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Is pannus a residue of inflammation.

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Is pannus a residue of inflammation?
To the Editor:
We have read with great interest the article by
Shiozawa et al(1). It is of note that they found in rheumatoid
arthritis that the course of destruction of the articular
cartilage occurs from the edge, that is, from the synovial
tissue. But the key question is whether the pannus is a
residue of inflammation.
The structural changes that Shiozawa and associates
describe are clearly early changes of the pannus. This
is evident from the cell composition, which corresponds to
young granulation tissue. It contains, as shown in their
figures, loosely layered fibroblasts, macrophages, lymphocytes, and plasma cells, as well as collagen fibers and blood
vessels. The fibroblast potential of the granulation tissue is
responsible for the new collagen formation and enables the
transition to fibrous scar tissue pannus. It should be noted
that the description by the authors is based on the analysis of
15 cases of defined rheumatoid arthritis (RA).
Granulation tissue is thought to represent the residual state of an inflammatory process. For many years we were
also of this opinion until we had the opportunity, through
examination of a large number of cases, to identify cell
formations which had revealed no relationship to the inflammatory process. Those cell formations represent “tumorlike’’ mesenchymal cell clusters. We were able to identify in
the synovial tissue all stages of transformation of the normal
loose connective tissue and its fibroblasts including a closed
formation of immature mesenchymal cells. These homogenous cell clusters consist of round cells with large, often
folded nuclei, which may contain multiple nucleoli. Mitoses
and cytophotometric polyploid nuclei were also identifiable
The cytoplasm contains numerous lysosomes. Of
special significance is the fact that these cell clusters infringe
upon the cartilage from the direction of the synovial tissue or
can also invade directly in the area of the naked zone
between the cartilage and the onset of the synovial tissue,
thereby destroying bone. These advancing cell formations
consist of a solid cell cluster which is absolutely homogenous, that is, which contains no lymphocytes, plasma cells,
or leukocytes and is free from vessels. In this stage it is
possible to recognize the collagen fibers which have been
stripped of proteoglycan. The resulting cuticular border-like
edges in the area of the penetration front are the morphologic
indication for the breaking up of the cartilage substance,
presumably through the release of enzymes (Figures 1 and
Because these aggressive cell clusters are free from
vessels, and can be nourished only by diffusion from the
joint cavity, we estimate that their life span is only a matter
of days. We were able to observe the step-by-step destruction of these formations and the maturation of the surviving
cells into fibroblasts. The latter synthesize collagen and
thereby introduce the transition to granulation tissue as the
preliminary step of the final scar pannus. At this point begins
the increasing vascularization of the pannus.
The destruction phase is limited by the short life span
of these compact, aggressive cell formations, for which the
term “tumor-like proliferation” was proposed to us by the
Krebsforschungsinstitut der Schweiz (Cancer Research Institute of Switzerland).
We have no explanation of why these aggressive
tumor-like cell clusters encroach upon the cartilage from the
direction of the synovial tissue, where their destructive cell
elements further multiply. To date, this process has been
observed only in rheumatoid arthritis and in no other rheumatic disease. Our statement is based on the analysis, by
light microscopy and in some cases electron microscopy, of
approximately 8,000 cases of RA.
Figure 1. Invasion of immature, monoform cell clusters on and into
the articular cartilage in rheumatoid arthritis.
Arthritis and Rheumatism, Vol. 27, No. 8 (August 1984)
Figure 2. Detail of Figure 1.
The results demonstrated by Shiozawa and colleagues correspond to the phase of transition from granulation tissue to an early pannus. This is proven by the mixed
cell picture, the loose layering of the cell elements, the
significant new formation of fibers, and the proportion of
newly formed blood vessels.
Our observations indicate that the destruction of
cartilage and bone in rheumatoid arthritis does not have an
inflammatory character, but rather is the work of repeated
assaults by invasive, compact, homogenous, immature synovial cell clusters which destroy the joint structures.
Antiphlogistic therapy may in fact influence the
inflammatory synovitic process, but not the tumor-like cell
clusters which are responsible for the destruction process.
These observations suggest that joint destruction may be
influenced not by antiphlogistics, but rather through cytostatic agents.
