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Erosive arthritis in monoclonal gammopathy of uncertain significanceReport of four cases.

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We report 4 case histories in which an erosive
arthritis was associated with the presence of a monodonaI gammopathy of uncertain significance. In all 4 cases,
the appearance of paraprotein was noted either before
or during the development of the arthritis. Two patients
had a rather atypical oligoarthritis, while the others had
a rheumatoid-like, symmetric polyarthritis. A synovial
amyloid deposit was present in 2 patients, while mild
mixed mononuclear infiltrates were the main pathologic
finding in the others. In 2 patients, immunohistochemical investigation demonstrated deposits of immunoglobulin-derived material of the same isotype as the monoclonal component in the synovial tissue.
The association of paraproteinemias and arthritis has been widely reported in the literature. In
particular, the development of chronic arthritis is not a
rare event during the course of multiple myeloma ( I ) ,
and has occasionally been noticed in Waldenstrom’s
macroglobulinemia (2) and in primary amyloidosis (3).
Amyloid deposition in the synovial tissue is regarded
as the most important mechanism underlying the deFrom the Clinical Immunology Unit, Istituto di Patologia
Medica I, University of Pisa, and the Histopathology Service,
Hospital of Pisa, Pisa, Italy.
Supported by grants from A.R. Med., Pisa, and the Ministen, delta Pubblica Isuuzione, Rome, Italy.
Claudio Vitali, MD: Investigator in Clinical Immunology/
Rheumatology; Paolo Baglioni: Assistant in Histopathology; 110
Vivaldi, M D Fellow in Rheumatology; Roberta Cacialli, MD:
Fellow in Rheumatology; Antonio Tavoni, MD, PhD: Investigator in
Clinical Immunology/Rheumatology; Stefan0 Bombardieri, MD:
Associate Professor of Clinical Immunology.
Address reprint requests to Claudio Vitali, MD, Clinical
Immunology Unit, Istituto di Patologia Medica I, via Roma 67,
56100 Pisa, Italy.
Submitted for publication December 11, 1989; accepted in
revised form July 10, 1991.
Arthritis and Rheumatism, Vol. 34, No. 12 (December 1991)
velopment of these articular features in the different
paraproteinemias (4). The appearance of either monoclonal gammopathy or different types of plasma cell
dyscrasias has also been reported in patients with
rheumatoid arthritis (5) and Sjogren’s syndrome (6),
such manifestations being commonly ascribed to
chronic B cell activation or to the reduced immunologic surveillance in these diseases (5,6).
We report here 4 cases in which a chronic
erosive arthritis appeared together with or after the
serologic finding of a monoclonal gammopathy of
uncertain significance. In none of these patients was
clear evidence of a malignant plasma cell dyscrasia
demonstrated during the followup.
Case reports. Patient 1 . Patient 1 was a 76-yearold man with arthritis of 2 years’ duration, which
involved the third and fourth proximal interphalangeal
(PIP) joints of both hands. On physical examination,
these joints appeared swollen and tender. Radiographic examination revealed erosive changes at these
articular sites (Figure 1). There were no other localizations of the arthritis, nor were there any rheumatoid
nodules, liver or spleen enlargement, or sicca syndrome features. Laboratory investigations showed an
erythrocyte sedimentation rate (ESR; Westergren) of
43 mmhour, but normal C-reactive protein (CRP)
levels and red blood cell (RBC) and white blood cell
(WBC)counts. Serum rheumatoid factor (RF), antitype I1 collagen antibodies (by enzyme-linked immunosorbent assay, according to a slightly modified
version of the technique described by Mottonen et a1
[7]), an tinuclear anti bodies (ANA), anti-ex tractable
nuclear antigen antibodies, and cryoglobulins were
absent. Serum protein electrophoresis and postelectrophoretic immunofixation revealed a slight in-
Figure 1. Radiograph of the hands of patient I , taken in 1987,
showing erosive changes of the third and fourth proximal interphalangeal (PIP) joints of the left hand and the fourth PIPjoint of the
right hand.
crease in gamma globulins (1.8 gm/dl) with the presence
of a monoclonal IgMA paraprotein. Immunoglobulin
levels were 626 mg/dl for IgG, 116 mgldl for IgA, and
1,990 mg/dl for IgM. The C3 fraction was normal,
whereas C4 was slightly reduced (10.5 mgldl). BenceJones proteins were not detected in the urine.
Bone marrow biopsy did not disclose any signs
of plasma cell proliferation, and no skeletal abnormalities were detected on total body scintiscan, using a
gamma camera with wmTc-pertechnetate as tracer.
