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Progressive joint destruction in a human immunodeficiency virus-infected patient with rheumatoid arthritis.

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ARTHRITIS & RHEUMATISM
Vol. 38, No. 9, September 1995, pp 1328-1332
0 1995, American College of Rheumatology
1328
PROGRESSIVE JOINT DESTRUCTION IN
A HUMAN IMMUNODEFICIENCY VIRUS-INFECTED PATIENT
WITH RHEUMATOID ARTHRITIS
ULF MULLER-LADNER, JORG KRIEGSMANN, RENATE E. GAY, WILLIAM J. KOOPMAN,
STEFFEN GAY, and W. WINN CHATHAM
This article reports the case of a 63-year-old
patient with rheumatoid arthritis (RA) whose symptoms
of RA improved after the occurrence of a secondary
human immunodeficiency virus (HIV) infection; however, the HIV infection did not affect the histologic
parameters of joint destruction to the same extent as it
did the clinical symptoms. Histologic and immunohistologic joint examinations of this patient revealed an
ongoing production of cartilage- and bone-degrading
enzymes by macrophages and fibroblasts, without the
presence of T cells. These findings demonstrate that
progressive joint destruction in RA can occur in the
absence of T cells. Moreover, our results support the
hypothesis that both T cell-dependent and T cellindependent pathways play a significant role in the
pathogenesis of RA.
During the last decade, a variety of rheumatic
symptoms and diseases in coexistence with human
immunodeficiency virus (HIV) infection have been
reported ( 1 4 ) . These reports have emphasized the
clinical occurrence of rheumatic symptoms in HIV
Supported by a grant of the German Academic Exchange
Service (DAAD).
Ulf Muller-Ladner, MD, Jorg Kriegsmann, MD, PhD,
Renate E. Gay, MD, William J. Koopman, MD, Steffen Gay, MD:
The University of Alabama at Birmingham; W. Winn Chatham, MD:
The University of Alabama at Birmingham and Department of
Veterans Affairs, Birmingham, Alabama.
Address reprint requests to Ulf Miiller-Ladner, MD, The
University of Alabama at Birmingham, Division of Clinical Immunology and Rheumatology, 1900 University Blvd., THT 433, Birmingham, AL 35294-0006.
Submitted for publication December 6, 1994; accepted in
revised form April 8, 1995.
patients, but case reports describing the clinical and
histologic course of rheumatoid arthritis (RA) followed
by a secondary HIV infection are rare. Reports of
patients with RA and subsequent HIV infection have
described frequent remission of the RA symptoms, an
effect attributed to the depletion of CD4+ T lymphocytes during HIV infection (5-8). However, a more
recent report has described continuing synovitis and
ongoingjoint destruction in a patient with RA who also
had acquired immunodeficiency syndrome (AIDS) (9),
which raises questions about the role of T cells in RA.
Because the main alteration of the immune
system caused by an HIV infection is the depletion of
CD4-t T lymphocytes, this provides insights concerning the disease mechanisms believed to be dependent
on T cells. There is growing evidence that T cellindependent pathways play a major, perhaps dominant, role in established RA (10,ll). In this report, we
review the synovial pathologic findings in a patient
with long-term RA and secondary HIV infection.
CASE REPORT
The patient was a 63-year-old man who, in 1979
at age 49, began to develop the typical signs and
symptoms of RA. At that time, articular symptoms
were predominant in both wrists, the metacarpophalangeal (MCP) and proximal interphalangeal (PIP)
joints of both hands, and the metatarsophalangeal
joints of both feet. These clinical symptoms were
associated with radiologic signs of early RA in the
affected joints, as well as the presence of rheumatoid
factor (titer 1:320). At the time of diagnosis, the patient
fulfilled 6 of 7 American College of Rheumatology
1329
JOINT DESTRUCTION IN AN HIV PATIENT WITH RA
(formerly, the American Rheumatism Association) criteria for RA (12). Symptoms responded favorably to
treatment with nonsteroidal antiinflammatory drugs
(NSAIDs) and parenteral gold salts. In 1983, at the age
of 53, the patient underwent a subtotal gastrectomy for
complications related to recurrent NSAID-related
peptic ulcer disease. A year later, he was diagnosed
with HIV (detected by enzyme-linked immunosorbent
assay, and confirmed on 2 occasions by Western blot),
which was thought to have been acquired as a result of
a blood transfusion given during the antecedent abdominal surgery. In the ensuing 10 years, the patient
remained free of any AIDS-defining illnesses. Other
medical problems included hypertension, chronic
bronchitis, and heavy use of cigarettes (2 packs per
day). From 1985 to 1989, the patient’s RA was treated
with various NSAIDs and, intermittently, with corticosteroids for flares of joint pain and swelling. In 1989,
he developed signs of chronic renal insufficiency,
thought to be secondary to long-term NSAID use.
