Type 1 Cryoglobulinemic Vasculitis Due to Monoclonal Gammopathy of Undetermined Significance Successfully Treated by Bortezomib Plus Dexamethasone

Abstract

Cryoglobulins are immunoglobulins that precipitate in cold conditions. Type I cryoglobulinemic vasculitis is associated with hematological malignancies. We herein report a case of steroid-resistant type 1 cryoglobulinemic vasculitis associated with monoclonal gammopathy of undetermined significance (MGUS) in a 47-year-old woman. By immunofixation of cryoglobulin, we found that the main component of cryoglobulin was the M protein due to MGUS, so treatment of MGUS was needed. Bortezomib+dexamethasone therapy resulted in a rapid decrease in cryoglobulin and improvement in the symptoms of cryoglobulinemic vasculitis. In refractory type I cryoglobulinemic vasculitis, treatment of the underlying gammaglobulinopathy should be considered.

Introduction

Cryoglobulin is an immunoglobulin that precipitates in vitro at temperatures below 37°C (1-3). The compositions of cryoglobulins are heterogeneous, and they are divided into three types. Type I cryoglobulins are monoclonal immunoglobulins, while type II and III cryoglobulins are classified as mixed polyclonal immunoglobulins (1-3). Type I cryoglobulinemic vasculitis (CV) is often seen in patients with hematological malignancies [i.e. Waldenstorm's macroglobulinemia (WM), multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), and other hematological malignancies] and can cause hyperviscosity syndrome (2,3). The percentage of patients with cryoglobulin who develop symptoms ranges from 2% to 50% (1,4).

CV causes skin purpura, ulceration and digital necrosis (1,2). Treatment of type I CV is necessary for symptomatic disease and is directed against the underlying disease (5). Patients with MGUS are thought to have premalignant conditions, and a relatively low intensity of treatment can initially be attempted for cases of MGUS-related type I CV (5,6). However, in some cases, rapid progression of symptoms has been reported despite a low level of M protein (7-10).

We herein report a case of steroid- and cyclophosphamide-refractory type I CV associated with MGUS in which toe gangrene developed. Although the levels of M protein were relatively low, an analysis of cryoglobulin revealed direct evidence of M protein acting as a cryoglobulin. The symptoms of CV were rapidly improved by bortezomib plus dexamethasone (Bd) therapy.

Case Report

A 47-year-old woman was admitted to our hospital due to pain and purpura in the lower limbs and progressive cyanosis of the toes in both feet. One year prior to admission, she had developed pain in her Achilles tendon, and a diagnosis of spinal arthritis had been made. Salazosulfapyridine combined with methotrexate had been administered without remarkable improvement of the symptoms. Four months before admission, she had visited a physician with a chief complaint of purpura and pain in her toes. She had been diagnosed with chilblains due to autoimmune vasculitis caused by arthritis and treated with adalimumab and aspirin. However, her symptoms worsened. She was then referred to our hospital.

At admission, her feet showed livedo and purpura, and she had severe pain (Fig. 1A-C). Her symptoms were exacerbated by cold exposure, and the pain was mitigated by active heating with warm blankets. A skin biopsy of the toe showed dermal vascular wall thickening and fibrin thrombi (Fig. 1D). A laboratory test showed cryoglobulinemia (Table 1). The level of free κ chain was increased (279.8 mg/dL) with a high κ/λ ratio of 30.41. Hepatitis C virus infection was not evident. The volume percentage of cryoglobulin (cryocrit) was 7.5% (Fig. 2A). A microscopic analysis showed amorphic deposits (Fig. 2B). Although serum globulin levels were within the normal range, electrophoresis showed an M protein of IgG-κ that was enriched in the cryoglobulin fraction (Fig. 2C). Bone marrow aspiration was performed, and 2% of plasma cells and 2.8% of 17p deletion cells were detected by a fluorescence in situ hybridization (FISH) analysis. FISH findings for IgH-FGFR3 and IGH-MAF were both negative. G-banding showed normal karyotypes. A bone marrow biopsy showed mildly hypocellular marrow with slight infiltration of κ-positive plasma cells. No bone lesions were observed by whole-body computed tomography. Based on these findings, she was diagnosed with type I CV due to MGUS.

Figure 1.

Skin findings on the day of admission: livedo, purpura, and darkened skin were observed with severe pain on the toe (A) and heel (B). Livedo was also observed on the thigh (C). (D) A skin biopsy of the toe dorsum showed vascular wall thickening without apparent vasculitis (arrow) and fibrin thrombus (arrowhead) in the reticular dermis. These findings suggested cryoglobulinemic vasculitis (Hematoxylin and Eosin staining).

Table 1.

Laboratory Data at Admission.

