Amyloidosis Secondary to Polyarticular Gout

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AMYLOIDOSIS SECONDARY TO POLYARTTCULAR GOUT ALAN RUBINOW and MOSHE SONNENBLICK

Although amyloidosis may complicate many chronic inflammatory arthropathies including rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis ( I ) , its association with gout is extremely rare ( 2 ) . We report here a patient with amyloidosis secondary to poiyarticular gout in whom amyloid A protein (AA) was demonstrated in the walls of amyloid-laden blood vessels. Colchicine therapy resulted in prevention of further attacks of gout, improvement in renal function, decrease in proteinuria, and restoration of serum albumin to normal. Case Report. An 85-year-old man was admitted to the hospital because of acute polyarthritis primarily affecting his elbows and distal interphalangeal (DIP) joints. During the previous 10 years, he had suffered from recurrent attacks of gout. He received indomethacin for these acute episodes, but he was noncompliant regarding medications prescribed for lowering his serum uric acid. Apart from these attacks, he was well and denied any previous illnesses, including tuberculosis, osteomyelitis, or any other chronic infectious or inflammatory disease. The physical examination was unremarkable except for severe tenderness, swelling, and diminished range of motion in his elbows -

From the Departments of Medicine and Geriatrics, ShaareZedek Medical Center, Jerusalem. Israel. Alan Rubinow. MD: Senior Physician, Department of Medicine, Chief. Rheumatology Section. Shaare-Zedek Medical Center. Jerusalem. Israel; Moshe Sonnenblick. MD: Senior Physician, Department of Medicine and Geriatrics. Shaare-Zedek Medical Center. Address reprint requests to Alan Rubinow, MD. Arthritis Section #337, University Hospital, 75 East Newton Street, Boston, MA02118. Submitted for publication December 23, 1980; accepted in revised form March 19. 1981. Arthritis and Rheumatism, Vol. 24,No. 11 (November 1981)

and DIPjoints. On the latter, small tophi were present, and joint aspiration revealed chalky white material containing abundant, negatively birefringent monosodium urate crystals. Cultures of the joint fluid were sterile. Pertinent laboratory studies revealed a hemoglobin of 14.4 gm/dl, hematocrit 42%, and a white blood count of 9,000/mm3. He had 4 + proteinuria (5.5 gm in 24 hours) and a normal urinary sediment. The erythrocyte sedimentation rate was 95 mmlhour. The serum uric acid was 16.8 mg/dl, blood urea nitrogen (BUN) 108 mg/dl, serum creatinine 6.0 mg/dl, and total serum protein 5. I g d d l , of which 1.7 gm/dl was albumin. Rheumatoid factors, antinuclear antibodies, and C-reactive protein were negative. Serum complement C3 and C4 (Hyland) were 88 mg/dl and 17 mg/dl respectively. An M-component, free kappa, and lambda light chains were absent from the serum and urine. A bone marrow aspiration and chest roentgenogram were normal. A rectal biopsy revealed heavy amyloid deposition in the blood vessels and mucosa (Figure 1). The patient was placed on colchicine 0.6 mg twice daily. Laboratory studies after 14 months, during which he was free of acute attacks of gout, showed a decrease in proteinuria (2.2 gm in 24 hours), a serum albumin of 3.0 gm/dl, B U N 42 mg/dl, and creatinine of 2.8 mg/dl. A rectal biopsy at this time showed no appreciable decrease in the degree of arnyloid infiltration. The rectal biopsy tissue was frozen in dry-ice acetone and kept at -70°C until used. Antiserum to amyloid A protein (AA) isolated from the spleen of a patient with amyloidosis and ankylosing spondylitis was produced in New Zealand white rabbits (3) and shown to be specific for isolated AA protein. It

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detected a serum factor (SAA) that showed complete immunologic identity with AA. Ten-micron sections of the rectal biopsy tissue were mounted on gelatinized slides, covered with anti-AA serum and incubated at 37°C for 20 minutes. The sections were washed three times and overlaid with fluorescinated goat anti-rabbit IgG. The sections were washed three more times, mounted and examined under a fluorescent microscope. Additional control preparations were covered with normal rabbit serum and antiserum to IgG, IgM, IgA, and C3. These indirect immunofluorescent studies showed intense uptake of the anti-AA antibody localized in the subintima and media of blood vessels infiltrated with amyloid (Figure 2). The remaining sections were negative. Discussion. Despite the prevalence of gout in the United States (0.2-1.5%) (4), its association with amyloidosis is rare. Two of the 3 patients reviewed by Talbott and Terplan (2), as well as 2 of the 4 additional patients described by Talbott (4), had tuberculosis and chronically infected sinuses from urate tophi, suggesting their causal relationship to production of amyloid in these cases. The rare occurrence of amyloidosis in patients with polyarticular gout in contrast to a 6 1 6 % incidence found in rheumatoid arthritis ( 5 ) deserves comment. Differences in the inflammatory response and amyloidogenic stimulus are probably responsible for this discrepancy. Although chemotaxis and inflammation are intense during acute attacks of gout, this activity is usually self-limited, of short duration, and not maintained during the intercritical periods between attacks. In contrast, chronic inflammation occurring in