Synovial biopsy of the third PIP joint of the left hand
revealed the presence of amyloid material on Congo
red staining, together with a few scattered lymphocytes and plasma cells and some polymorphonuclear
cells. The patient was treated with nonsteroidal antiinflammatory drugs (NSAIDs), which produced some
symptom improvement. Two years after the first observation, the patient was well, and the disease state
was not substantially changed, except for a mild
progression of the arthritis in the same joints.
Patient 2. This patient, a 54-year-old man with
a history of myocardial infarction, began to experience
pain and swelling, first in the metatarsophalangeal
(MTP) joints and then in the metacarpophalangeal
(MCP) joints, PIP joints, and the wrists of both hands
in a symmetric distribution. Routine laboratory investigations performed at the onset of the symptoms
revealed an increased ESR (130 m d h o u r ) , positive
CRP, and a large increase in gamma globulins (4.5
gm/dl). The patient was hospitalized, and further serologic studies confirmed the presence of hypergammaglobulinemia with a monoclonal component (IgGK).
Immunoglobulin levels were 3,784 mg/dl for IgG, 48
mg/dl for IgA, and 44 mg/dl for IgM. Results of a bone
marrow biopsy were normal, except for a slight increase in the plasma cell number.
The patient was treated with melphalan (5 mgl
day, for 1 week each month), but this treatment was
stopped after 5 months because of severe anemia. In
the following years, the patient’s symptoms were
successfully treated with 4-6 rng of 6-methylprednisolone daily plus indomethacin.
Four years after the first observation, the patient was again hospitalized. On physical examination,
a symmetric, deforming, rheumatoid-like arthritis involving the MCP and PIP joints, wrists, ankles, and
feet was observed. No rheumatoid nodules, spleen or
liver enlargement, or sicca syndrome features were
present. The ESR was 21 mm/hour; CRP, RF, and
ANA were persistently negative. Serum complement,
urine and serum calcium, RBC and WBC counts, and
plasma viscosity values were all within normal limits.
Serum protein electrophoresis and immunoelectrophoresis confirmed the presence of an IgGK monoclonal peak. The IgG level was 1,984 mg/dl, with slightly
reduced IgA and IgM levels.
Bone marrow biopsy showed no abnormality in
the plasma cell number o r features. Both the radiographic skeletal survey and 99mTc-pertechnetatescintigraphy were negative for the presence of myelomalike lesions. Hand and foot radiographs showed
erosive changes of the PIP and MTP joints, resembling
those of rheumatoid arthritis. A synovial biopsy of the
third PIP joint (left hand) revealed only a mild inflammatory mononuclear infiltrate, consisting of lymphocytes and a few plasma cells. No amyloid deposits
were observed in the synovial tissue. The patient was
maintained on a regimen of steroids and NSAIDs and
was followed up for 2 years more without any significant change in the disease course.
Patient 3. Patient 3 , a 64-year-old man, was
referred t o our Rheumatic Disease Unit in May 1979,
because of symmetric arthritis involving the wrists,
MCP, distal interphalangeal (DIP), and PIP joints,
knees, and MTP joints bilaterally. The disease had
begun 8 months before with a monarthritis, which
affected the left knee. A synovial biopsy at this site
had disclosed the presence of mononuclear infiltrates,
while routine laboratory investigations had revealed a
hypergammaglobulinemia (35%), with a monoclonal
peak (IgGK). The clinical and laboratory investigations
performed at the time of the first observation confirmed the presence of this monoclonal gammopathy.
The ESR was 120 mm/hour, CRP was positive, the
WBC count was slightly reduced (3,000/mm3), and the
IgC level was increased (2,340 mg/dl). The RBC and
platelet counts, blood urea nitrogen and creatinine
levels, urinalysis, urinary Bence-Jones protein, serum
transaminases, alkaline phosphatase, amylase, calcium, and findings of the ANA, RF, and cryoglobulin
studies were all within normal limits.
A bone marrow biopsy and a radiographic skeletal survey showed no abnormality that would suggest
the diagnosis of multiple myeloma. No erosive
changes were identified on hand and foot radiographs.
Treatment with 6-methylprednisolone (6 mg/day) plus
indomethacin (100-1 50 mglday) was begun and continued for the following months.
One year later, the patient was again examined.
