sufficiently explained by this disease alone. Immunofixation electrophoresis revealed monoclonal IgM-κ and polyclonal IgG-κ. The presence of precipitated cryoglobulin and elevated rheumatoid factor levels confirmed a diagnosis of type II cryoglobulinemia for this patient. To the best of our knowledge, this case represents the first report of a patient with CLL/SLL, SjD, and type II cryoglobulinemia, which increased our understanding of immune system-related disorders. Because certain similar mechanisms are involved in the pathogenesis of these three diseases, a combination treatment of rituximab, ibrutinib, and dexamethasone resulted in a favorable prognosis for this patient.

Keywords

Cryoglobulinemia cryoglobulin chronic lymphocytic leukemia small lymphocytic lymphoma Sjögren’s disease rituximab ibrutinib dexamethasone

Introduction

Cryoglobulinemia is a rare disorder characterized by the presence of circulating immunoglobulins (Igs) in the serum that precipitate at low temperatures and redissolve upon warming.^1,2 The well-accepted classification by Brouet and colleagues categorizes cryoglobulinemia into three types.³ In type I cryoglobulinemia, the abnormal Igs, called cryoglobulins, are commonly monoclonal IgM and occasionally monoclonal IgG. Type I cryoglobulinemia has been associated with patients with hematological malignancies, including myeloma, B-cell lymphoma, and chronic lymphocytic leukemia (CLL).^1,4,5 The cryoglobulins in type II cryoglobulinemia consist of a mixture of monoclonal IgM (or IgG/IgA) and polyclonal Igs with rheumatoid factor (RF) activity, while the cryoglobulins related to type III cryoglobulinemia only contain polyclonal Igs with RF activity.^1,6 Accordingly, type II and III cryoglobulinemia are also referred to as mixed cryoglobulinemia. The manifestations of mixed cryoglobulinemia are broad, ranging from systemic vasculitis, peripheral neuropathy, purpura, arthralgia, and weakness to cutaneous necrosis and ulcers.⁷ Mixed cryoglobulinemia has been associated with chronic infections, most frequently with hepatitis C virus (HCV), B-cell malignancies, such as B-cell non-Hodgkin’s lymphoma (B-NHL), and autoimmune diseases, including lupus and Sjögren’s disease (SjD).^1,2,6,8

The most recognizable symptoms of SjD are dryness of the eyes and mouth because of chronic lymphocyte infiltration into the exocrine glands, which thereby damages the gland functions.⁹ Other common features of SjD include fatigue, polyarthralgia, salivary gland enlargement, and Raynaud’s phenomenon.¹⁰ Notably, these clinical features can be from either primary SjD (pSjD) or secondary SjD associated with other diseases, such as systemic lupus erythematosus, rheumatoid arthritis, scleroderma, or NHL.¹¹ The incidence of SjD is approximately 1 in 400, with a female-to-male patient ratio of 10:1.^12,13

CLL and small lymphocytic lymphoma (SLL) are considered as one disease with different clinical presentations. In CLL patients, a large number of abnormal lymphocytes typically manifest in the peripheral blood, bone marrow, and lymphoid tissues, while immature lymphocytes predominately accumulate in the lymph nodes and bone marrow in SLL patients.¹⁴ CLL/SLL is the most prevalent form of adult leukemia in individuals of European descent. However, it is 10- to 20-fold less common among Asians, including Chinese.^14–16 Here, we report a unique case in which a female patient manifested type II cryoglobulinemia, SjD, and CLL/SLL. To the best of our knowledge, this is the first report of one patient with all three disorders. We implemented a therapeutic plan of rituximab, ibrutinib, plus dexamethasone. The patient responded well and was released from the hospital after treatment. This reporting meets the requirements of the CARE case report guidelines.¹⁷