WBC	9,100	/µL	TP	7.4	g/dL	ANA	×160, homo, speckled		IgA	118	mg/dL
Neutro	87.4	%	ALB	4.1	g/dL	RF	<4.5	IU/mL	IgG	1,467	mg/dL
Lympho	9.6	%	T-Bil	1.0	mg/dL	LA	1.18		IgM	94	mg/dL
Mono	2.6	%	D-Bil	0.1	mg/dL	Anti-CL IgG	9.6	U/mL	Cryoglobulin	(+)
Eosino	0.1	%	AST	13	U/L	Anti-CL IgM	3.8	U/mL	Free-κ chain	279.8	mg/L
Baso	0.3	%	ALT	10	U/L	Anti-β2GPI IgG	<6.4	U/mL	Free-λ chain	9.2	mg/L
RBC	3.63×106	/µL	LD	167	U/L	Anti-β2GPI IgM	2.2	U/mL	κ/λratio	30.41
Hb	12.0	g/dL	ALP	58	U/L	Anti-SS-A	<0.3	U/mL
Plt	286×103	/µL	γ-GTP	14	U/L	MPO-ANCA	<0.3	U/mL	HCV antibody	(-)
			BUN	15	mg/dL	PR3-ANCA	<0.4	U/mL	HBc antibody	<1.0	mIU/mL
PT-INR	1.1		Cr	0.75	mg/dL	C3	114	mg/dL	HIV antibody	<1.0	S/CO
APTT	33.0	s	Na	137	mEq/L	C4	46	mg/dL
Fbg	420	mg/dL	K	3.9	mEq/L	CH50	66.9	U/mL
D-dimer	0.91	mg/dL	Cl	105	mEq/L
			Ca	8.9	mg/dL
			CRP	0.61	mg/dL
			sIL-2R	393	U/mL

Figure 2.

Cryoglobulin in the patient. (A) After chilling in a refrigerator and centrifugation, cryoglobulins were precipitated in serum. Without refrigeration, no precipitate was observed. (a) Whole serum, (b) supernatant, (c) cryoglobulin. The cryoglobulin volume (Cryocrit) was 7.5% of serum. (B) Amorphic cryoglobulin was observed in the precipitate. (C) Electrophoresis and immunofixation of each fraction of the serum. M protein was detected by electrophoresis and immunofixation in the whole serum (a) and cryoglobulin (c) fraction, but M protein was not detectable in the supernatant of the cryoprecipitate (b).

Her creatinine levels were normal, and her urinalysis was not remarkable, so we concluded that there was no obvious renal involvement and did not perform a renal biopsy. Initially, she was treated with prednisolone (1 mg/kg=50 mg) and intravenous cyclophosphamide (IVCy), but necrosis occurred in her toes despite treatment (Fig. 3). The progression of necrosis was not stopped by additional steroid pulse therapy (methylprednisolone of 1,000 mg/day for 3 days), and bilateral lower leg amputation was considered for treatment of the necrosis.

Figure 3.

Clinical course. (a) Toe findings on the day of admission. (b) Toe gangrene appeared despite IVCy treatment. (c) Toe gangrene progressed even after steroid pulse therapy. (d) After the disappearance of cryoglobulin, purpura disappeared, with a brighter skin color being noted, and minimal amputation with preservation of the toe dorsum was performed.

Although the levels of M protein were relatively low, analysis of cryoglobulin clearly showed a direct contribution of M protein. Her monoclonal gammopathy was no longer of “unknown significance” but definitely pathogenic, requiring targeting. The results of a FISH analysis showing 2.8% of cells with TP53 loss also suggested the existence of plasma cell malignancy. Treatment with Bd therapy (oral dexamethasone at a dose of 40 mg on days 1-2, 4-5, 8-9, and 11-12 and subcutaneous bortezomib at a dose of 1.3 mg/m² on days 1, 4, 8, and 11 every 21 days) was therefore initiated. After 1 cycle of Bd treatment, the pain and purpura of the feet remarkably improved, and the progression of necrosis was halted. The κ/λ ratio decreased to 1.76, and cryoglobulin disappeared. Her skin color brightened along with the disappearance of cryoglobulin. Minimal toe amputation with preservation of her toe dorsum was performed on hospital day 70 (Fig. 3). M protein was not detected in immunofixation, but low levels of free κ chain (20-30 mg/dL) persisted, resulting in a slightly higher κ/λ ratio at 2 to 3.

She was discharged on day 105 and followed with monthly Bd treatment. She remains able to drive her car and walk without needing a cane.

Discussion

We encountered a case of MGUS-related type I CV with normal immunoglobulin levels but severe cutaneous symptoms that were refractory to steroid and IVCy treatment. Although the level of M protein was relatively low compared to MGUS, the cryocrit was 7.5%, and the fraction consisted of M protein. A cryocrit of ≥5% is more frequently characterized by symptomatic cryoglobulinemia than a cryocrit of ＜5% (4). A cryocrit of ≥1% is abnormal, but even a minute amount of cryoglobulins can be pathogenic in some cases (3).