His clinical manifestations were practically unchanged. A synovial biopsy at the second DIP joint of
the right hand showed the persistence of mononuclear
infiltrates, together with a few scattered polymorphonuclear cells. Congo red staining revealed the presence of amyloid deposits. In February 1981, the patient was again hospitalized because of a flare of his
arthritis. He also described pain and stiffness in his
cervical spine. On physical examination, the liver and
spleen, but not the lymph nodes, were slightly enlarged. Radiographic skeletal survey revealed large
erosive changes in the wrists, feet, and hands (Figure
2), but no abnormalities suggestive of multiple myeloma. A bone marrow biopsy was again performed,
but no changes in the plasma cell number or appearance were observed. The laboratory evaluation, however, confirmed the presence of a monoclonal gammopathy (gamma globulins 30%, with an 1gGK
monoclonal peak, and increased IgG levels, but normal IgA and IgM values). The ESR was 119 mm/hour
and the CRP was positive. Other routine laboratory
investigations, including complement, RF, ANA, and
anti-type I1 collagen antibodies, showed persistently
negative results.
During the following 3 years, the patient was
treated continuously with steroids and NSAIDs, and
for a short period of time in 1984, he took cyclophosphamide (100 mglday). The patient’s articular symptoms and clinical and radiologic features remained
practically unchanged. A worsening of pain on motion
of the cervical spine necessitated the use of a cervical
Figure 2. Radiograph of the hands of patient 3, showing erosive
articular lesions in the carpal bones and in the second distal
interphalangeal joints symmetrically.
collar. At that time, mild arterial hypertension and
electrocardiographic evidence of ischemic changes,
with isolated ventricular beats, were first observed. In
late 1984, the patient died suddenly of cardiac failure.
Patient 4. This patient was a 65-year-old
woman who was first hospitalized in our Rheumatic
Disease Unit in October 1988, because of a 2-year
history of arthritis involving the PIP joint of the second
finger of both hands. A previous serum protein electrophoresis study had shown the presence of an apparently isolated monoclonal component in the gamma
globulin region. Laboratory investigations disclosed a
raised ESR (62 m d h o u r ) and the presence of hypergammaglobulinemia; immunoelectrophoresis revealed
an IgGA monoclonal peak. The IgG level was 3,900
mg/dl, with a slight reduction in the IgM and IgA
fractions. All other laboratory data, including CRP,
RF, complement levels, ANA, and anti-type I1 collagen antibodies, were normal. Hand films showed soft
tissue swelling and erosive changes at the second PIP
joint of the right hand (Figure 3).
A synovial biopsy was performed at this site,
and revealed the presence of synovial hyperplasia and
inflammatory infiltrates made up of lymphocytes, a
few plasma cells, and polymorphonuclear cells. No
amyloid deposits were observed after staining with
Congo red. Both the radiographic skeletal survey and
the bone scintigraphy were negative for the presence
of myeloma-like lesions. Bone marrow examination
Figure 3. Radiograph of the right second proximal interphalangeal
joint of patient 4, showing an erosive arthritis.
did not reveal any plasma cell abnormality that might
have suggested a proliferative plasma cell disorder.
The patient was treated with NSAIDs and has been
followed up until the present as an outpatient. After 1
year, her clinical, serologic, and radiologic profile
remains practically unchanged.
Methods. Immunohistochemical study. Immunohistochemical studies were retrospectively carried
out on synovial biopsy material from patients 1 and 4,
who had sufficient synovial tissue remaining after the
routine histologic studies had been performed. To
identify and characterize the deposits of amyloid or
other immunoglobulin-related materials, sections of
these synovial tissues were analyzed by immunocytochemical procedures using different commercially
available antisera (Dakopatts, Copenhagen, Denmark)
with avidin-biotin complexes. Antisera against the
following antigens were used: K and A light chains,
amyloid A component, and p,-microglobulin (&m).
The staining intensity was graded 0-3 by a blinded
observer, as follows: 0 = absent, 1 = weak, 2 =
moderate, 3 = strong. While there was no staining of
either biopsy sample when tested with antisera against
amyloid A component and &m, grade 3 staining was
observed in both patients’ synovial tissue sections
when the anti-A antiserum was used. Grade 1 staining
was seen with the antisera against the K light chains.
This material was distributed as microdeposits in the
collagen matrix of the synovial tissue.
Discussion. We have presented 4 cases in which
a monoclonal gammopathy of uncertain significance
accompanied or preceded the appearance of an erosive
arthritis. Although other diagnoses could not at first be
excluded, it seems likely that these two features were
closely related. Patients 1 and 4 had a rather atypical
disease: an erosive oligoarthritis without clinical or
serologic signs of inflammation. In these 2 cases, the
diagnosis of rheumatoid arthritis could be excluded
with certainty, and psoriatic arthritis and other types
of seronegative arthritides could be also ruled out
based on the patient’s history and clinical course.
