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Polyarthritis with birefringent lipid within synovial fluid macrophagescase report and ultrastructural study.

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BRIEF REPORT
POLYARTHRITIS WITH BIREFRINGENT LIPID WITHIN
SYNOVIAL FLUID MACROPHAGES:
CASE REPORT AND ULTRASTRUCTURAL STUDY
PETER A. SCHLESINGER, M. THOMAS STILLMAN, and LoANN PETERSON
The presence of synovial fluid lipid has been
reported in a variety of disorders (1-4). We report here
a case of chronic polyarthritis associated with unusual
synovial fluid, characterized by macrophages with
prominent intracellular lipid in the form of birefringent
droplets.
Case report. The patient (RH) is a 14-year-old
white boy, who initially sought medical attention elsewhere for the development, over 2-3 months, of
anorexia, lethargy, night sweats, vague abdominal
discomfort, and weight loss. Examination reportedly
revealed only joint tenderness. Laboratory studies
revealed a white cell count (WBC) of 2,600/mm3,
erythrocyte sedimentation rate (ESR) of 6 mm/hour,
mild liver function abnormalities, and negative results
on monospot and hepatitis B surface antigen (HBsAg)
tests; a diagnosis of non-B viral hepatitis was made.
Although the liver functions returned toward normal,
the patient continued to lose weight and experienced
pain and symmetrical swelling of large and small
peripheral joints so that he curtailed his athletic activiFrom the Departments of Medicine (Rheumatology Division) and Laboratory Medicine, Hennepin County Medical Center
and the University of Minnesota Medical School, Minneapolis, MN.
Peter A. Schlesinger, MD: Medical Resident, Hennepin
County Medical Center and University of Minnesota Medical
School; M. Thomas Stillman, MD, FACP: Assistant Professor of
Medicine, Hennepin County Medical Center and University of
Minnesota Medical School; LoAnn Peterson, MD: Assistant Professor of Laboratory Medicine, Hennepin County Medical Center and
University of Minnesota Medical School .
Address reprint requests to M. Thomas Stillman, MD,
Director, Division of Rheumatology, Department of Medicine,
Hennepin County Medical Center, 701 Park Avenue South, Minneapolis, MN 55415.
Submitted for publication January 4, 1982; accepted in
revised form March 16, 1982.
Arthritis and Rheumatism, Vol. 25, No. 11 (November 1982)
ty. He experienced diffuse hair loss and a transient,
patchy erythema over his anterior chest.
After several months, the patient was referred
to the Rheumatology Section of Hennepin County
Medical Center for further evaluation. Upon referral,
no other pertinent history or symptoms were obtained.
Physical examination revealed the patient to be pale,
with a temperature of 38°C; pulse, 80; blood pressure,
116/80 m m Hg; height, 6 ft, 2 in; weight, 180 lbs
(compared with 240 lbs 5 months earlier). Skin abnormalities included erythematous scaly lesions overlying
the metacarpophalangeal joints and a dusky periorbital
erythema. Slight liver tenderness was noted without
hepatosplenomegaly . Joint examination revealed limited range of motion associated with symmetrical synovitis of the proximal interphalangeal, metacarpophalangeal, wrist, elbow, knee, ankle, and metatarsophalangeal
joints. Muscle strength was slightly reduced, but consistent with the patient’s chronic illness, and there was
no muscle tenderness. The results of the remainder of
the examination were normal.
The WBC was 3,100/mm3 with 45% neutrophils, 43% lymphocytes, 8% monocytes, and 4% eosinophils; the hemoglobin was 13.7 g d d l , the ESR 27
mm/hour, and the platelet count, 182,000/mm3. The
serum transaminases-serum
glutamic oxaloacetic
transaminase (SGOT) and serum glutamic pyruvic
transaminase-were elevated to twice normal. Results
of the following tests were normal or negative:
urinalysis; electrolytes; creatinine; creatine phosphokinase
(CPK); ald.olase; alkaline phosphatase; amylase; lipase; protein electrophoresis; ffuorescent antinuclear
antibody; rheumatoid factor; third and fourth cornPonents of Complement (c3, c4); HLA-B27; antibodies
to hepatitis A virus, HBsAg, rubeola, mumps, herpes,
-
BRIEF REPORTS
1366
A
B
Figure 1. A, Intracellular Maltese crosses under polarized light,
consistently oriented with respect to the axis of the red plate
compensator (arrow). (Unstained synovial fluid. Original magnification x 1,000.) B, Lipid-laden macrophages in synovial aspirate.