Case presentation

A 61-year-old Chinese woman presented in the emergency department with fever, chills, and severe skin ulcers on both lower legs. Ulceration, scabs, hyperpigmentation, and inflammation occurred simultaneously (Figure 1(a)). She had obvious fatigue, shortness of breath, and enlarged left axillar lymph nodes. The leg ulcers had developed over a period of almost three years. Initially, red papules about the size of a grain of rice appeared on both lower limbs without itching or pain. These then enlarged and ruptured, eventually developing into ulcers over six months that led to pain after walking. The ulcers failed to heal and became repeatedly infected, but the inflammation subsided following treatment with antibiotics. A computed tomography (CT) scan of the lungs showed interstitial changes that indicated decreased lung permeability, ground-glass density changes in both lungs, and pleural effusion (Figure 1(b)).¹⁸ The F-fluoreodeoxyglucose positron emission tomography/CT scans in Figure 1(c) revealed multiple highly metabolically active lymph nodes (SUVmax 9.31) in the paracentral lung, mediastinum, bilateral axilla, right ventricular septum, bilateral superior pleural lateral retroperitoneum, hepatic portal area, splenic portal area, bilateral pelvic cavity, abdominal wall, and inguinal area, as well as skin in the right lower leg (SUVmax 5.67).

Figure 1.

The clinical features of the patient. (a) Ulceration, scabs, hyperpigmentation, and inflammation occurred simultaneously on her right lower leg. (b) The lung computed tomography (CT) scan showed interstitial changes and pleural effusion in both lungs. (c) 18F-fluoreodeoxyglucose positron emission tomography/computed tomography (18FFDG-PET/CT) revealed multiple highly metabolically active lymph nodes and skin on the right lower leg. (d) The results of immunofixation electrophoresis analysis of the serum. A small cluster of monoclonal bands can be seen in the far-left lane. The lanes labeled as G, M, and κ demonstrated a monoclonal IgM-κ band and polyclonal IgG-κ band, respectively. The lambda anti-sera were performing normally and the tests were conducted using serum and urine separately, with equivalent results observed and (e) the cryoglobulin testing showed positive results and the cryocrit was approximately 65%. Specifically, 20 mL of blood was drawn into collection tubes that were prewarmed to 37°C without anticoagulants. After clotting at 37°C for 30 minutes, the serum was separated by centrifugation at 37°C, placed into a graduated tube, and refrigerated at 4°C to allow cryoglobulin precipitation after 24 hours.

A complete blood count analysis showed pancytopenia with a hemoglobin level of 35 g/L, white blood cell count of 3.4 × 10⁹/L, and platelet count of 113 × 10⁹/L. The total protein level was 48.1 g/L, albumin level was 28.9 g/L, and globulin level was 19.2 g/L, with a main increase in IgM (3.27 g/L) and slight decreases in the other Igs. The urinalysis showed proteinuria and hematuria. Tests for anti-glomerular basement membrane antibodies, anti-neutrophil cytoplasmic antibody 1 (ANCA1), and ANCA2 were negative. Serum electrophoresis showed a slight monoclonal band in the gamma zone. Immunofixation electrophoresis data for blood and urine samples showed a monoclonal IgM-κ band and polyclonal IgG-κ band (Figure 1(d)). HAV, HBV, HCV, and human immunodeficiency virus (HIV) serologies were all negative. Complement tests demonstrated reduced C4 levels (0.05 g/L [normal, 0.10–0.40 g/L]), slightly reduced C3 levels (0.56 g/L [normal, 0.70–1.40 g/L]), and increased RF levels (588 IU/mL). The patient complained of dryness of the eyes and mouth over the last 5 years, with salivary scintigraphy showing damaged intake functions of the parotid and submandibular glands. Evaluations of serum antibodies against Sjögren’s syndrome A (SSA) and Ro-52 showed strong positivity, approximately 3+, indicating that the patient also suffered from SjD.⁹ The antinuclear antibodies were positive at a dilution of 1:100, while the anti-double-stranded DNA antibody was negative. However, the observed severe anemia and skin ulcers are not typical features of SjD patients. We further performed cryoglobulin testing, bone marrow aspiration, as well as skin and lymph node biopsies. The cryoglobulin testing showed positive results and the cryocrit was approximately 65% (Figure 1(e)). Flow cytometry analysis of the bone marrow revealed 12.95% of monoclonal B cells with the classical CLL immunophenotype (4–5 scores): CD5+, CD19+, CD20+, CD23±, FMC7−, CD22±, CD79b−, and slg−. Flow cytometry analysis of the blood revealed this phenotype in 0.7% of total cells (Figure 2(a)). IGHV, EGR2, and SPEN mutations were detected. Biopsy of the inguinal lymph nodes indicated SLL, with immunophenotyping analysis of cell surface markers revealing CD20+, Ki-67(1%+), CD10−, CD5+, CD19+, CD3(partial+), CD23+, Bcl2+, Bcl6−, and CyclinD1− (Figure 2(b/c)). The skin biopsy indicated sclerosing panniculitis with SLL cell infiltration (Figure 2(d)). The immunophenotyping markers were CD19+, CD20+, CD3−, CD5+, CyclinD1−, SOX11−, CD23+, CD10−, LEF1+, and Ki-67 (20%+). From the collected data, the patient was therefore diagnosed with CLL/SLL with type II cryoglobulinemia.