Skin manifestations are the most common symptoms in patients with type I CV (5,6). Skin symptoms include purpura, livedo reticularis, Raynaud's phenomenon, acrocyanosis, skin necrosis, ulcers, and digital gangrene (5). For the management of type I CV, treatment of the underlying blood disorder is recommended (5). In the French Cryo Vas survey, 28 (43.8%) of 64 cases with type I CV had MGUS as an underlying condition. The first-line therapy in patients with MGUS-related type I CV was mainly based on single-agent prednisone (median dose of 60 mg/day), while second-line therapy included mainly rituximab and alkylating agent-based regimens (6). Among the 28 cases with MGUS-related CV, sustained remission was achieved in 8 (35%), whereas 6 (26%) were nonresponders, and 9 (39%) relapsed after initial response (6).

MGUS can be divided into two types: IgM-MGUS and non-IgM-MGUS. Anti-myelomatherapies are considered for the treatment of non-IgM-MGUS-related CV, and rituximab or anti-WM therapies are considered for the treatment of IgM-MGUS (5). The proteasome inhibitor bortezomib is a key drug for MM and can rapidly reduce the level of M protein. Bortezomib is potentially effective against autoimmune vasculitis, such as ANCA-associated vasculitis and IgA vasculitis (11,12). Although a consensus guideline for the treatment of type I CV has not been established, some case reports have shown the efficacy of bortezomib for the treatment of MGUS-related type I CV (7-10). Reported cases of MGUS-related type I CV treated with bortezomib are shown in Table 2. Interestingly, the levels of IgG (M protein) were not shown to be increased in any cases, including our own, although all cases had cryoglobulin and cutaneous symptoms. The time to the response was rapid, with a response shown after one to two cycles of bortezomib therapy. Clinical improvements were striking, with a decreased level of M-protein being noted. Cryoglobulins disappeared entirely in one reported case (7), whereas the amount remained detectable, albeit reduced, in other cases (8-10). In the present case, the cryoglobulin disappeared after the first course of bortezomib, which seemed sufficient to achieve clinical improvement. Immunofixation became negative after the second course, despite the treatment being halted due to consultation with a plastic surgeon for toe amputation. We continued Bd therapy after achieving negative conversion of cryoglobulin with a reduced dose because the treatment was stopped in one reported case due to the development of peripheral neuropathy (9). Our patient still had a slightly increased level of free κ chain, and we are unsure how long maintenance therapy should be continued. The intensity and duration of treatment for type I CV remain issues for future consideration. Other anti-myeloma agents, such as immunomodulatory drugs (IMiDs) or CD38 antibodies, might be effective, but there have been no relevant reported case thus far.

Table 2.

Reported Cases of MGUS-related Type I CV Treated with Bortezomib.

Reference	Age, Gender	Type of M protein	IgG (mg/dL)	Cryocrit (%)	Cutaneous vasculitis	Cutaneous symptoms	Renal involvement	Peripheral nerve involvement	Time to response (bortezomib cycles)
(7)	48, M	IgG-κ	1,290	NA	+	Purpura, acrocyanosis	-	-	NA
(8)	40, M	IgG-λ	1,260	14	+	Purpura, ulcer	-	-	1
(8)	77, M	IgG-κ	1,000	3	+	Purpura, ulcer	-	-	1
(9)	46, F	IgG-κ	600	NA	+	Purpura, ulceros	-	-	2
(10)	51, M	IgG-κ	NA	6	+	Purpura, necrosis acrocyanosis,	+	+	2
Our case	47, F	IgG-κ	1,467	7.5	+	purpura, necrosis acrocyanosis	-	-	1

M: male, F: female, NA: not available

When clinicians detect a low level of M protein, they usually assume that monoclonal gammopathy is asymptomatic. When MGUS has been diagnosed, basically no treatment is necessary, and only regular monitoring is required as long as MGUS is of “unknown clinical significance.” However, the monoclonal gammopathy in our case was apparently pathogenic and showed clinical significance that needed to be treated. Without treatment, acrocyanosis and gangrene progress. To improve the early recognition and treatment of symptomatic monoclonal gammopathy, the concept of MGCS was proposed (13). The spectrum of MGCS includes not only type I CV but also AL amyloidosis, immunotactoid glomerulopathy, MGUS neuropathy, acquired Fanconi syndrome, crystal-storing histiocytosis, crystalline keratopathy, and acquired von Willebrand syndrome (13,14).

In conclusion, we presented a case of steroid-refractory non-IgM-MGUS-related CV that responded to Bd therapy. Type I CV can worsen rapidly, and early recognition of cryoglobulin and M protein is important. The concept of MGCS may prompt us to consider targeting the underlying monoclonal gammopathy that is apparently pathogenic causing CV. Our case showed that the clearance of cryoglobulin is the main treatment target for achieving clinical improvement; however, we need to carefully monitor the remaining M protein.

The authors state that they have no Conflict of Interest (COI).