(Wright’s-Giemsa. Inclusions stained positively with oil red-0. Original magnification x 1,000.)
toxoplasma, and mycoplasma; and chest roentgenogram. Hand films showed only periarticular demineralization, without erosions or joint space narrowing, and
knee films were remarkable only for soft tissue swelling.
Aspiration of the right knee joint yielded 15 ml
of viscous, hazy, yellow fluid. The WBC was 5,900/
mm3 with 100% lipid-containing macrophages (see
Special studies); the red cell count was 1,350/mm3.
Other synovial fluid values were as follows: glucose,
40 mg/dl (serum glucose, 90 mg/dl); protein, 3.66 g d d l
(serum protein, 7.2 mg/dl); negative results on a test
for rheumatoid factor; negative Gram stain and culture
results; C3, 35 mg/dl, C4, 22 mg/dl (respective serum
values of 154 and 30); cholesterol, 45 mg/dl, triglycerides, 18 mg/dl (respective serum values of 112 and 70).
The patient was initially treated with salicylates, and his arthritis and strength improved. However, his SGOT rose to 10 times normal while the CPK
remained normal; a leukopenia of 2,400/mm3 persisted. A percutaneous liver biopsy revealed fatty metamorphosis with minimal inflammation, consistent with
a response to systemic illness. Bone marrow biopsy
material and aspirate were normal. No lipid-laden
macrophages were noted in the peripheral blood, liver,
or bone marrow. A biopsy of involved skin revealed a
mild perivasculitis composed of chronic inflammatory
cells. A synovial biopsy was obtained (see Special
studies). Results of electromyography were normal.
Therapy was changed from aspirin to tolmetin
sodium with continued symptomatic relief and with
normalization of liver function. Repeat arthrocentesis
of both knees I and 2 months later revealed synovial
fluid WBC of 100,000/mm3 and 26,900/mm3, respectively, consistently showing 100% macrophages with
lipid inclusions. Knee examinations at those times
were notable for synovitis qualitatively similar to that
in other joints. The synovitis regressed over several
months, but remained minimally active; the patient
regained 20 pounds. Tests for rheumatoid factor remained negative, and the peripheral WBC rose to
5 ,800/mm3.
Special studies. Virtually all of the cells in the
synovial fluid were macrophages that contained multiple, round, refractile inclusions throughout the cytoplasm. The inclusions appeared as Maltese crosses
under polarized light. Under compensated polarized
light, these crosses had a consistent orientation that
we termed “positive birefringence” (Figure 1A). The
inclusions did not stain with Wright’s-Giemsa (Figure
lB), but did stain with oil red-0 (9,Sudan black (6),
and occasionally with periodic acid-Schiff (5). The
cytoplasm surrounding the inclusions was strongly
positive for nonspecific esterase; this reaction was
completely inhibited when fluoride was included in the
reaction mixture (7). Occasional cells were positive for
myeloperoxidase (8). All cells were strongly positive
for acid phosphatase (9). No extracellular lipid was
present. Ultrastructural examination of the synovial
fluid showed macrophages containing numerous
round, homogeneous, slightly electron-dense cytoplasmic inclusions that were not usually membrane
bound. The cytoplasm of 1 cell contained a tubuloreticular structure consisting of irregularly anastomosing
tubules (Figure 2).