Figure 2.

The diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was made through pathological and flow cytometry analyses. (a) Flow cytometry analysis of P3 of the blood revealed CD5+, CD19+, CD20+, CD23±, FMC7−, CD22±, CD79b−, and slg− in 8.4% of all lymphocytes and 0.7% of the total cells. P2 was lymphocytes; 8.3% of the total cells. P4 was granulocytes; 86.0% of the total cells. P6 was monocytes; 4.3% of the total cells. (b) Immunophenotyping analysis of the lymph node revealed CD20+, Ki-67(1%+), CD10−, CD5+, CD19+, CD3(partial+), CD23+, Bcl2+, Bcl6−, and CyclinD1−. (c) Inguinal lymph node biopsy indicated SLL (hematoxylin and eosin [H&E] stain, 40×) and (d) skin biopsy indicated sclerosing panniculitis with SLL/CLL cell infiltration (H&E stain, 100× and 400×).

The ibrutinib–rituximab regimen has been shown to result in superior overall survival and progression-free survival for CLL patients.¹⁸ For patients with moderate-to-severe mixed cryoglobulinemia syndrome, treatment with glucocorticoids in combination with rituximab is effective.¹⁹ The pathogenesis of pSjD is characterized by B cell activation, with rituximab treatment demonstrating positive clinical efficacy for this disease. Because of the patient’s diagnosis and poor general health, she was administered ibrutinib 420 mg per day, rituximab 375 mg/m² on day 1 of a 21-day cycle, and dexamethasone 5 mg per day. Her shortness of breath and pulmonary inflammatory exudate symptoms were significantly alleviated after two cycles of therapy (Figure 3(a)). Her performance status was improved and the hemoglobin level increased to 82 g/L, which further increased to 102 g/L after four cycles. Additionally, the enlarged lymph nodes became much smaller. The skin ulcers and cyanosis on both lower legs were improved (Figure 3(b)). The patient obtained partial remission and continued to take oral ibrutinib for 6 months, then stopped treatment because of severe mouth ulcers. She has remained in a stable condition to date.

Figure 3.

Patient improvement after treatment. (a) The pulmonary inflammatory exudate was significantly alleviated after two cycles of therapy and (b) the skin ulcers and cyanosis on the patient’s right lower leg were improved.

Discussion and conclusions

Cryoglobulinemia is defined as the persistent presence of cryoglobulins in the serum that precipitate at low temperatures (<37°C) and redissolve when the temperature is increased. Cryoglobulinemia is classified into three types (I, II, and III) according to Brouet’s classification based on the Ig composition. Type II and type III are referred to as mixed cryoglobulinemia.³ HCV infection is the most common cause of mixed cryoglobulinemia, while other causes include systemic autoimmune diseases, lymphoproliferative disorders, and other viral infections (HBV, HIV).²⁰

Here, we reported the case of a cryoglobulinemia patient with both SjD and lymphoproliferative disorders, which is a very rare clinical scenario that has not been reported previously. The manifestations of mixed cryoglobulinemia vary and often depend on small vessel involvement in the skin, musculoskeletal system, nervous system, kidneys, gastrointestinal tract, and lungs. Only about a third of patients present with the representative triad of purpura, arthralgia, and weakness, with purpura being the most common manifestation.²¹ If cryoglobulin deposition in small blood vessels leads to clinical manifestations, then it is referred to as cryoglobulinemia vasculitis. This patient presented with recurring ulcers on both lower legs, with the pathological examination revealing sclerosing panniculitis with infiltration of SLL cells. We believed that the sclerosing panniculitis was partially caused by cryoglobulinemia vasculitis. The patient also presented with interstitial lung disease and nephritis, which could be caused by SjD and cryoglobulinemia. Notably, the involvement of organs other than the kidneys suggests mixed, rather than type I, cryoglobulinemia. The prognosis is usually poor in patients with gastrointestinal and pulmonary involvement.²¹ We believed that this patient's pancytopenia, especially the severe anemia, was potentially caused by SjD and CLL/SLL. Taken together, the complicated conditions of this case caused the diagnosis to be difficult.