With discontinuation of NSAIDs, the renal function
remained stable, but stiffness and swelling increased in
the MCP, PIP, and wrist joints of both hands.
In 1991, the patient’s CD4 cell count was noted
to be 1,373/mm3,the serum rheumatoid factor level at
that time was 1:160, and radiographs of the feet
revealed erosions of the third, fourth, and fifth metatarsal heads bilaterally. Periodic flares of swelling and
stiffness continued to occur in the hands until 1993,
when the joint swelling and morning stiffness abated
without treatment. During 1993, the patient’s peripheral CD4 cell count fell from 639/mm3 (in June) to
258/mm3 (in December). A bone scan performed this
same year, as part of an evaluation for a renal mass
and hematuria, revealed no abnormal uptake in the
peripheral joints. During January 1994, the patient
developed pneumococcal pneumonia, labile hypertension, and deterioration of renal function. The peripheral joints remained asymptomatic, without swelling
or stiffness.
In March 1994, the patient was readmitted to
the hospital with methicillin-resistant Staphylococcus
aureus pneumonia and bacteremia, accompanied by
worsening azotemia and altered mental status. His
peripheral CD4 cell count had fallen to 125/mm3;
cerebrospinal fluid cell counts revealed a mild pleocytosis, with negative results for bacterial, fungal, or
mycobacterial pathogens. Physical examination by
two rheumatologists revealed ulnar deviation in the
MCP joints and swan neck deformities in several
digits, but no evidence of synovial swelling or tender-
ness in the PIP, MCP, or wrist joints of either hand.
The patient subsequently died. The autopsy revealed
evidence of acute pneumonia due to staphylococci,
but no evidence of Pneurnocystis carinii or other
atypical pathogens. Two of the MCP joints were
excised for further studies, with permission from the
patient’s family.
METHODS
The 2 MCP joints were fixed in formalin and
embedded in paraffin. After deparaffinization, several
sections were either stained with hematoxylin and
eosin (H & E) or examined by immunohistochemistry
analysis. An immunohistochemistry examination was
performed on the MCP joints using the diaminobenzidine staining method, resulting in a stable, brown
reaction product. Monoclonal antibodies against T
cells (pan-T cell, OPD4, and CD45RO; Dako, Carpinteria, CA), B cells (CD20; Dako), macrophages (CD68;
Dako), cathepsin B (The Binding Site, San Diego,
CA), and cathepsin D (Calbiochem, La Jolla, CA)
were used as primary antibodies. Photographs were
taken with a Zeiss microscope on Kodak film.
RESULTS
Histologically, the H & E-stained sections of
the 2 MCP joints showed a nearly unaffected surface at
the directly opposing cartilage surfaces, and barely
any sign of inflammatory infiltration. However, numerous focal areas of joint destruction in the lateral
recesses, at the cartilage-bone junction of the joint,
were present (Figure IA). These sites consisted of
infiltrative synovial tissue, with multiple cells attached
directly to the site of bone or cartilage destruction.
Higher magnification showed fibroblastoid and
macrophage-like cells (Figure 1B), whereas only single
lymphocytes could be detected within these areas
(Figure 2A).
The lack of cells bearing markers for T cells
(Figure 2A) or B cells (results not shown) was also
confirmed by immunohistochemistry . However, staining with the macrophage antibody (anti-CD68) revealed that about two-thirds of the cells in the proliferative, invasive areas of synovial growth were
positive for this marker (Figure 2B). Because no
marker exists for RA synovial fibroblasts, cells negative for CD68 in these sites were regarded as fibroblasts, due to their appearance. The presence of
matrix degradation, i.e., bone and cartilage destruction, was confirmed by immunohistochemical detec-
Figure 1. Metacarpal joint of a 63-year-old male patient with rheumatoid arthritis and secondary human immunodeficiency virus infection.
