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Nonarticular gouthyperuricemia and tophus formation without gouty arthritis.

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The sequence of events from asymptomatic
hyperuricemia to acute gout, intercritical gout, and
finally chronic tophaceous gout is well established.
One-fifth of patients who suffer acute gout eventually
develop tophaceous deposits if not treated with hypouricemic drugs (1). The patients described here
paradoxically developed tophi without any history of
acute gouty arthritis. One patient had coexistent rheumatoid arthritis and the other four showed various
degrees of renal impairment, a situation inviting speculation on the mechanism of inhibitory factors involved
in acute gout.
Patient 1. A 46-year-old man developed definite
seropositive rheumatoid arthritis at the age of 28 with
progressive joiqt destruction. Despite careful questioning, no history suggestive of acute gout could be
elicited and at no time have urate crystals been identified in the synovial fluid. Since the onset he had
received regular medication with aspirin and prednisoFrom the Kennedy Institute of Rheumatology and Charing
Cross Hospital, London, England and the Wellington Clinical
School of Medicine, Wellington, New Zealand.
P. Hollingworth, MRCP: Senior Registrar in Rheumatology, Charing Cross Hospital, Fulham Palace Road, London W6.
England; J. T. Scott, MD, FRCP: Consultant Physician, Charing
Cross Hospital and Honorary Physician, Kennedy Institute of
Rheumatology; H. C. Burry, FRACP, FRCP: Associate Professor of
Medicine, The Wellington Clinical School of Medicine.
Address reprint requests to Dr. J. T. Scott, Kennedy
Institute of Rheumatology, Bute Gardens, London W6 7DW. England.
Submitted for publication September 14, 1981; accepted in
revised form May 12, 1982.
Arthritis and Rheumatism, Vol. 26, NO. 1 (January 1983)
lone approximately 7 mg daily, and in 1978 penicillamine was started. After taking penicillamine 6 months
he developed proteinuria, and a chalky deposit was
noted on the pinna of one ear (Figure 1). Salient
investigations included a normal pyelogram and urine
microscopy, creatinine clearance of 126 ml/minute,
and proteinuria of 2.1 gm/24 hours.
Renal biopsy showed no abnormality by light
microscopy in the cortex. Immunofluorescent staining
showed diffuse and discrete granular deposits of IgG
around the periphery of the glomerular capillary loops.
By electron microscopy, numerous small electrondense deposits were identified on the epithelial cell
aspect of the glomerular basement membrane. There
was fusion of the foot processes of the epithelial cells
but the mesangial regions were within normal limits.
These changes are compatible with penicillamine-induced glomerulonephritis. In addition, a typical gouty
tophus was identified in the medulla (Figure 2). Dissolution of urate from the tissues had been minimized
since urate is relatively insoluble in the alcoholic
acidic fixative used (Duboscq-Brazil). Polarized light
microscopy showed the presence of crystals that
stained positively by the Gomori methenamine technique, identifying them as salts of either calcium or
urate (2). However preincubation of the sections in a
saturated solution of lithium carbonate dissolved out
the crystals, specifically identifying them as urate
which, unlike calcium salts. is soluble in such a
solution. A positive urate control specimen and a
duplicate specimen preincubated in lithium carbonate
confirmed these findings.
Polarized light microscopy of the deposit in the
ear showed variable sized needle-shaped crystals that
gave a negative sign of birefringence typical of mono-
mmole. There was no proteinuria, and microscopy and
culture of urine gave negative results, but creatinine
clearance was impaired at 40 ml/minute; the patient
declined a pyelogram. Probenecid was given and he
was followed for 14 months; during this time the
plasma urate fell to normal and the tophus disappeared. No acute attack of gout was precipitated.
Patients 3-5. The salient features of these patients, together with those of patients l and 2, are
summarized in Table 1 . In each instance there was no
history of acute gout, and tophi were confirmed by
polarized light microscopy of the aspirate. In no case
was there radiologic evidence of damage to bones or
joints by tophi.