Compared with other autoimmune diseases, pSjD is associated with an increased risk of lymphoproliferative malignancies, especially B-NHL.^22,23 The most common type of SjD-associated lymphoma is parotid gland marginal zone lymphoma, followed by diffuse large B cell lymphoma and follicular lymphoma.²⁴ In addition, SjD combined with cryoglobulinemia, palpable purpura, low C4, lymphopenia, lymphadenopathy, persistent salivary gland enlargement, or cutaneous vasculitis is associated with a notably higher incidence of NHL, with cryoglobulinemia being the strongest independent lymphoma-associated factor.²⁵

SjD patient cryoglobulins are represented by monoclonal IgM-κ and polyclonal IgG.²⁶ In our case, the cryoglobulins included monoclonal IgM-κ and polyclonal IgG-κ.²⁷ CLL/SLL has rarely been related to SjD or type II cryoglobulinemia, which is notable.²⁸ The clinical features and treatment methods of CLL/SLL patients with cryoglobulinemia described in the literature are summarized in Table 1. In CLL/SLL with cryoglobulinemia, the most common type is monoclonal IgG-κ, then monoclonal IgM-κ with or without poly IgG. The cryocrit is generally between 2% and 7% in type II and between 1% and 3% in type III disease.²⁷ We speculated that the presence of monoclonal IgG-κ and significantly high percentage of cryoglobulins in the patient were associated with CLL/SLL. Alternatively, this phenomenon was caused by SjD, an autoimmune disorder,²⁹ or both.

Table 1.

Summary of reported cases with cryoglobulinemia and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

No.	Ref.	Year	No. of patients	Age/Sex	Type	Cryoglobulins	Related diseases	Treatment	Clinical consequence
1	³⁰	1949	1	43/M	N/A	N/A	No	N/A	N/A
2	³¹	1979	2	62/M	I	Monoclonal IgG-κ	No	CS, CTX, and CLB	Deceased
2	³¹	1979	2	53/F	I	Monoclonal IgG-κ	No	CS and CTX	Deceased
3	³²	1992	5	41/M	II/III	IgG and IgM	No	CLB and CS	Deceased
				60/M	II/III	IgG and IgM	No	N/A	Deceased
				74/M	II/III	IgG and IgA	No	MOPP	Deceased
				63/F	I	Monoclonal IgG-κ	No	CLB and CS	CR
				71/M	N/A	N/A	No	CLB and CS	CR
4	³³	2002	1	52/M	I	Monoclonal IgG-κ	No	CLB	PR
5	³⁴	2002	1	70/M	I	Monoclonal IgM-κ	No	N/A	N/A
6	³⁵	2005	1	53/M	I	Monoclonal IgG-λ	No	Ituximab and fludarabine	PR
7	³⁶	2007	1	58/F	I	Monoclonal IgG-κ	No	N/A	N/A
8	³⁷	2010	1	53/M	III	Polyclonal IgG	No	RFC	CR
9	³⁸	2011	1	70/M	N/A	N/A	Parvovirus infection	CS, CTX, rituximab, alemtuzumab, hemodialysis	Progression
10	³⁹	2014	1	90/N/A	II	Monoclonal IgM and polyclonal IgG	No	CS	Deceased
11	⁴⁰	2015	5	N/A	I	Both monoclonal IgG	No	N/A	N/A
12		2015	3	67/F	II	N/A	No	Not treated	Progression
	⁴¹			65/F	I	Monoclonal IgG-κ	No	CLB and rituximab	CR and relapse
				63/F	I	Monoclonal IgG-κ	No	CLB	CR and relapse
13	⁴²	2016	1	60/F	I	Monoclonal IgG-κ	No	R-CVP and plasma exchange	Deceased
14	⁴³	2018	1	60/M	I	Monoclonal IgM-λ	No	Iloprost, CS, plasma exchange, and rituximab	N/A
15	⁴⁴	2018	1	63/M	I	Monoclonal IgG-κ	No	Not treated	N/A
16	⁴⁵	2019	1	56/M	I	Monoclonal IgM-λ	HCV infection	CS, rituximab, bendamustine, plasma exchange, and CTX	CR
17	⁴	2019	1	69/M	I	Monoclonal IgM-κ	No	Plasma exchange, rituximab, CS, and ibrutinib	CR
18	⁴⁶	2021	1	91/M	I	Monoclonal IgG-κ	hMPV infection	Not treated	N/A
19	⁴⁷	2022	1	59/F	II	Monoclonal IgM-κ and polyclonal IgG	No	R-COP and ibrutinib	CR
20	This case		1	61/F	II	Monoclonal IgM-κ and polyclonal IgG-κ	Sjögren’s disease	Ibrutinib, rituximab, and CS	PR

