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Regression of the nephrotic syndrome in rheumatoid arthritis and amyloidosis treated with azathioprine.

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ARTHRITIS & RHEUMATISM
Vol. 38, No. 12, December 1995, pp 1851-1854
0 1995, American College of Rheumatology
1851
REGRESSION OF THE NEPHROTIC SYNDROME IN
RHEUMATOID ARTHRITIS AND AMYLOIDOSIS
TREATED WITH AZATHIOPRINE
A Case Report
DEBORAH L. SHAPIRO and HARRY SPIERA
Secondary or reactive (AA) amyloidosis is a
well-known complication of certain rheumatic diseases,
particularly rheumatoid arthritis (RA). This case report
describes a patient with RA complicated by amyloidosis
and the nephrotic syndrome, which regressed after
treatment with azathioprine. The AA amyloidosis was
documented by renal and lymph node biopsies and by
the presence of proteinuria. Evaluation for other etiologies of proteinuria was negative. After treatment with
azathioprine, the proteinuria resolved and the serum
albumin level increased from 1.9 mg/dl to normal. This
is the first published report of azathioprine therapy
resulting in a reversal of the nephrotic syndrome in a
patient with RA and secondary amyloidosis.
Secondary (AA) amyloidosis as a complication
of rheumatoid arthritis (RA) is uncommon, but it
remains an important problem. The incidence of
amyloidosis in adult RA has been estimated at 5-15%
in Europe (1,2). In juvenile rheumatoid arthritis (JRA),
the incidence of amyloidosis has been estimated at
5-10% in Europe, and at < I % in the US (3,4). In AA
amyloidosis, deposition of amyloid fibrils in the kidney
occurs. Affected patients commonly present with proteinuria, later progressing to the nephrotic syndrome
and renal failure. The prognosis for patients with
amyloid nephropathy has been considered extremely
poor, but there have been reports of improvement
Deborah L. Shapiro, MD: Mount Sinai School of Medicine,
New York, New York; Harry Spiera, MD: Mount Sinai Medical
Center, New York, New York.
Address reprint requests to Deborah Shapiro, MD, Box
1244, Division of Rheumatology, Mount Sinai Medical Center, One
Gustave L. Levy Place, New York, NY 10029-6574.
Submitted for publication December 16, 1994; accepted in
revised form June 8, 1995.
after treatment with alkylating cytostatic drugs and
methotrexate.
The case presented here is that of a patient with
RA complicated by amyloidosis and the nephrotic
syndrome. Following treatment with azathioprine, the
proteinuria resolved, and the serum albumin value
returned to normal levels. Therapy resulted in a reversal of the nephrotic syndrome.
CASE REPORT
The patient, a 48-year-old woman, first presented in 1977 with chronic, symmetric synovitis of
the knees, shoulders, hands, and feet. Tests for antinuclear antibodies (ANA) and (dsDNA) antibodies
were negative. The latex fixation titer was 1:640, and a
diagnosis of RA was made.
The patient was initially treated with prednisone. The synovitis persisted, and intramuscular
gold treatment was given for 20 weeks. However, little
clinical improvement was noted, and gold was discontinued. There was no proteinuria. The patient did not
wish to take any other remittive agent, and she was
maintained on a regimen of prednisone only. Her
disease activity continued.
Physical examination in 1986 revealed synovitis
of the wrists, fingers, and ankles, as well as bilateral
axillary, supraclavicular, and inguinal adenopathy.
She was taking only aspirin (4 gm/day) at that time.
She had 1+ peripheral edema and proteinuria. A
percutaneous renal biopsy revealed focal segmental
nodular expansion of the mesangial areas; capillary
walls were filled by eosinophilic homogeneous acellular material. This material was also seen in the walls of
arterioles and some tubular basement membrane in-
1852
volvement was noted. A Congo red stain revealed
focal and segmental green birefringence. Electron microscopy of the renal biopsy specimen showed the
mesangium to be focally expanded by fine fibrils
characteristic of amyloid, which extended through the
glomerular basement membrane and formed spike-like
aggregates beneath the epithelium. Epithelial cell foot
processes over these areas were effaced, and similar
material was seen focally in the wall of an arteriole.
These findings are characteristic of amyloidosis. A
24-hour urine collection contained 6.2 gm of protein.
Immunofluorescence studies were not done.
The patient was referred to Boston University
Medical Center (Boston, MA) for further evaluation.