Examination of the synovial biopsy material by
both light and electron microscopy revealed edema-
BRIEF REPORTS
1367
Figure 2. Synovial fluid macrophage with lipid inclusions on right and tubuloreticular inclusion on left (arrow). (Original
magnification x 6,500.)
tous synovial tissue denuded of synovial cells, with
fibrin deposition on the surface. Scattered chronic
inflammatory cells and scattered lipid-laden macrophages were present subjacent to the synovial surface.
There were heavy perivascular infiltrates of lymphocytes and occasional plasma cells. One focus of vasculitis, involving a small arteriole, was noted; it was
characterized by transmural inflammation that merged
with the perivascular infiltrate and obliterated the
vessel wall.
Discussion. We have described an unusual constellation of findings in a case of chronic polyarthritis
with severe systemic manifestations. Cytochemical
stains demonstrated the monocytehacrophage origin
of the synovial fluid cells and the lipid nature of the
cytoplasmic inclusions. Ultrastructural examinations
supported these findings, and revealed tubuloreticular
inclusions, which have been reported in a number of
disorders, primarily those with an immunologic basis
(10). These cells differed from previously described
“RA cells” (1 l), which are polymorphonuclear leukocytes with dark inclusions by light microscopy.
Increased synovial fluid lipid, both intracellular
and extracellular, has been noted in a number of
conditions , including trauma, aseptic necrosis, and
lymphatic obstruction (1-4). Weinstein described a
case of acute monarticular arthritis with occasional
anisotropic lipid bodies within synovial leukocytes (2).
The source of lipid, however, was not always apparent. Studies of chylous effusions in the setting of
underlying rheumatoid arthritis or systemic lupus erythematosus have demonstrated that local lipid biosynthesis can occur (3,4). In vitro data suggest that
leukocytes synthesize lipid, possibly for utilization
during phagocytosis (12). That the inclusions in this
case were usually not membrane bound may imply
their de novo synthesis. The lipid may also represent
products of tissue destruction or it may be the result of
altered transport across the inflamed synovial membrane .
The nature of this patient’s underlying illness is
uncertain. His clinical course to date most closely
resembles rheumatoid arthritis initially complicated by
hepatic dysfunction, possibly secondary to rapid
BRIEF REPORTS
weight loss, salicylate toxicity, or both. The chronicity, the pattern of joint involvement, and the symptomatic response to nonsteroidal antiinflammatory agents
are consistent with rheumatoid arthritis. Studies during the first month of synovitis in patients eventually
diagnosed as having rheumatoid arthritis show a predominance of mononuclear cells, both lymphocytes
and monocytes/macrophages, in the fluid, as well as
the presence of a nonnecrotizing vasculitis involving
small-caliber synovial vessels (13). The protracted
course of the distinctive synovial fluid findings in this
case was therefore highly unusual.
Certain features of this patient’s illness, namely
the rash and weakness, suggested an overlap component of dermatomyositis. In light of the clinical and
laboratory findings, however, myositis was not
thought to be present. A differential diagnosis of this
illness includes several other entities, none of which
adequately explains all features. No infectious agent
has been demonstrated. Multicentric reticulohistiocytosis, a rare disease with mucocutaneous and joint
manifestations and with mononuclear cell inclusions,
seems unlikely in the absence of typical cutaneous and
histologic changes (14). Several cases of acute monocytic arthritis have been reported ( 1 9 , characterized
by fever, rash, and polyarthritis with a nonnecrotizing
vasculitis of the skin and synovium. These cases were
generally self-limited, however. They resembled viral
arthritides and were considered a possible subset of
acute hypersensitivity angiitis.
This case of chronic polyarticular monocytic
arthritis may therefore represent a response to a
chronic, as yet unidentified, stimulus; or it may be a
nonspecific phenomenon seen early in the course of
inflammation in previously recognized disorders such
as rheumatoid arthritis.
Acknowledgments. The authors wish to thank
Drs. Thomas J. Bloss, David Zoschke, Patrick C.J.
Ward, and Thomas W. Bunch for valuable discussions, and Miss Kathleen Hein for secretarial assistance.
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