Renal Failure

ISSN: 0886-022X (Print) 1525-6049 (Online) Journal homepage: http://www.tandfonline.com/loi/irnf20

Tocilizumab Treatment for Nephrotic Syndrome

Due to Amyloidosis in Behcets Disease
M.D. Redondo-Pachn, R. Enrquez, A.E. Sirvent, E. Andrada, R. NogueraPons, I. Milln & F. Amors
To cite this article: M.D. Redondo-Pachn, R. Enrquez, A.E. Sirvent, E. Andrada, R. NogueraPons, I. Milln & F. Amors (2013) Tocilizumab Treatment for Nephrotic Syndrome Due to
Amyloidosis in Behcets Disease, Renal Failure, 35:4, 547-550
To link to this article: http://dx.doi.org/10.3109/0886022X.2013.773913

Published online: 11 Mar 2013.

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Date: 15 November 2015, At: 01:23

Renal Failure, 2013; 35(4): 547550

Copyright Informa Healthcare USA, Inc.
ISSN 0886-022X print/1525-6049 online
DOI: 10.3109/0886022X.2013.773913

CASE REPORT

Tocilizumab Treatment for Nephrotic Syndrome Due to Amyloidosis in

Behcets Disease
M.D. Redondo-Pachn1, R. Enrquez1, A.E. Sirvent1, E. Andrada2, R. Noguera-Pons3, I. Milln1
and F. Amors1
Nephrology Section, Hospital de Elche, Elche, Spain; 2 Pathology Section, Hospital de Elche, Elche, Spain; 3 Rheumatology
Section, Hospital de Elche, Elche, Spain

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Abstract
Renal involvement is an unusual but significant Behcets disease (BD) complication and AA amyloidosis appears to be the
most common etiology. IL-6 is a pro-inflammatory cytokine with an important role in AA amyloidosis development.
Tocilizumab (TCZ) is a humanized anti-IL-6 receptor antibody that has emerged as an effective and specific treatment in
AA amyloidosis secondary to chronic inflammatory disorders. We report on a patient diagnosed with BD who developed
nephrotic syndrome caused by renal AA amyloidosis with an excellent response to TCZ therapy.
Keywords: tocilizumab, amyloidosis, Behets disease, nephrotic syndrome, interleukin-6 (IL-6)

amyloidosis. She showed an excellent response to humanized anti-IL-6 receptor antibody tocilizumab (TCZ)
therapy.

INTRODUCTION
Behets disease (BD) is a multisystemic vasculitis that
causes mucocutaneous, ocular, gastrointestinal, neurological, respiratory, cardiovascular, and renal
involvement.1
Renal involvement in BD covers a wide clinical spectrum, from asymptomatic hematuria/proteinuria to endstage chronic kidney disease. AA amyloidosis secondary
to chronic systemic inflammation appears to be the most
common form of renal disease in BD.2
BD treatment is based on the affected organs, the
extent of the disease, and symptom severity. The treatment goals in this disease are to alleviate the symptoms,
decrease inflammation to prevent its progression, reduce
flare-up frequency and severity, and prevent complications. Corticosteroids combined with immunosuppressive therapy have been used to reduce inflammation and
control symptoms, albeit unsuccessfully in the most
aggressive cases.1
Recently, interleukin-receptor antagonists have
become a more specific treatment for AA amyloidosis
secondary to chronic inflammatory disorders.3
We describe a patient diagnosed as having BD 16 years
ago, developed nephrotic syndrome caused by renal AA

CASE REPORT
A 51-year-old female patient was diagnosed with BD 16
years ago with genital and oral ulcerations and erythema
nodosum. She was treated with low-dose corticosteroids.
She suffered from iridocyclitis 9 years ago, with no new
signs of disease activity since then.
The patient had mild renal failure and subnephrotic
proteinuria for a year; rectal biopsy was negative.
Proteinuria increased and she was admitted for a new
evaluation.
Physical examination was normal, with no edema,
mucocutaneous lesions, respiratory symptoms, or fever;
blood pressure was 120/80 mmHg. An eye examination
did not reveal any inflammatory findings.
Family history was unremarkable.
Table 1 shows the most relevant laboratory data.
Immune test, including C3-C4, ANCA, anti-GMB,
ANA, anti-DNA, anti-cardiolipin antibodies, lupus anticoagulant antibodies, and cryoglobulins, was normal/negative. HLA B51 was positive. Viral serology tests (hepatitis

