Finger necrosis due to cryoglobulinemic vasculitis in association with membranous nephropathy

Abstract

Cryoglobulinemic vasculitis is a small vessel vasculitis that has been associated with chronic infections and autoimmune, lymphoproliferative, and neoplastic disorders. When no significant etiological factors are identified, it is called essential mixed cryoglobulinemia. A detailed and thorough laboratory investigation is required to exclude all possible causes of cryoglobulin formation. Although cryoglobulin testing is simple, careful temperature regulation is needed to avoid false-negative results. Consensus diagnosis should be developed and implemented for appropriate cryoglobulin detection and accurate clinical diagnosis for cryoglobulinemic vasculitis. Here we present an interesting, first-ever case report of a 54-year-old Hispanic-American woman with essential mixed cryoglobulinemia presenting with significant digital necrosis in association with membranous nephropathy.

Cryoglobulins are immunoglobulins that precipitate in vitro at temperatures below 37°C, producing organ damage through two main mechanisms: vascular sludging and immune-mediated mechanisms. The terms cryoglobulinemic disease and cryoglobulinemic vasculitis (CV) are used to describe patients with symptoms related to the presence of cryoglobulins (1, 2). CV was first described in 1966 by Meltzer and colleagues, who reported 29 patients with cryoglobulins and a common clinical presentation (purpura, arthralgias, and weakness), accompanied by organ dysfunction and raised serum concentrations of rheumatoid factor (3). The most commonly used classification for CV was created in 1974 and remains useful because of its consistency for the clinical features of the three cryoglobulin subsets (4). When the cause of the CV cannot be identified, the disease is termed “idiopathic” or “essential” cryoglobulinemia (4). CV is associated with a wide range of symptoms, etiologies, and outcomes, being considered an entity that combines fundamental elements of autoimmune, infectious, inflammatory, and lymphoproliferative disorders (2, 5). Here, we describe a Hispanic-American woman with essential mixed CV presenting with significant digital necrosis in association with membranous nephropathy (MN).

CASE PRESENTATION

A 54-year-old Hispanic-American female architect presented to our institution with the chief complaint of pain at the distal tip of her right little finger. Her symptoms started 6 weeks prior to presentation, getting progressively worse over the previous 4 days. Her past medical history was significant for systemic hypertension, diabetes mellitus, primary hypothyroidism, and chronic kidney disease with histopathological confirmation of MN 8 weeks prior to her admission. She received initial immunosuppressive treatment with prednisone, cyclophosphamide, and mycophenolate mofetil for MN; however, cyclophosphamide was discontinued after 3 weeks, as she had an episode of rectal bleeding and complaint of finger pain and numbness. Her review of systems was significant for a 20 kg unintentional weight loss, generalized fatigue, weakness, and arthralgias of both hands.

On physical examination, the patient was pale and had dry gangrene at the tip of her right little finger and black discoloration at the tip of the left index finger. Also noted was the purplish discoloration at the distal phalanx of both hands (Figure 1). Allen's maneuver was normal in both hands, and her radial and ulnar pulses were palpable bilaterally. Blood pressure measurements were similar in both arms, and ultrasonographic Doppler revealed patent vessels from the subclavian to the radial and ulnar arteries. The erythrocyte sedimentation rate, C-reactive protein, serum creatinine, and blood urea nitrogen were elevated with a decreased glomerular filtration rate (GFR). She was mildly anemic with significant proteinuria. Hepatitis serologies, serum cryoglobulins, an HIV screen, and a hypercoagulable workup were negative. An extensive workup for systemic vasculitis was negative, including antinuclear antibody, double-stranded DNA, serum complement, rheumatoid factor, anticardiolipin, anti SS-A and SS-B, anticentromere, anti-Scl-70, anti-C3, and anti-myeloperoxidase antibodies (Table 1). A punch biopsy with immunofluorescence of the necrotic lesion in the right little finger was performed and revealed granular IgM, C3, IgG, C5b-9, and fibrinogen depositions in and around superficial and middermal small blood vessels, supporting the diagnosis of CV type II (Figure 2). A workup to rule out infection and malignancy was negative and included a transesophageal echocardiogram, chest x-ray, computed tomography of abdomen and pelvis, mammogram, colonoscopy, and endovaginal ultrasonography.

Figure 1.

(a) On admission, gangrene is noted at the tip of the right little finger (red arrow) with purple hue discoloration at the distal phalanxes (white arrow). (b) On admission, a black papule is present on the index finger of the left hand (red arrow) with purple hue discoloration at the distal phalanxes. (c) On follow-up, the bilateral purple hue discoloration resolved into a pinkish hue (white arrow); the black papule on the left index finger also resolved, but generalized pallor and dry gangrene at the tip of the right little finger persisted (red arrow).

Table 1.