CS, corticosteroids; CTX, cyclophosphamide; CLB, chlorambucil; R-COP, rituximab, cyclophosphamide, verodoxin, and dexamethasone; CR, complete remission; hMPV, human metapneumovirus; R-CVP, rituximab, cyclophosphamide, vincristine, and prednisone; RFC, ituximab, fludarabine, and cyclophosphamide; PR, partial remission; MOPP, nitrogen mustard, vincristine, procarbazine, and prednisone; N/A, not available.

Compared with HCV-related cryoglobulinemia, the pathogeneses of other mixed cryoglobulinemia cases, such as those caused by autoimmune diseases, are still under investigation.⁶ Overactivity or overgrowth of B cells may cause B cell clonal expansion, thus producing cryoglobulins.⁸ Oncogene translocation to Ig loci or tumor suppressor gene inactivation in B cell dysregulation may also contribute to the initiation and development of B-NHL. Chronic antigenic stimulation has been suggested to lead to the activation of abnormal B cells in the salivary glands and appearance of auto-reactive B cell clones in SjD patients, with the emergence of cryoglobulins potentially accelerating this process.⁴⁸ Type II cryoglobulinemia has also been suggested to represent a transition phase between autoimmune disorders and malignancies.⁴⁹

Treatment of the disease underlying the cryoglobulinemia, especially hematological malignancies, is the priority. Immunosuppressive therapy is the cornerstone of care for patients with severe manifestations, including the first-line immunosuppressant rituximab or cyclophosphamide and corticosteroids. However, more aggressive plasmapheresis is needed if life-threatening diseases develop, such as rapidly progressive glomerulonephritis, gastrointestinal ischemia, central nervous system involvement, and pulmonary hemorrhage.⁵⁰ Bruton’s tyrosine kinase inhibitors are effective therapies for CLL/SLL. Barot et al. reported a case of refractory monoclonal gammopathy of undetermined significance related to type II cryoglobulinemia that was treated with ibrutinib, resulting in a complete clinical response and durable therapeutic effect that reversed kidney damage.⁵¹ Here, we used ibrutinib, rituximab, and dexamethasone for a patient with complicated type II cryoglobulinemia, SLL/CLL, and pSjD, obtaining a good response. Remarkably, this treatment plan worked well for the patient, although the therapeutic mechanism of ibrutinib for cryoglobulinemia requires further investigation.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605241285228 - Supplemental material for Type II cryoglobulinemia in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma and Sjögren’s disease

Supplemental material, sj-pdf-1-imr-10.1177_03000605241285228 for Type II cryoglobulinemia in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma and Sjögren’s disease by Renjie Bian, Xiaojing Yan, Chaoxu Zhang, Yuan Tao and Xiaoxue Wang in Journal of International Medical Research

Footnotes

Acknowledgements

We thank our colleagues, Dr. Shuang Wang and Dr. Jinxing Wang, for their contributions to clinical and lab data collection. We are grateful to Dr. Hongcang Gu for reviewing the manuscript.

Author contributions

RB and XY wrote the main manuscript text. The figures were prepared by CZ and YT, while XW prepared . All authors contributed to the writing and final approval of the manuscript.

Declaration of conflicting interest

The authors declare that there is no conflict of interest.

Ethics statement

This study was reviewed and approved by the Institutional Review Board (IRB) of the First Hospital of China Medical University (Approval No. 2023546). The patient provided written informed consent to participate in this study. The written informed consent is ready for review upon request.

Funding

This work was supported by the Natural Science Foundation of Liaoning Province (Grant No. 2022-YGJC-62) and the Project on the xinrui cancer support therapy (Grant No. cphcf-2022-102).

ORCID iDs

Renjie Bian

Xiaoxue Wang

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