H. G. Fassbender, MD
Mainz, West Germany
I . Shiozawa S, Shiozawa K , Fujita T: Morphologic observations in
the early phase of the cartilage-pannus junction. Arthritis Rheum
26:472-478, 1983
2. Fassbcnder HG, Simmling-Annefeld M, Stoffet E: Transforma-
tion der Synovialzellen bei rheumatoider Arthritis (Transformation of synovial cells in rheumatoid arthritis). Vcrh Dtsch Ges
Pathol 64:193-212, 1980
3. Fassbender HG, Simmling-Annefeld M: The potential aggressiveness of synovial tissue in rheumatoid arthritis. J Pathol
1391399-406, 1983
4. Fassbcnder HG: Histomorphological basis of articular cartilage
destruction in rheumatoid arthritis. Coll Relat Kes 3: 141-155,
Process of cartilage destruction by the pannus in
rheumatoid arthritis
To the Editor:
We thank Dr. Fassbender for his interest in and
favorable comments on our paper.
According to our study ( l ) , there are 3 stages in the
process of cartilage destruction by the pannus in rheumatoid
arthritis. 1) The pannus extends over the surface of rheumatoid cartilage, morphologically as the layers of fibroblast-like
cells. At this stage, the pannus does not invade the cartilage
matrix. 2) Then the invasion of the cartilage matrix by
macrophage-like cells starts beneath this layer of fibroblastlike cells. The invading edge of the pannus is usually focal,
and often- continuous into the lacunar spaces of chondrocytes. The invading portion consists predominantly of macrophage-like cells. We believe this part of the pannus corresponds to the cell cluster of “tumor-like proliferation”
suggested in Dr. Fassbender’s letter.
3 ) In the more advanced stage, the pannus becomes
thick with cellular infiltrations. Here, the pannus could be
divided into 2 parts by the presence of the fibroblast-like cell
layers. It is important to note, when comparing the sides of
the pannus above and below the layer offibroblast-like cells,
that the pannus beneath this layer is either active or inactive
in morphology when the upper part is morphologically
However, if the upper part is inactive and fibrous,
the lower part of the pannus is always inactive in morphology. We also have observed that the proliferative activity of
the invading front of the pannus is short-lived, as was
observed by Dr. Fassbender. Therefore, for the pannus to
continually invade, the presence of active inflammation in
the upper part of the fibroblast-like cell layers is necessary.
Probably some factors, either humoral or cellular, will be
transferred through capillaries or by diffusion.
Immune complexes (2-5) or fibronectin (6,7) may be
an important inducer for the extension of pannus over the
surface of cartilage at stage 1. As discussed by Dr. Fassbender, we do not know about the factor(s) stimulating the
proliferative invasion of the pannus at stage 2. However, this
factor(s) will be of primary importance, as Dr. Fassbender
indicates, in the pathogenesis of cartilage destruction by the
Although we do not know the cause of the aggressive
invasion, we consistently observed that the invasive front of
the active pannus easily turned into inactive fibroblastic
scar. Therefore, we believe that the influence of active
inflammation in the rheumatoid synovium plays a key role in
the invasiveness of the pannus at stage 3 .
Shunichi Shiozawa, MD
Kobe Universio School of Medicine
Kobe, Japan
1. Shiozawa S, Shiozawa K , Fujita T: Morphologic observations in
the early phase of the cartilage-pannus junction. Arthritis Rheum
26:4?2478, 1983
Cooke TD, Hurd ER, Jasin HE, Bienenstock J, Ziff M: Identification of immunoglobulins and complement in rheumatoid articular collagenous tissues. Arthritis Rheum 18:541-551, 1975
Ishikawa H, Smiley JD, Ziff M: Electron microscopic demonstration of immunoglobulin deposition in rheumatoid cartilage. Arthritis Rheum 18563-576, 1975
Jasin HE, Cooke TD: The inflammatory role of immune complexes trapped in joint collagenous tissues. Clin Exp lmmunol
33:416-424, 1978
Shiozawa S, Jasin HE, Ziff M: Absence of immunoglobulins in
rheumatoid cartilage-pannus junctions. Arthritis Rheum 23:816821, 1980
Rich AM, Pearlstein E, Weissmann G , Hoffstein ST: Cartilage
proteoglycans inhibit fibronectin-mediated adhesion. Nature
293~224-226, 1981
Noms DA, Clark RAF, Swigart LM, Huff JC, Weston WL,
Howell SE: Fibronectin fragment(s)are chemotactic for human
peripheral blood monocytes. J Immunol 129:1612-1618, 1982
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pannus, inflammation, residue
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