These patients were reliable witnesses but, despite careful questioning, gave no history suggestive of
acute gout. Urate crystals have never been detected in
Figure 1. Patient 1. Tophus in pinna of the ear indicated by arrow.
sodium urate. After the patient was on a low purine
diet 5 days, the plasma urate was 610 pmole/liter
(normal 100-400 pmole/liter) and 24-hour urinary
urate 4.6 mmole (normal <3.6 mmole).
Penicillamine was replaced by azathioprine.
Proteinuria ceased after 6 months, renal function has
remained static since then, active synovitis has regessed, but the tophus in the ear has persisted. There
still have been no acute attacks of gout.
Patient 2. A 69-year-old man was referred with
stiff fingers of 12 months' duration. He had been taking
aspirin for this condition. There was no history of
acute gout, even though he had fractured the proximal
phalanx of his great toe 5 months previously. Examination showed bony swelling of several of the proximal interphalangeal joints characteristic of osteoarthritis, which was confirmed radiographically. A chalky
deposit was found in the pulp of the second right
finger. Polarized light examination of an aspirate of
this deposit showed it to have the characteristics Of
monosodium Wate as described for patient
urate was 550 pmolehiter and 24-hour urinary urate 4.9
Figure 2. Histology of renal medulla (patient 1) showing a typical
gouty tophus surrounded by chronic inflammatory cells (X 280). See
text for fixation and staining technique. Reproduced by kind permission of Dr. D. Woodrow, Department of Experimental Pathology,
Charing Cross Hospital Medical School.
Table 1. Summary of clinical and laboratorv features of Datients 1-5
Urate deposit
Other diseases
Rheumatoid arthritis
Generalized osteoarthritis
Recurrent pulmonary emboli
Finger, toes, and
olecranon bursa
Finger pulp
Chronic pyelonephritis
Generalized osteoarthritis
the synovial fluid of the patient with rheumatoid
arthritis, the only patient whose synovial fluid has
been available for examination. All patients had hyperuricemia and chalky subcutaneous deposits shown by
polarized light microscopy to contain variable sized
needle-shaped crystals, giving a negative sign of birefringence entirely typical of monosodium urate. Similarly, the staining properties of the crystals within the
renal tophus were typical of urate. Points of particular
interest are the presence of various degrees of renal
impairment in 4 elderly patients and rheumatoid arthritis in the other. All 5 patients described here were
receiving urate-retaining drugs and 3 were receiving
antiinflammatory drugs. Patient 4 had chronic pyelonephritis and patient 1, who was found to have a
tophus on renal biopsy, had normal renal function.
The cause of renal impairment in the others is not
Acute gout is remarkably rare in association
with rheumatoid arthritis or chronic renal failure. It
has been estimated, for example, that there should be
1680 patients in the United States with coexisting gout
and rheumatoid arthritis (3), yet there are only 4
previous unequivocal case reports (4-6). Tophi are
occasionally reported to be present at the time of the
first attack of gout (7), but interestingly, one recent
report of tophi without acute gout concerned a patient
who also had rheumatoid arthritis (6). The infrequency
of acute gout in chronic renal failure (8), where hyperuricemia is common, is surprising; one explanation
suggested is that the duration of untreated renal impairment may be insufficient for the miscible pool to
reach the critical level (9). Polymorphonuclear leukocytes are generally necessary for the acute inflammatory reaction to gout, and their phagocytic activity is
impaired in both chronic renal failure (10) and rheumatoid arthritis (11). Moreover the inflammatory response to sodium urate crystals injected intradermally
and subcutaneously in uremic patients has been reported to be diminished (12). Three of the patients
described here were receiving aspirin, which might
have suppressed the inflammatory response to urate
However, deposition of urate in tophi is often
gradual and painless, and urate crystals may be detected in asymptomatic joints of gouty patients (13); in
both these circumstances urate crystals are failing to
excite an acute inflammatory response. This suggests
that in rheumatoid arthritis and possibly chronic renal
failure, urate crystals are changed in some way, perhaps by the acquisition or alteration of a protein coat,
when laid down in tophaceous deposits, so that they
do not stimulate an acute inflammatory response.
