Finger necrosis due to cryoglobulinemic vasculitis in
association with membranous nephropathy
Mateo Porres-Aguilar, MD, Carlos E. Rodriguez-Castro, MD, Padilla Osvaldo, MD, Fátima Saifuddin, MD, Tariq Siddiqui,
MD, Jerry Fan, MS, Debabrata Mukherjee, MD, Kanchan Pema, MD, and Aamer Abbas, MD
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.
C
ryoglobulins are immunoglobulins that precipitate
in vitro at temperatures below 37ºC, 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
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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, antiScl-70, anti-C3, and anti-myeloperoxidase antibodies (Table 1).
From the Department of Internal Medicine (Porres-Aguilar, Rodriguez-Castro,
Pema), the Department of Pathology (Osvaldo), and the Division of Cardiovascular
Diseases (Siddiqui, Mukherjee, Abbas), Texas Tech University Health Sciences
Center/Paul L. Foster School of Medicine, El Paso, Texas; medical student, Texas
Tech University Health Sciences Center/Paul L. Foster School of Medicine, El
Paso, Texas (Fan); and the Department of Internal Medicine, Jinnah Postgraduate
Medical Centre, Karachi, Pakistan (Saifuddin).
Corresponding author: Mateo Porres-Aguilar, MD, Department of Internal
Medicine, Texas Tech University Health Science Center, 4800 Alberta Avenue, El
Paso, TX 79905 (e-mail: [email protected]).
Proc (Bayl Univ Med Cent) 2015;28(1):72–74
a
b
c
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).
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.
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 dis-
Table 1. Autoimmune workup in our patient with significant
vasculitic digital necrotic lesion
Test
Result
Test
Result
ESR (mm/hr)
114
Anti-cardiolipin Ab IgG and
IgM
Negative
CRP (mg/L)
0.46
Scleroderma-70 Ab IgG
Negative
Hemoglobin (g/dL)
11.1
Beta-2 glycoprotein Ab
Negative
BUN (mg/dL)
57
RNP Ab IgG
Negative
1.52
Anti-Smith Ab IgG
Negative
36
SSA (Ro)
Negative
6.5
SSB (La)
Negative
CCP Ab IgG
Negative Jo-1 Ab
Negative
Myeloperoxidase Ab
Negative Histone Ab IgG
Negative
pANCA, cANCA IgG
Negative HIV screening
Negative
Hepatitis serology
Negative ANA
Negative
Anti-dsDNA
Negative
Creatinine (mg/dL)
GFR (mL/min/1.73
m2)
Protein in urine (g)
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.
January 2015
charged 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
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.
Finger necrosis due to cryoglobulinemic vasculitis in association with membranous nephropathy
73
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 Europeanbased 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
74
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.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Tedeschi A, Baratè C, Minola E, Morra E. Cryoglobulinemia. Blood Rev
2007;21(4):183–200.
Ramos-Casals M, Stone JH, Cid MC, Bosch X. The cryoglobulinaemias.
Lancet 2012;379(9813):348–360.
Meltzer M, Franklin EC. Cryoglobulinemia—a study of twenty-nine
patients. I. IgG and IgM cryoglobulins and factors affecting cryoprecipitability. Am J Med 1966;40(6):828–836.
Trejo O, Ramos-Casals M, García-Carrasco M, Yagüe J, Jiménez S, de
la Red G, Cervera R, Font J, Ingelmo M. Cryoglobulinemia: study of
etiologic factors and clinical and immunologic features in 443 patients
from a single center. Medicine (Baltimore) 2001;80(4):252–262.
Damoiseaux J. The diagnosis and classification of the cryoglobulinemic
syndrome. Autoimmun Rev 2014;13(4–5):359–362.
Terrier B, Cacoub P. Cryoglobulinemia vasculitis: an update. Curr Opin
Rheumatol 2013;25(1):10–18.
Stone MJ. Pathogenesis and morbidity of autoantibody syndromes
in Waldenstrom’s macroglobulinemia. Clin Lymphoma Myeloma Leuk
2011;11(1):157–159.
Ferri C, Sebastiani M, Giuggioli D, Cazzato M, Longombardo G, Antonelli A, Puccini R, Michelassi C, Zignego AL. Mixed cryoglobulinemia:
demographic, clinical, and serologic features and survival in 231 patients.
Semin Arthritis Rheum 2004;33(6):355–374.
Quartuccio L, Isola M, Corazza L, Maset M, Monti G, Gabrielli A, Tzioufas AG, Ferri C, Ferraccioli G, Ramos-Casals M, Voulgarelis M, Lenzi
M, Mascia MT, Sansonno D, Cacoub P, Tomsic M, Tavoni A, Pietrogrande
M, Zignego AL, Scarpato S, Pioltelli P, Steinfeld S, Lamprecht P, Galli M,
Bombardieri S, De Vita S. Performance of the preliminary classification
criteria for cryoglobulinaemic vasculitis and clinical manifestations in
hepatitis C virus-unrelated cryoglobulinaemic vasculitis. Clin Exp Rheumatol 2012;30(1 Suppl 70):S48–S52.
Bakker AJ, Slomp J, de Vries T, Boymans DA, Veldhuis B, Halma K,
Joosten P. Adequate sampling in cryoglobulinaemia: recommended
warmly. Clin Chem Lab Med 2003;41(1):85–89.
Vermeersch P, Gijbels K, Mariën G, Lunn R, Egner W, White P, Bossuyt
X. A critical appraisal of current practice in the detection, analysis, and
reporting of cryoglobulins. Clin Chem 2008;54(1):39–43.
Matignon M, Cacoub P, Colombat M, Saadoun D, Brocheriou I, Mougenot B, Roudot-Thoraval F, Vanhille P, Moranne O, Hachulla E, Hatron
PY, Fermand JP, Fakhouri F, Ronco P, Plaisier E, Grimbert P. Clinical
and morphologic spectrum of renal involvement in patients with mixed
cryoglobulinemia without evidence of hepatitis C virus infection. Medicine
(Baltimore) 2009;88(6):341–348.
Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis—a new
look at an old entity. N Engl J Med 2012;366(12):1119–1131.
Baylor University Medical Center Proceedings
Volume 28, Number 1