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Renal disease in rheumatoid arthritis.

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78 1
pako (4) on in vitro PGE2-induced contractions of the
rat stomach strip. We have personally observed a nonselective antagonism of chloroquine (5) on several agonist-induced contractions, including the effect of PG in
the guinea pig isolated ileum. In vivo chloroquine is
also able to antagonize PG actions. It suppresses cardiac
rhythm disturbances induced by PG in the rat (6). It is
able to promote closure of patent ductus arteriosus in
premature infants, a condition known to persist when
high levels of PG are achieved (2).
On the basis of these results, Manku and Horrobin (2) suggested that binding sites for chloroquine including those to nucleic acids might be binding sites for
PG. Actually they have shown that PG can block the
binding of chloroquine to DNA. But more important is
the fact that chloroquine might interfere with PG membrane binding sites which trigger cyclic-AMP production. The results of Teitz and Chrisman (7) cited by Fulkerson et a1 (1) are easily explained by this hypothesis.
The intraarticular injection of PG in the rabbit knee induces a synovitis that is not prevented by systemic salicylate, since it is not due to stimulation of PG synthetase
but is abolished by systemic chloroquine because of its
PG antagonist effect.
We propose a similar interpretation of the results
of Fulkerson et a1 (1). If chloroquine is truly a PG antagonist, it is not surprising that the in vitro effects of
PGE on cartilage slices are abolished by this drug.
However, in our interpretation the main effect of
chloroquine must take place at the membrane binding
sites for PG. An additional action on DNA-dependent
RNA synthesis is still possible, but it would not be necessary for obtaining the inhibition of the stimulation of
hexosamine cartilage depletion by PGE.
Laboratory of Pharmacology
Rheumatology Unit
School of Medicine and Institute of Pharmacy
University of Brussels
1. Fulkerson JP, Landenbauer-Bellis IM, Chrisman OD: In
vitro hexosamine depletion of intact articular cartilage by
E-prostaglandins: prevention by chloroquine. Arthritis
Rheum 22:1117-1121, 1979
2. Manku MS, Horrobin DF: Chloroquine, quinine, procaine,
quinidine and clomipramine are prostaglandin agonists
and antagonists. Prostaglandins 12:789-80 1, 1976
3. Horrobin DF, Manku MS, Karmazyn M, Ally AI, Morgan
RO, Karmali RA: Quinacrine is a protaglandin antagonist.
Biochem Biophys Res Commun 76:1188-1193, 1977
4. Okpako DT: Interactions of aminoquinolines and mepacrine with prostaglandin E2 in tissues of rats and guinea
pigs. Gen Pharmacol 9:25-28, 1978
5. Famaey JP, Fontaine J, Reuse J: An analysis of the inhibitory effects and of possible prostaglandins antagonism of
chloroquine in the guinea pig isolated ileum. J Pharm
Pharmacol29:761-762, 1977
6. Swift A, Karmazyn M, Horrobin DF, Manku MS, Karmali
RA, Morgan RO, Ally AI: Low prostaglandin concentrations cause cardiac rhythm disturbances: effect reversed by
low levels of copper or chloroquine. Prostaglandins
15:651-657, 1978
7. Teitz CC, Chrisman OD: The effect of salicylate and
chloroquine on prostaglandin-induced articular damage in
rabbit knees. Clin Orthop 108:264-274, 1975
Renal disease in rheumatoid arthritis
To the Editor:
The association of renal disease with rheumatoid
arthritis (RA) has been debated for many years. A recent review (1) and case report (2) have suggested that a
membranous glomerulonephritis (GN) occasionally occurs in the course of the joint disease. The nature of the
relationship has been difficult to clarify, since agents
used in the treatment of RA have themselves been implicated in the production of proteinuric renal disease.
In fact, Samuels ( 1 ) hypothesized that the GN might be
pathogenetically linked to the rheumatoid disease and
that gold or penicillamine treatment could produce the
nephrotic syndrome in only appropriately predisposed
patients. Most patients studied who developed proteinuria in the course of rheumatoid disease had also taken
some potentially nephrotoxic therapy before the detection of proteinuria. Those with well documented RA
had long-standing joint disease before the renal disease
became manifest.
Case report. We have recently seen a 40-year-old
man who came to the New York Veterans Administration Medical Center complaining of pain and swelling
in his right ankle and right temporomandibular joint.
