systemic al amyloidosis mimicking rheumatoid arthritis

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□ CASE REPORT □

Systemic AL Amyloidosis Mimicking Rheumatoid Arthritis

Nagaaki Katoh, Ko-ichi Tazawa, Wataru Ishii, Masayuki Matsuda and Shu-ichi Ikeda

Abstract

We report a patient with myeloma-associated systemic AL amyloidosis who showed chronic polyarthralgiaas the main symptom. The clinical picture was similar to that of rheumatoid arthritis with regard to symmet-rical swelling with tenderness in multiple joints, but inflammatory reactions were almost normal and autoanti-bodies were negative. He was diagnosed as having systemic AL amyloidosis based on deposition of κ-lightchain-immunoreactive amyloid in biopsied tissue and Bence Jones protein in serum and urine. Magnetic reso-nance imaging and bone scintigraphy suggested this disease as the cause of the polyarthralgia. Systemic ALamyloidosis may be important in the differential diagnosis of chronic polyarthralgia.

Key words: bone scintigraphy, magnetic resonance imaging, polyarthralgia, systemic AL amyloidosis

(Inter Med 47: 1133-1138, 2008)(DOI: 10.2169/internalmedicine.47.0961)

Introduction

Systemic AL amyloidosis is an intractable disorder char-acterized pathologically by deposition of insoluble fibrils de-rived from immunoglobulin light chains and clinically bydysfunction of multiple organs, particularly the heart andkidneys (1). This disease complicates multiple myeloma at afrequency of 6-15% (2). In this case report we describe apatient with myeloma-associated systemic AL amyloidosiswho showed symmetrical swelling with tenderness in multi-ple joints as the main symptom. Polyarthropathy due toamyloid deposition occurs often in β2-microgloblin-derivedamyloidosis but it is uncommon in AL amyloidosis (3-8).According to a cohort study in a large set of patients withmultiple myeloma, amyloid arthropathy develops at a fre-quency of 3.5% (6). The clinical picture of the present pa-tient was similar to that of rheumatoid arthritis (RA) exceptfor negative results of autoantibodies and almost normal lev-els of inflammatory reactions, and we suggest that systemicAL amyloidosis may be important in the differential diagno-sis of chronic polyarthralgia.

Case Report

A 64-year-old man with no chronic disease or significantfamily history gradually developed pain on motion and

swelling in the right hand with no precipitating cause. Thesesymptoms soon extended to the other hand and subsequentlyto the joints of the lower extremities, such as knees and an-kles, within 3 months after onset. He became unable to raiseboth arms because of pain on motion in the shoulders, andhis activity of daily living deteriorated quickly. Five monthslater he noticed numbness and a decrease in grasping powerin both hands, and was successfully treated with surgicaltherapy on a diagnosis of bilateral carpal tunnel syndrome(CTS) in a neighboring hospital. Neither C-reactive protein(CRP) nor rheumatoid factor (RF) was positive in serum.Pain and swelling in systemic joints persisted, and he wasadmitted to our hospital 9 months after the onset of disease.On admission, he was in an almost bedridden state withsevere appetite loss and marked emaciation. Physical exami-nation showed symmetrical swelling with tenderness in mul-tiple joints of extremities, particularly in knees, shoulders,wrists and metacarpo-phalangeal (MCP) and proximal inter-phalangeal (PIP) joints (Figs. 1A, 1B). He complained ofdifficulty in walking and severe pain on passive movementwith limited range of motion in all fingers. His grip strengthwas less than 1 kg on both sides. There were no abnormalfindings in his chest or abdomen suggestive of involvementof visceral organs. Dysarthria and dysphagia ascribable tomacroglossia were present (Fig. 1C), and other neurologicalfindings were normal except for orthostatic hypotension anddisuse muscle atrophy in the extremities. Routine laboratory

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, MatsumotoReceived for publication January 29, 2008; Accepted for publication March 25, 2008Correspondence to Dr. Masayuki Matsuda, [email protected]

Inter Med 47: 1133-1138, 2008 DOI: 10.2169/internalmedicine.47.0961

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Figure 1. Photographs of the patient, showing swollen hands (A), symmetrical swelling of both shoulders, the so-called ‘shoulder-pad sign’ (B), and macroglossia (C) with teeth indentation (arrows).