Address correspondence to M.D. Redondo-Pachon, Calle Cam de lAlmazara, n 11. Elche CP: 03203 Alicante, Spain; E-mail:
dolypa@hotmail.com
Received 17 November 2012; Revised 23 January 2013; Accepted 1 February 2013

547

548 M.D. Redondo-Pachn et al.

Table 1. Laboratory data.
Complete Blood Count

Hemoglobin
Hematocrit
White blood cells
Platelets
VSG

9.9 g/dL
30.6%
10.33  103/L
310.000/L
92 mm/h

Normal values
1317 g/dL
4050%
4.011.0  103/L
130.000000/L
<20

Urine analysis
Density
24 h protein
High-resolution electrophoresis
Sediment

1010
9.504 mg
Glomerular protein
24 WBC

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Biochemisty

Creatinine
Urea
Sodium
Potassium
Calcium
Phosphorus
Uric acid
C-reactive protein
Total cholesterol
Albumin
Lactate dehydrogenase
Immunoglobulin A
Immunoglobulin M
Immunoglobulin G

1.7 mg/dL
41 mg/dL
141 mmol/L
4.1 mmol/L
8.2 mg/dL
5.1 mg/dL
7.4 mg/dL
52.8 mg/L
208 mg/dL
2.3 g/dL
435 U/L
448 mg/dL
1450 mg/dL
99 mg/dL

B virus, hepatitis C virus, and HIV) were negative and

CMV and EBV serology tests showed prior exposure.
Quantiferon was positive and skin tuberculin test was
negative. Chest X-ray and chest CT were normal.
Kidney ultrasound revealed normal-sized kidneys with
good corticomedullary differentiation; echo Doppler
scan: preserved flow in both renal veins and normal
resistive index.
Percutaneous renal biopsy (35 glomeruli) showed five
sclerotic glomeruli and amyloid deposit in the remaining
30%, 50% with global distribution, and the rest with a
focal segmental pattern; amyloid was also seen in vascular walls, tubular basement membranes and interstitium.
These deposits were confirmed as positive for AA amyloid by immunohistochemistry; immunofluorescence
was negative (Figure 1).
The patient was treated with colchicine (1 mg/day) and
TCZ (8 mg/kg body weight/month) for a year; isoniazid was
also administered prophylactically for latent tuberculosis for
6 months. After the second dose of TCZ, the proteinuria
decreased from 9.5 g/24 h to 2.19 g/24 h and C-reactive
protein (CRP) levels from 52.8 mg/dL to <5 mg/dL.
Figure 2 shows creatinine and proteinuria follow-up.
At the 1-year follow-up, laboratory test revealed the following: creatinine 1.4 mg/dL, albumin 4.4 g/dL,
CRP < 5 mg/dL, total cholesterol 201 mg/dL (LDLcholesterol 117 mg/dL), urine protein 165 mg/24 h, and

Normal values
0.661.25 mg/dL
1943 mg/dL
137145 mmol/L
3.55.1 mmol/L
8.410,2 mg/dL
2.54.5 mg/dL
2.58.5 mg/dL
<5 mg/L
<200 mg/dL
3.55.1 g/dL
313618 U/L
70.400 mg/dL
6801530 mg/dL
60260 mg/dL

Figure 1. Glomerular amyloid deposition in mesangiocapillary

pattern (Congo red stain 10).

normal sediment. There have been no adverse reactions to

TCZ.