Sections were stained with hematoxylin and eosin. A, Arrows show focal sites of cartilage and bone destruction (original magnification X 50).
B, Fibroblastoid cells associated with macrophages are attached to the foci of destruction (original magnification X 640).
Figure 2. Formalin-fixed, paraffin-embedded serial sections of a metacarpal joint of the patient. Immunohistochemical diaminobenzidine
staining and counterstaining with hematoxylin was performed. Staining was done with antibodies against A, T lymphocytes (arrow) (original
magnification x 500), B, macrophages (CD68) (original magnification x 125), C, cathepsin B (original magnification X 200), and D, cathepsin
D (original magnification x 300). Only CD68-positive macrophages and cathepsin B- and D-producing fibroblastoid cells were found at sites
of destruction. Only single T lymphocytes were present throughout the tissue specimen.
1331
JOINT DESTRUCTION IN AN HIV PATIENT WITH RA
tion of 2 degrading enzymes, cathepsin B and D, in the
cells adjacent to encoded areas of bone and cartilage.
As previously demonstrated in a typical RA synovium
(13), both molecules were present in abundance directly at the sites of invasive growth. The majority of
cells producing cathepsin B and D were fibroblastoid
in shape (Figures 2C and D). Thus, the ongoing
production in the synovium of bone- and cartilagedegrading enzymes by synovial cells attached to the
bone or cartilage, without the presence of T cells or
other inflammatory cells, was demonstrated.
DISCUSSION
The current concept for the initiation and perpetuation of RA is based on 3 major factors. These are
1) inflammation, 2) alteration of cellular and humoral
immune responses, and 3) synovial hyperplasia (14).
Cells believed to have a definite role in the course of
this disease are type A (macrophage) and type B
(fibroblast) synoviocytes, as well as neutrophils and
lymphocytes, particularly CDCpositive T cells (15).
The abundant presence of T lymphocytes,
which has frequently been observed in highly inflamed
synovial specimens in active RA, supports the notion
that T lymphocytes are essential for the pathogenesis
of RA; additionally, the growing elucidation of the
cytokine network, with a number of these molecules
elaborated as a result of T cell activation, supports this
idea. Consequently, therapeutic strategies have been
developed to suppress the proliferation of T cell subsets, including trials using anti-CD4 antibody. In these
studies, initially positive results were short-term, and
adverse side effects occurred (16).
Studies in our laboratory investigating the cellular basis of rheumatoid joint destruction have demonstrated the presence of synovial fibroblasts that
express collagenase and cathepsins B and L, with
bone and cartilage destruction at the site of cell
attachment (13). Moreover, in studies of human RA
synovium co-implanted with normal human cartilage
under the renal capsule of SCID (severe, combined
immunodeficiency) mice, histologic and immunohistochemical examinations indicated that synoviocytes are
primarily responsible for the invasive growth of synovial RA tissue into normal cartilage; T cells did not
appear to participate in this process (17). More recent
studies indicate that synoviocytes isolated from RA
tissue are able to degrade cartilage and bone in the
absence of T or B cells (18).
In this case report of progressive joint destruction by proliferating RA synovium that lacks T cells
because of HIV infection, we have demonstrated, for
the first time, progression of joint destruction associated with the production of matrix-degrading proteinases such as cathepsin B and D, which are produced
by fibroblast-shaped cells at the site of invasion.
Presumably, part of this invasive growth of the synovial fibroblasts was enhanced by synovial macrophage
derived cytokines such as interleukin-1 . Most interestingly, there were no clinical features of inflammation
in the examined joints. This finding might explain the
clinical observation of the absence of swelling and
tenderness, very likely due to the depletion of T
cellderived, proinflammatory cytokines. Our observations also support the concept that, in addition to
the known T cell-dependent pathways, T cellindependent pathways play a significant role in rheumatoid joint destruction (14), and may persist in the
absence of overt inflammation.
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MULLER-LADNER ET AL
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