tests demonstrated slight anemia (hemoglobin 10.9 g/dl, nor-mal 12.9-17.4 g/dl) with hypoalbuminemia (albumin 3.6 g/dl, normal 4.2-5.1 g/dl), but hepatobiliary enzymes and renalindices in serum were within normal limits. CRP was almostnormal (0.15 mg/dl, normal <0.1 mg/dl), and autoantibodies,including RF, the anti-cyclic citrullinated peptide (CCP) an-tibody, anti-nuclear antibody, and anti-neutrophil cytoplas-mic antibody, were all negative. Serum immunoglobulinshowed a slight decrease in IgA (48 mg/dl, normal 110-410mg/dl) and IgM (14 mg/dl, normal 35-220 mg/dl) with nor-mal levels of IgG (993 mg/dl, normal 870-1,700 mg/dl),IgD (0.4 mg/dl, normal <9.0 mg/dl) and IgE (108 IU/ml,normal <361 IU/ml). No significant proteinuria was seen inurinalysis. There were no abnormal findings in either chestX-ray or electro- and echocardiogram. Despite the lack of amonoclonal peak on protein electrophoresis, immunofixationdemonstrated κ-type Bence Jones protein (BJP) in both se-

rum and urine, and plasma cells with abnormal morphologywere increased in smear specimens of the bone marrow(11% of total nucleated cells, normal 0.5-3.9%). Histopa-thology of the gastroduodenal mucosa and abdominal fat tis-sue showed massive deposition of ALκ-immunoreactiveamyloid (Fig. 2). X-ray examinations revealed multipleirregular-shaped hyperlucencies in the proximal epiphysis ofbilateral humeri (Fig. 3A) and carpal bones (Fig. 4A), whichcoincided with low-intensity signals on both T1- and T2-weighted images of magnetic resonance imaging (MRI)(Figs. 3B, 3C，Figs. 4B, 4C). Synovial tissues aroundflexor muscles at the wrist showed high-intensity signals onthe T2-weighted image (Fig. 4C). Bone scintigraphy usingtechnetium-99m methylene diphosphonate (99mTc-MDP)demonstrated clear uptake in swollen and tender joints(Fig. 5). Gallium scintigraphy was negative.The patient received two courses of VAD (vincristine 0.4mg/day and doxorubicin 9 mg/m2/day by continuous infu-sion on days 1-4, and dexamethasone 40 mg/day by infusionon days 1-4, 9-12 and 17-20; all were repeated four weekslater) followed by oral hydrocortisone at a dose of 20 mg/day. His activity of daily living gradually improved in con-junction with a decrease in systemic arthralgia. M-proteinwas detectable in serum but not in urine. Bone marrow aspi-rates demonstrated a marked decrease in abnormal plasmacells. Further chemotherapy was not perfromed in this pa-tient because of combined infection with pneumocystis ji-roveci and aspergillus.

Discussion

The present patient was diagnosed as having systemic ALamyloidosis based on deposition of ALκ-immunoreactiveamyloid in the biopsied tissues as well as BJPκ-type M-protein in serum and urine. His macroglossia is a clinicalfinding characteristic of AL amyloidosis. Bilateral CTStreated 1 month prior to admission to our hospital can alsobe ascribed to this disease, although histopathological ex-amination of soft tissue obtained from the carpal tunnel wasnot performed. Systemic survey demonstrated no obvious in-volvement of vital organs such as the heart and kidneys. Ac-cording to the diagnostic criteria proposed by the Interna-tional Myeloma Working Group, multiple myeloma wasconsidered to underlie systemic AL amyloidosis in the pres-ent patient with regard to the presence of more than 10%plasma cells in the bone marrow (9).The most interesting point in this patient is that his pre-dominant symptom was systemic chronic polyarthralgia.There are three possible causes of the polyarthralgia in thepresent patient. The first is a complication of other disorderscausing chronic polyarthralgia, particularly RA. The clinicalpicture of the present patient resembled that of RA with re-spect to symmetrical swelling with tenderness in multiplejoints of extremities, including MCP and PIP joints, but se-rological markers, such as RF and the anti-CCP antibody,were negative. According to a recent report from Japan the


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Figure 2. Histopathology of the gastric mucosa taken at biopsy, showing severe deposition of Congo red-positive substances mainly in the submucosal area (A, Congo red staining, bar=100 μm). On immunohistochemistry these substances were positively stained with anti-ALκ antibody (B, bar=100 μm).

Figure 3. X-ray demonstrates multiple irregular-shaped hyperlucencies in the proximal epiphy-sis of the right humerus (A, arrowheads), which coincided with low-intensity signals on both T1- (B, arrowheads) and T2-weighted images (C, arrowheads) of magnetic resonance imaging. Amyloid deposits are seen also in the periarticular soft tissue (B and C, arrows).

diagnostic specificity and positive predictive value of theanti-CCP antibody were 94.9% and 87.8% for RA, respec-tively (10). Inflammatory reactions were also almost nega-tive in the present patient before and after admission to our

hospital. CRP should have shown a marked increase if ac-tive RA was the cause of such pain and swelling of multiplejoints as seen in the present patient. There were no symp-toms or signs suggestive of other associated collagen dis-