Indeed plasma proteins, particularly IgG, do
adhere to urate crystals in vitro (14). This may be a
prerequisite to phagocytosis by polymorphonuclear
leukocytes; the resulting phagolysosome then digests
the coat with phagolysomal lysis, release of hydrolytic
enzymes, cellular autolysis, and an ensuing acute
inflammatory response (15). Should the protein coat
acquired by urate crystals in rheumatoid synovial fluid
differ in some way so that phagocytosis is not stimulated, then acute gout might not occur. It has been
suggested that the acquisition of a protein coat other
than immunoglobulin, perhaps from the breakdown
products of polymorphonuclear leukocytes, might be
the mechanism whereby the uncomplicated acute
gouty attack is terminated (14). In such an attack large
numbers of intra- and extracellular urate crystals are
frequently seen in the synovial fluid of the patient with
already resolving arthritis.
Finally it is possible, in the patients described
here, that preferential deposition of crystals occurred
in the soft tissues rather than in the joints themselves.
The nature of any possible connective tissue abnormality in this respect is quite unknown.
I . Grahame K. Scott JT: Clinical survey of 354 patients
with gout. Ann Kheum Dis 29:461-468, 1970
2. Drury RAB, Wallington EA: Methenamine silver method for urates (modified from Gomori 19521, Carleton's
Histological Techniques. Fifth edition. Edited by KAB
Drury, EA Wallington. Oxford, Oxford University
Press, 1980, p 219
3. Wallace DJ, Klinenberg JR. Morhaim D. Berlanstein B.
Biren PC, Callis G : Coexistent gout and rheumatoid
arthritis: case report and literature review. Arthritis
Rheum 22:81-86. 1979
4. Owen DS. Toone E, lrby R: Coexistent rheumatoid
arthritis and chronic tophaceous gout. JAMA 197:953956, 1966
5 . Schwarzberg M, Leiberman DH, Gupta VP. Erlich GE:
Kheumatoid arthritis and chronic gouty arthropathy.
JAMA 240:2568-2659, 1978
6. Raman D, Abdalla AM. Newton DKL. Haslock I:
Coexistent rheumatoid arthritis and tophaceous gout: a
case report. Ann Rheum Dis 40:427-429. 1981
7. Wyngaarden JB. Holmes EW: Clinical gout and the
diagnosis of hyperuricemia, Arthritis and Allied Conditions. Ninth edition. Edited by DJ McCarty. Philadelphia, Lea and Febiger. 1979, pp 1193-1228
8. Wallace SC. Bernstein 0: The relationship between gout
and the kidney. Metabolism 12:440-446, 1963
9. Sorenson CB: The pathogenesis of gout. Arch Intern
Med 109:379-390, I962
10. Jorstad S, Vikcn KE: Inhibitory effects of plasma from
uraemic patients on human mononuclear phagocytes
cultured in vitro. Acta Pathol Microbiol Scand ( C )
85:169-177. 1977
I I . Turner RA. Schumacher HR, Allen KM: Phagocytic
function of polymorphonuclear leukocytes in rheumatic
diseases. J Clin Invest 52:163?-1635. 1973
12. Buchanan WW Jr, Klinenberg JR, Seegmillcr JE: The
inflammatory response to injected microcrystalline
monosodium urate in normal, hyperuricemic. gouty and
uremic subjects. Arthritis Rheum 8:361-367, 1965
13. Agudelo CA, Weinberger A, Schumacher HR, Turner
R. Molina J: Definitive diagnosis of gout by identification of urate crystals in asymptomatic metatarsophalangeal joints. Arthritis Rheum 22:559-560. 1979
14. Kozin F, McCarty DJ: Protein adsorption to monosodium urate. calcium pyrophosphate dihydrate and silica
crystals: relationship to the pathogenesis of crystalinduced inflammation. Arthritis Rheum 19:433-438.
IS. Wallingford WK, McCarty DJ: Differential membranolytic effects of microcrystalline sodium urate and calcium
pyrophosphate dihydrate. J Exp Med 133: 100-1 12, 1971
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without, formation, gout, tophus, arthritis, gouthyperuricemia, nonarticular
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