Laboratory studies at that institution revealed that the
total serum protein level was 4.4 gm/dl and the serum
albumin level was 1.9 gm/dl. The erythrocyte sedimentation rate was 95 mmhour. Latex fixation test results
were positive. The C3 level was 172 &ml, and the
VDRL test result was negative, Findings from liver
function tests were normal. Examination of the kidney
biopsy specimen with potassium permanganate yielded
a sensitive reaction, as did a lymph node biopsy. The
use of potassium permanganate can demonstrate amyloid AA fibrils and distinguish them from amyloid AL.
A bone marrow aspirate and biopsy showed a hypocellular marrow with 3% plasma cells; there was no
evidence of a plasma cell dyscrasia. The serum amyloid A (SAA) level was 3,036 ng/ml in February 1987,
3,072 ng/ml in March 1987, and 23,040 ng/ml in June
1987 (normal <1,000).
A diagnosis of secondary or AA amyloidosis
due to RA was made. The patient was started on a
regimen of oral colchicine 0.6 mg twice daily; however, there was no change in the proteinuria during a
3-month period. In December 1987 oral azathioprine
(100 mg/day) was added to the treatment regimen, and
she experienced clinical improvement of the joint
inflammation. During the next 2 years the albumin
level gradually increased from 1.9 gm/dl to 3.5 gm/dl,
and the proteinuria resolved.
From 1990 to 1994 the patient’s serum albumin
level ranged from 3.8 gm/dl to 4.1 gm/dl, and there was
no proteinuria. In October 1992, she developed a basal
cell carcinoma of the face. The lesion was excised and
azathioprine was discontinued. The arthritis was in
remission, and she remained free of proteinuria for 18
months while taking only colchicine (0.6 mg orally
twice daily) and trilisate (750 mg orally twice daily). In
April 1994, the proteinuria recurred and the serum
SHAPIRO AND SPIERA
albumin level decreased to 3.3 gm/dl. Azathioprine
was restarted at 50 mglday.
DISCUSSION
Renal involvement with amyloidosis has been a
significant cause of death in patients with JRA (4,7)
and with adult RA (5,6). In a recent review from
Finland (8), the mortality rate due to amyloidosis in
JRA decreased markedly in the 1980s compared with
the period from 1969 to 1979. The authors speculate
that this decline was caused by the introduction of
immunosuppressive therapy for JRA in the late 1970s.
In amyloidosis associated with RA, several
case reports have suggested that alkylating cytostatic
drugs can induce remission of the nephrotic syndrome.
Treatment of JRA and amyloidosis with chlorambucil
has been reported to decrease proteinuria and improve
joint symptoms (9,lO) and to increase survival (7). In
adult RA, a patient treated with prednisone and cyclophosphamide for 2 years had stabilization of joint
symptoms, resolution of proteinuria, and histologic
regression of renal amyloid deposits on posttreatment
renal biopsy (1 1). A patient with RA and amyloidosis
who was treated with chlorambucil had resolution of
the nephrotic syndrome. This patient had a history of
pulmonary tuberculosis, which was treated less than a
year before the onset of proteinuria (12). Ahlmen et a1
(13) performed a prospective, randomized study of 22
patients with RA and amyloidosis and noted a significant postponement in progression to end-stage renal
disease and a marked increase in survival in the group
that received cytotoxic drugs. The treatment protocol
was not uniform: 3 patients were given chlorambucil, 3
were given azathioprine, and 1 was treated with cyclophosphamide. Eight patients were given podophyllotoxin, a microtubule antagonist.
Fourteen patients with rheumatic diseases and
amyloidosis were treated with both chlorambucil and
cyclophosphamide, but the 2 drugs were not directly
compared (14). Nine of the patients had RA, 4 had
ankylosing spondylitis, and 1 had JRA. In 19 of the 22
treatment periods, renal amyloidosis was considered
“satisfactory or somewhat improved” (14).
In a retrospective study of 64 patients with AA
amyloidosis, 31 patients had RA, 5 had ankylosing
spondylitis, 3 had psoriatic arthritis, and 1 had JRA.
Four of these patients whose rheumatic disease responded to immunosuppressive therapy with either
methotrexate or cyclophosphamide had a marked reduction or complete resolution of proteinuria (15).
REGRESSION OF NEPHROTIC SYNDROME
Table 1. Serum albumin levels and proteinuria in the patient after
treatment with azathioerine*
Date
2/87
10187 (azathioprine
started)
1/88
4/88
6/88
12/88
4/89
7/89
11/89
3/90
6/90
10190
4191
9191
5/92
10/92 (azathioprine
discontinued)
2/93
10193
4/94
4/94 (azathioprine
50 mglday
restarted)
8/94
1195
1/95 (azathioprine
increased to 100
mgfday)
* ND
=
Serum
albumin,
mgldl
Proteinuria
1.9
2.7
3+
2.3
2.4
2.5
3.0
3.1
3.4
3.5
3.5
3.2
4.1
4.1
3.8
3.7
ND
3+
3+
3+
Trace
Trace
1+
Absent
3.8
3.7
3.3
ND
Absent
Absent
3+
ND
3.2
3.6
ND
3+
3+
ND
1+
1+
Absent
Absent
Absent
Absent
ND
not determined.