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Figure 4. X-ray demonstrates multiple irregular-shaped hyperlucencies in the right carpal bones (A, arrowheads), which coincided with low-intensity signals on both T1- (B, arrowheads) and T2-weighted images (C, arrowheads) of magnetic resonance imaging. Amyloid deposits with edema are seen also around the flexor muscles (B, C, arrows).

eases causing chronic polyarthralgia. The second possiblecause of polyarthralgia is multiple myeloma. It is wellknown that this disease can cause osteoarthralgia due to in-filtration of myeloma cells, particularly in the spine, but thepresent patient showed pain on motion in articular regionsalone. Bone marrow aspirates demonstrated no remarkableincrease of plasma cells, and 99mTc-MDP scintigraphyshowed obvious uptake localized to joints, suggesting thatmultiple myeloma was not the cause of the polyarthralgia inthe present patient.The third possible cause of polyarthralgia is AL amyloid-

osis itself. Among the amyloidoses, arthropathy preferen-tially occurs in the β2-microglobulin-derived one, whichcomplicates chronic renal failure with hemodialysis (3, 4).Amyloid deposition develops in the bone but also in thesynovial membrane, leading to polyarthralgia and swellingdue to destructive arthropathy (3, 4). This type of arthropa-thy can occur also in AL amyloidosis (5-7). The present pa-tient showed symmetrical swelling of both shoulders, the so-called ‘shoulder-pad sign’, and limited range of motion inmultiple joints from the early phase of illness, as is fre-quently seen in amyloid arthropathy due to AL amyloidosis(6, 11, 12). To detect amyloid deposition in joints, MRI andscintigraphy are useful (4, 13). In the present patient X-rayexaminations of bones demonstrated multiple hyperlucencies

in epiphyseal regions, which coincided with low-intensitysignals on both T1- and T2-weighted images of MRI. Multi-ple myeloma usually shows low- and high-intensity signalson T1- and T2-weighted images of MRI, respectively, whileamyloid deposition, including that in soft tissue, appears aslow-intensity signals on both these images, as seen in thepresent patient (4, 6, 14, 15). Bone erosion in RA shows thesame intensity pattern on MRI as in multiple myeloma (16,17). Diphosphonate has a high affinity to amyloid fibrils ir-respective of precursor proteins (12, 18, 19), and bone scin-tigraphy using 99mTc-MDP demonstrated obvious uptake inswollen joints. These radiographical findings suggest thatdeposition of amyloid in the bone and synovial membranemay have caused polyarthralgia and swelling of joints in thepresent patient. Soft tissues around flexor muscles at thewrist showed high-intensity signals on the T2-weighted im-age in the present patient, and inflammatory edema mayhave been concurrent with amyloid deposition (6). Synovialbiopsy is recommended in order to confirm deposition ofamyloid (4, 6, 11-13), but in the present patient we did notperform this examination because of his poor general status.Treatment of amyloid polyarthropathy in AL amyloidosishas not yet been established, but chemotherapy for multiplemyeloma should be effective with regard to reduction ofpathognomonic plasma cells producing precursor proteins of


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Figure 5. Bone scintigraphy using technetium-99m methy-lene diphosphonate demonstrates symmetrical uptake in swollen and tender joints (left: anterior view, right: posterior view).

amyloid. Because of the well-preserved function of vital or-gans, such as the heart and kidneys, we selected cyclic VADas a chemotherapeutic regimen in the present patient (20,21). Polyarthralgia quickly improved, probably in responseto the dexamethasone in VAD, but his poor general statuswith infection did not allow us to perform more than 2courses of this intensive chemotherapy. M-protein in urinedisappeared after VAD in conjunction with a marked de-crease in plasma cells in the bone marrow. Polyarthralgiahas been well controlled with oral hydrocortisone alone.In conclusion, systemic AL amyloidosis occasionallycauses arthralgia and swelling in multiple joints, which areindistinguishable from polyarthritis due to active RA. Whenserological markers of RA, such as RF and the anti-CCP an-tibody, are negative in patients with polyarthralgia, amyloidarthropathy might be a possible diagnosis, and an intensivesurvey, including histopathological examinations and detec-tion of M-protein, should be performed as early as possible.

AcknowledgementThe authors are grateful to Drs. Y. Hoshii and T. Ishihara, De-partment of Pathology, Yamaguchi University School of Medi-cine, for their help with immunohistochemical staining of the bi-opsy specimens. This work was supported by a grant from theIntractable Disease Division, the Ministry of Health and Welfare,Research Committee for Epochal Diagnosis and Treatment ofAmyloidosis in Japan.

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systemic al amyloidosis mimicking rheumatoid arthritis

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