He had experienced a symmetrical but migratory pain
in his shoulders and hands and morning stiffness of 1hour duration for 1 year before admission. Physical examination revealed moderate synovitis of the metacarpophalangeal and proximal interphalangeal joints
bilaterally and reduced range of motion in both shoulders. His laboratory data consisted of a latex fixation titer of 1:2560 and sheep cell agglutination at 1:320. His
hematocrit (HCT) was 47.3% and white blood cell count
Figure 1 . Electron micrograph of the first renal biopsy Only a few electron-dense deposits (arrows) are present in subepithelial sites of the glomerular basement membrane (b) of a peripheral
capillary loop (X 8000)
Figure 2. Electron micrograph of the second renal biopsy. There are more numerous electrondense deposits than previously. Deposits are separated by projections of the glomerular basement membrane (b) in a peripheral capillary loop (X 4800).
Figure 3. Glomerulus from the second renal biopsy stained with fluorescein-conjugated antiserum to IgG. Diffuse uniform finely granular
deposits are present in glomerular capillary walls (X 800).
(WBC) was 6,300/ml. The antinuclear antibody was
weakly positive with a diffuse pattern, while the ENA,
HbAg, LE prep and cryoglobulins gave negative results.
The ESR was 71 mm/hour total; serum hemolytic complement was 178; the BUN was 16 mg/dl; serum cholesterol, 299 mg/dl; serum albumin-to-globulin, 4.1/3.1;
creatinine 0.8 mg/dl; 24-hour urine protein, 6 gm/liter.
The urine sediment contained 2 to 4 white blood cells
per high power field.
A diagnosis of rheumatoid arthritis was made.
The patient began taking enteric-coated aspirin, 16 tablets per day. He noted lessening of his morning stiffness
and joint pains over the next few months. A renal
biopsy showed focal segmental proliferative glomerulonephritis in I of 10 glomeruli, while others were normal
by light microscopy. Ultrastructurally, there were scattered electron-dense deposits restricted to subepithelial
sites (Figure 1). Immunofluorescence microscopy re-,
vealed mild, diffuse, finely granular staining for IgG
and C3; there was focal staining for IgM but none for
IgA. He was seen monthly over the next year and continued to take both salicylates and a nonsteroidal antiinflammatory agent (ibuprofen).
His physical examination continued to show
mild-to-moderate synovitis of the ankles and hands. No
erosive changes were noted on x-ray. He subsequently
developed peripheral and periorbital edema. Laboratory results during this period revealed a serum albumin-to-globulin ratio of 3.7 to 3.0, serum cholesterol of
430 mg/dl, ESR of 96 mm/hr, and a 24-hour urine protein of 6 gm/liter. The HCT was 41%, and the WBC
6,30O/ml. He was given a thiazide diuretic which reduced his peripheral edema. Over the next several
months, the arthritis of his ankles became more severe.
He was hospitalized for additional antiinflammatory
therapy, bed rest, and intraarticular steroid injections.
After 2 weeks he improved and was discharged. Despite
diuretic therapy, his peripheral edema recurred. A second renal biopsy 1 year after the first contained 18
glomeruli, all showing normal cellularity and more capillary wall thickening than in the previous biopsy. Electron microscopy revealed more numerous deposits than
in the previous biopsy in a subepithelial location, and
more glomerular basement membrane thickening (Figure 2). There was now strong staining for all Igs and C3
(Figure 3).
Discussion. The course of our patient demonstrates that progressive glomerular disease can occur
with rheumatoid arthritis in the absence of any therapy
known to produce the nephrotic syndrome. It was not
associated with either long-standing or particularly aggressive joint disease but was clearly progressive morphologically with increasing immune complex deposition.
Given the occurrence of such an entity in several
other reported patients who received no potential nephrotoxic therapy (3), it seems germane to ask if those patients who developed the nephrotic syndrome during
penicillamine or gold therapy for RA did so as a result
of their disease or their therapy. Perhaps patients whose
renal disease did not resolve after cessation of therapy
were, in fact, suffering from rheumatoid membranous
glomerulonephritis, an unusual complication of rheumatoid arthritis.
New York University Medical Center
New York VA Medical Center
New York City
1. Samuels B, Lee JC, Engelman EP, Hopper S Jr: Mem-
branous nephropathy in patients with rheumatoid arthritis:
relationship to gold therapy. Medicine 57:3 19-327, 1978
2. Davis JA, Cohen AH, Weisbart R, Paulus HE: Glomerulonephritis in rheumatoid arthritis. Arthritis Rheum
22: 1018- 1023, 1979
3. Row PG, Cameron JS, Turner DR, Evans DJ, White
RHR, Ogg CS, Chantler C, Brown CB: Membranous nephropathy: long-term follow-up and association with neoplasia. Quart J Med (new series) 44:207-239, 1975
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renar, arthritis, disease, rheumatoid
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