Autoimmune workup in our patient with significant vasculitic digital necrotic lesion

Test	Result
ESR (mm/hr)	114
CRP (mg/L)	0.46
Hemoglobin (g/dL)	11.1
BUN (mg/dL)	57
Creatinine (mg/dL)	1.52
GFR (mL/min/1.73 m2)	36
Protein in urine (g)	6.5
CCP Ab IgG	Negative
Myeloperoxidase Ab	Negative
pANCA, cANCA IgG	Negative
Hepatitis serology	Negative
Anti-dsDNA	Negative
Anti-cardiolipin Ab IgG and IgM	Negative
Scleroderma-70 Ab IgG	Negative
Beta-2 glycoprotein Ab	Negative
RNP Ab IgG	Negative
Anti-Smith Ab IgG	Negative
SSA (Ro)	Negative
SSB (La)	Negative
Jo-1 Ab	Negative
Histone Ab IgG	Negative
HIV screening	Negative
ANA	Negative

Ab indicates antibody; ANA, antinuclear antibody; anti-dsDNA, anti-double-stranded DNA antibody; cANCA, cytoplasmic antineutrophil cytoplasmic antibody; BUN, blood urea nitrogen; CCP, cyclic citrullinated peptide; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; GFR, glomerular filtration rate; Ig, immunoglobulin; pANCA, perinuclear antineutrophil cytoplasmic antibodies; RNP, ribonucleoprotein.

Figure 2.

Hematoxylin and eosin stain (40×) of a skin punch biopsy from the right small finger demonstrating eosinophilic, amorphous material within blood vessels that occludes the vascular lumen. Immunofluorescence studies demonstrated granular IgM, C3, C5b-9, and fibrinogen deposition in and around superficial blood vessels, which is consistent with small vessel vasculitis and features supportive of cryoglobulinemia types II or III.

Her hospital treatment included prednisone, mycophenolate mofetil, aspirin, and low-molecular-weight heparin. When the biopsy results suggested CV, the heparin was discontinued. Symptomatic and clinical improvement were achieved, kidney function predominantly normalized, and the patient was discharged home. On follow-up, she developed a purpuric rash over the upper back, which resolved over a 2-week period; her serum creatinine and GFR normalized; and the black discoloration in her left index finger resolved.

DISCUSSION

CV is classified into three serological categories. Type I is composed of a monoclonal immunoglobulin that is always linked to a B-cell lymphoproliferative disorder such as Waldenström's macroglobulinemia or multiple myeloma. Type II or mixed CV contains a mixture of polyclonal IgG and monoclonal IgM with rheumatoid factor activity. Type III comprises polyclonal IgM and IgG with rheumatoid factor activity as well (3, 6). Types II and III most often produce constitutional symptoms, as well as palpable purpura with cutaneous vasculitis; the female-to-male ratio is often reported as 2–3:1, with waxing and waning of clinical features and spontaneous remissions and exacerbations (3). CV can be classified as “essential” in the absence of other well-defined infectious disorders (e.g., hepatitis C virus [HCV], which accounts for approximately 80% of all cases of CV), immunological disorders, or neoplastic disorders (2, 6). Two pathophysiological mechanisms are mainly involved in the development of various degrees of CV: 1) cryoglobulin precipitation in the microcirculation, causing vascular occlusion, and 2) immune complex–mediated deposition within blood vessels, causing subsequent systemic vasculitis (1, 2).

The so-called “essential” mixed CV is characterized by a clinical triad (Meltzer's triad): purpura, weakness, and arthralgias with multisystem organ involvement, representing nearly 10% of all CV, a percentage that rises to 25% in HCV-negative patients (2, 5, 6). According to Stone, non-HCV and rheumatoid factor–negative CV is a rare finding (7). Unfortunately, there are no validated classification/diagnostic criteria for CV. A patient series involving 231 patients from Italy proposed preliminary criteria for CV based on clinical, serological, and pathological features (8). In this series, the female-to-male ratio was 3:1, Meltzer's triad was present in almost 80%, palpable purpura was present in 98%, and Raynaud's phenomenon was present in 36%, with renal involvement present in 20%; however, 30% developed renal complications over time (8). A more recent European-based diagnostic/classification criteria for CV has been studied based on questionnaire, clinical findings, and laboratory criteria. In HCV-negative patients, the sensitivity and specificity of the classification were 89.5% and 90.3%, respectively (9).

Since the diagnosis of CV requires the presence of cryoglobulins in serum, appropriate sample collection and handling is crucial. Blood should be collected in prewarmed syringes and tubes, transported, clotted, and centrifuged at 37° to 40°C, ensuring that the temperature never falls below 37°C (10). A negative test for cryoglobulins does not exclude the diagnosis of CV, because of the possibility of false-negative results due to improper collection and handling of laboratory samples or inconsistent laboratory techniques (11).

Renal involvement in non-HCV–related CV patients has been poorly described. Matignon et al (12) retrospectively studied kidney biopsies in 20 patients, with 10 classified as idiopathic or “essential” CV. The most common clinical presentation was nephrotic-range proteinuria (85%), microscopic hematuria (100%), and renal failure (85%). Interestingly, 100% exhibited membranoproliferative glomerulonephritis, with immunofluorescence demonstrating subendothelial and intraglomerular deposits of IgG, IgM, and C3. A review article by Sethi and Fervenza examined the conditions associated with membranoproliferative glomerulonephritis in which hepatitis C or E with or without cryoglobulinemia was an important cause (13). Our case represents the first report of non-HCV–related CV in the setting of MN.