Patients 2 and 3, however, had symmetric arthritis that was similar to rheumatoid arthritis, but a
diagnosis of rheumatoid arthritis could not be confirmed based on their clinical and epidemiologic features. The absence of rheumatoid factor in both patients, the negative CRP in patient 2, and the
involvement of the DIP joints in patient 3 (which is
considered to be exceptional in rheumatoid disease),
rule out the possible diagnosis of rheumatoid arthritis
(8). This diagnosis seems even more unlikely considering the temporal relationship between the development of the arthritis and the appearance of paraprotein. Although the association of rheumatoid arthritis
with monoclonal gammopathy has been reported (9),
the arthritis in all the previously described cases,
including asymptomatic monoclonal gammopathy and
well-defined multiple myeloma or Waldenstrom’s
macroglobulinemia, antedated the appearance of the
paraprotein by no less than 10 years. In addition,
almost all of the rheumatoid arthritis patients had the
classic form, characterized by the presence of rheumatoid nodules, serum RF, and a clear-cut chronic
inflammatory process in multiple articular sites.
In view of these considerations, it seems more
likely that the development of the erosive arthritis in
our 4 patients was directly linked to the production of
paraprotein. The considerable medical literature concerning the development of an erosive arthritis during
the course of such paraproteinemias as multiple my-
elomas, Waldenstrom’s macroglobulinemia, and primary amyloidosis seems to support this hypothesis
Our findings of an association between similar
articular manifestations and monoclonal gammopathy
of uncertain significance extends this concept to the
entire spectrum of paraproteinemias. Indeed, in our
patients who were followed up for 3-6 years, a rather
long period of time, there were no clinical, radiologic,
or hematologic features indicative of a malignant
plasma cell proliferation. In this respect, our patients
are similar to those recently described by Hurst et al,
in which a seronegative atypical polyarthritis coexisted with a monoclonal gammopathy of uncertain
significance (1 1).
Different mechanisms for the association between paraproteinemias and arthritis have been suggested. Deposition of amyloid material in the synovial
tissue is the most frequently postulated, and certain
peculiar clinical aspects of the disease, such as the
noninflammatory nature of the joint involvement and
some specific findings in the synovial fluid, strongly
support this mechanism (4,lO). The fact that in 2 of the
4 cases described here amyloid material was not found
in the synovial biopsy sample does not rule out this
hypothesis. Indeed, this pathologic process was only
hypothesized in explanation of previously reported
cases, having been directly observed in only a few of
them (4,lO). It is worth noting, however, that articular
amyloidosis is not a feature specific for paraproteinemia-associated arthritis; it is also seen in patients
with completely unrelated conditions (12,131.
Histochemical studies of the synovial tissue
from patients 1 and 4 demonstrated local deposits of
immunoglobulin-derived material of the same light
chain isotype of serum paraprotein and allowed us to
exclude the possible presence of amyloid A and &m.
Since this was observed independently of the presence
of Congo red-stained material (which was observed in
patient 1 and not in patient 4), one may conclude that
this staining is probably due to the specific conformation of the immunoglobulin-derived deposits, which is
fibrillar in the case of amyloid substance (14). Therefore, its absence does not absolutely exclude the
possibility that monoclonal immunoglobulins or their
fractions may be deposited in the synovial tissue.
Whether this immunoglobulin-derived material is produced in situ or comes from outside the synovial tissue
remains uncertain. In fact, the mononuclear cells
found in the synovial biopsy samples from our patients
did not consist of monoclonal cells, but rather, of
different cell types and clones resembling c h r o n i c
inflammatory infiltrates. This finding seems t o s u p p o r t
the hypothesis that in these cases, there is local
precipitation of paraprotein or its fractions, with the
consequent activation of the inflammatory reaction (15).
The present study, then, seems to demonstrate
that the development of an erosive arthritis in patients
with monoclonal gammopathy does not depend on the
type or grade of malignancy of the underlying plasma
cell dyscrasia. In addition, in all these conditions, the
deposition of a paraprotein-derived material in the
synovium (which may or may not possess the characteristics of amyloid), together with the consequent
activation of a nonspecific inflammatory response, are
the pathologic mechanisms potentially responsible for
the arthritic process.
Acknowledgments. We are grateful to our colleagues,
Dr. Paola Migliorini and Dr. Lucrezia Riente, who performed the assays for the detection of antibodies to type I1
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