DISCUSSION
Clinically apparent renal involvement in BD
is uncommon, although subclinical manifestations
(microalbuminuria and increased beta-2 microglobulin
Renal Failure

Tocilizumab Treatment for AA amyloidosis

549

1.8
Tocilizumab therapy (8 mg/kg/month)

1.6
1.4
1.2

Plasma creationine (mg/dL)

1
0.8
0.6
1

Renal
biopsy

+1

+2

+3

+4

+5

+6

+10 Time
(month)

10
9
8
Tocilizumab therapy (8 mg/kg/month)

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6
5
4
3

Proteinuria
(g/24 h)

2
1
0

Renal
biopsy

+1

+2

+3

+4

+5

+6

+10

Time
(month)

Figure 2. Creatinine and proteinuria follow-up.

excretion) are not as rare.4 Renal disease in BD may be

classified into 5 groups: (a) glomerulonephritis (diffuse
proliferative, focal and segmental, IgA, membranous
proliferative, and other); (b) amyloidosis; (c) renal vascular disorder; (d) interstitial nephritis; and (e) others,
such as nephrotoxicity.5
AA amyloidosis is an infrequent but significant BD
complication. Although published data in the literature
are limited, it appears to be the most common cause of
renal disorder and renal failure in BD; its estimated prevalence is 0.043%.6 BD-related amyloidosis is more
common in Mediterranean countries, and in Turkey, it
accounts for 3.6% of secondary amyloidosis, although
some of these patients may have Familial Mediterranean
fever mutations.7
Akpolat et al.8 have published one of the largest series,
with 33 patients diagnosed with BD and renal involvement. Of these, 11 patients present AA amyloidosis and,
unlike our case, almost 90% are males. These authors
analyze 253 published cases, of which 108 include amyloidosis. The mean interval between BD and AA amyloidosis diagnosis is 11 years (range from 7-month to 30year); this time is shorter in men than in women.9 In our
case, the interval between the onset of the first symptom
of BD and the diagnosis of amyloidosis was 16 years and
9 years, respectively, with no BD clinical manifestations.
In BD, amyloidosis usually occurs in patients with peripheral artery disease, lung disorders, and arthritis,10 and
2013 Informa Healthcare USA, Inc.

it is not common to find cases such as this, with mucocutaneous and eye involvement alone.6
BD pathogenesis is not clearly established; apparently,
environmental factors act on a genetic predisposition,
which leads to immune activation with an accompanying
inflammatory response. There seems to be a complex
interaction between T cells, neutrophils, and antigenpresenting cells, with cytokine release.11
Hamzaoui et al. have analyzed the cytokine profile in
BD patients and have noted that the blood levels of IL-4,
IL-6, IL-10, IL-12, and IFN- cytokines were significantly higher in BD patients compared with the control
subjects. IL-4, IL-10, and IL-12 levels were similar
between the patients with active BD and BD in remission, whereas IL-6 and IFN- levels were higher in
patients with active BD. Therefore, patients with active
BD exhibit higher IL-6 levels, and these are correlated
with the degree of disease activity.12
IL-6 is a pro-inflammatory cytokine with an
important role in immune response regulation and
acute phase response; it stimulates serum amyloid A
(SAA) synthesis in the liver and plays a key role in
AA amyloidosis development.13
TCZ has been approved as a biological therapy for
several autoimmune and chronic inflammatory diseases. TCZ inhibits IL-6 pro-inflammatory activity,
thus reducing SAA production, and also interferes
with T-cell function.14

550 M.D. Redondo-Pachn et al.

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This patient had an excellent response to TCZ therapy, with a fast decrease in proteinuria and improvement/
stabilization of renal function. This response to TCZ
suggests that IL-6 has a more direct effect on the glomerular filtration barrier.3 Colchicine in BD is indicated for
joint and mucocutaneous involvement, but does not
appear to prevent or affect the course of the amyloidosis10; therefore, we believe that the dramatic improvement in proteinuria was due to TCZ. To the best of our
knowledge, this would be the first BD-related AA amyloidosis case treated with TCZ.
We conclude that TZC may be the treatment of choice
for nephrotic syndrome secondary to renal AA amyloidosis in BD patients, and it could change the unfavorable
outcome in amyloidosis.
Declararion of interest: The authors report no conflicts of interest. The authors alone are responsible for the
content and writing of the paper.

[4]
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[7]

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Renal Failure