Figure 1. Rectal biopsy tissue showing amyloid deposition in the media of blood vessel walls (Congo red stain, x450).

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Figure 2. Immunofluorescent stain with anti-AA antiserum of rectal biopsy tissue demonstrating dense fluorescence in the media and subintima of a blood vessel (~860).

rheumatoid arthritk results in the persistent elevation of acute phase reattants, including SAA, the putative serum precursor of AA protein amyloid fibrils (6). However, heterogeneity of human SAA proteins (7) suggests that possibly not all species of SAA are precursors of amyloid A protein, and consequently only certain individuals with persistently high SAA levels would be prone to develop amyloid. The association of gout and amyloidosis in our patient probably reflects the rare combination of frequent attacks of polyarticular gout causing prolonged elevations of SAA and a possible predisposition to convert the SAA into the beta-pleated sheet conformation of amyloid fibrils. The rare association of amyloidosis and gout in our patient could be considered fortuitous without the biochemical characterization of the amyloid fibril. However, the absence of a serum M-component, free lambda or kappa light chains in the serum or urine, and plasma cell proliferation in the bone marrow do not support a diagnosis of amyloidosis associated with a plasma cell dyscrasia. Furthermore, the demonstration by indirect immunofluorescence of AA protein in the amyloid-infiltrated blood vessels by use of monospecific antiserum provides striking evidence for a reactive systemic amyloidosis (7). Using an identical method, Benson et a1 (8) found similar deposits in the kidney transplant of a patient with amyloidosis associated with familial Mediterranean fever. It is generally accepted that treatment of the underlying disease slows the progression of amyloidosis associated with chronic inflammatory or infec-

BRIEF REPORTS

tious diseases (1). In this context, it is noteworthy that, following colchicine administration, our patient’s attacks of polyarticular gout ceased, and an improvement in renal function and a restoration of serum albumin to normal values were observed. Colchicine inhibits amyloid formation in the casein-mouse model (9,lO) and may have therapeutic effect in patients with generalized amyloidosis (1 1). Conceivably, the infrequent association of gout and amyloidosis may be related in part to the time-honored use of colchicine for preventing acute attacks of gout. Indeed, it is possible that the current trend of prescribing indomethacin or other nonsteroidal antiinflammatory drugs in the management of gouty patients could result in the emergence of more gout patients with amyloidosis.

REFERENCES I . Cohen AS: Amyloidosis. N Engl J Med 277:522-530, 574-583, 628-638, 1967 2. Talbott JH, Terplan KL: The kidney in gout. Medicine 39:405-462, 1960 3. Benson MD, Skinner M, Lian J , Cohen AS: “A” protein

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of amyloidosis: isolation of a cross-reacting component from serum by affinity chromatography. Arthritis Rheum 18:315-322, 1975 4. Talbott JH: Gout. Third edition. New York, Grune & Stratton, 1967 5. Cohen AS: Amyloidosis in association with rheumatoid arthritis. Med Clin of North Am 52:643-652, 1968 6 . Ilusby G, Natvig JB: A serum component related to nonimmunoglobulin amyloid protein AS, a possible precursor of the fibrils. J Clin Invest 53:1054-1061, 1974 7. Glenner GG: Amyloid deposits and amyloidosis: the beta-fibrilloses. N Engl J Med 302:1283-1292, 13331343, 1980 8. Benson MD, Skinner M, Cohen AS: Amyloid deposition in a renal transplant in familial Mediterranean fever. Ann Intern Med 87:31-34, 1977 9. Kedar I , Ravid M, Sohar E, Gafni J: Colchicine inhibition of casein induced amyloidosis in mice. Isr J Med Sci 10:787-789, 1974 10. Shirahama T, Cohen AS: Blockage of amyloid induction by colchicine in an animal model. J Exp Med 140: 11021107, 1974 1 1 . Ravid M, Robson M , Kedar I: Prolonged colchicine treatment in four patients with amyloidosis. Ann Intern Med 87568-570, 1977