Berglund et a1 (16) recently updated the data on
the 16 RA patients treated with alkylating cytostatic
drugs in their 1987 study (14). Patients were treated
with chlorambucil when they had active arthritis and
Table 2.
Diagnosis
2
5
1
3
3
4
Infection
Infection
Infection
FMF
FMF
JRA
RA; history of
tuberculosis
RA
Psoriatic arthritis
JRA
Psoriatic arthritis
AA amyloidosis;
etiology
unknown
RA
2
1
1
1
1
1
an increase in serum creatinine levels or proteinuria.
Disease activity was assessed by joint counts and
serum C-reactive protein (CRP) levels, which were
considered equivalent to SAA levels. Renal function
was preserved from 4 to 2 1 years (median 1 1 years) for
the 16 patients. Berglund et a1 consider chlorambucil
to be the preferred drug for treatment of RA complicated by amyloidosis, because other agents do not
normalize CRP levels. However, CRP may not correlate well with SAA, which may be a much more
sensitive indicator of inflammation and may also be
markedly elevated when the erythrocyte sedimentation rate is low (17). Because SAA is the precursor of
amyloid AA fibrils, its occurrence in high levels would
appear to be a more likely risk factor for amyloidogenesis than serum CRP levels.
There have been no controlled studies that
might establish an accepted treatment protocol for
cytotoxic drug therapy in RA and AA amyloidosis.
Although chlorambucil has been used more frequently, cyclophosphamide and azathioprine have
also been shown to be beneficial. Our patient had an
excellent response to azathioprine and remained free
of proteinuria for 5 years of followup, after which
azathioprine was discontinued. After 2 years, the
proteinuria recurred and azathioprine was restarted.
Currently, her arthritis is well controlled. The serum
albumin level at the most recent evaluation was 3.6
gm/dl, and the serum creatinine level was normal.
Although the patient did not have a repeat renal
biopsy or repeat testing for SAA levels, the cessation
of proteinuria for 5 years during azathioprine therapy
and its recurrence after azathioprine was discontinued
Reported cases of regression of the nephrotic syndrome in AA amyloidosis*
No. of cases
1
1853
Treatment
Reference
Antibiotics
Antibiotics
Antibiotics
Colchicine
Colchicine
Chlorambucil
Chlorambucil
18
19
20
21
22
10
12
Cyclophosphamide
Methotrexate
Methotrexate
Colchicine
Azathioprine, corticosteroids
15
15
15
23
24
Azathioprine
Present report
~
* FMF
arthritis.
=
familial Mediterranean fever; JRA = juvenile rheumatoid arthritis; RA
=
rheumatoid
1854
SHAPIRO AND SPIERA
suggest that suppression of amyloid deposition in the
kidney occurred during the treatment period. In addition, the patient’s condition would have been expected
to progress to renal failure if the amyloidosis had not
been treated, but her renal function remains normal 8
years after the diagnosis of amyloidosis. The patient
has never had hypocomplementemia, ANA, serologic
evidence of syphilis, abnormal serum glucose levels,
glycosuria, hematuria, or urinary casts. In addition,
the renal biopsy was diagnostic of amyloidosis; thus,
there is no evidence that the proteinuria was caused by
any other etiologic factor.
The course of the patient’s proteinuria is summarized in Table 1. She has taken colchicine since the
diagnosis of amyloidosis was made, and it is possible
that this has also had a beneficial effect. However,
review of the literature shows no reports of colchicine
causing regression of proteinuria due to RA-associated
amyloidosis (Table 2). We believe that the patient’s
nephrotic syndrome was due to secondary amyloidosis
and that it responded to azathioprine therapy. In a
review of the literature, we found no other case in
which proteinuria and the nephrotic syndrome due to
amyloidosis and RA regressed following treatment
with azathioprine. No convincing evidence exists that
any one of the alkylating cytostatic agents is superior
to others in the treatment of amyloidosis complicating
RA. A drug that successfully induces remission of
disease activity in an individual patient with RA may
also be effective in the treatment of amyloidosis.
Azathioprine may offer therapeutic benefit with a
lower risk of major toxicity than chlorambucil.
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regression, syndrome, arthritis, amyloidosis, treated, rheumatoid, nephrotic, azathioprine
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