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Proceedings of the northeastern regional meeting of the American rheumatism association.

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283
Proceedings of the Northeastern Regional Meeting
of the American Rheumatism Association
December 5-6, 1974
Newton, Massachusetts
Abstracts of Papers Presented
Relationship Between Cartilage “Healing” and Applied Stress
Howard G. Parker and Eric L. Radin, Boston, Massachusetts
Although degenerative joint disease has been characterized as a proliferative response that increases metabolic
activity in the tissues, it is generally accepted that this
proliferative response is never functionally successful and
that once begun joint degeneration is unrelenting. Experimental attempts to heal very large, full thickness defects in
articular cartilage have been unsuccessful. In order to examine the relative role of intraarticular pressure on the
healing of grossly damaged articular surfaces, the articular
cartilage was completely denuded from the weight-bearing
areas of both sides of one hip joint of 70 adult cats. These
animals were followed for periods up to 30 months. Onehalf the animals also had modified “hanging hip” procedures in conjunction with the cartilage removal. The control
animals stopped limping between postoperative months 3
and 6, but the limp reappeared in this group by month 12
and persisted. Limping in the tenotomized (experimental)
group disappeared between months 6 and 12 and did not
reoccur. Hypertrophic lips and spurs were consistently
found in the control animals at month 24. Most of the
animals in this group had a limited range of motion of
the hip, and the capsule about the joint was thickened.
Frank fibrous ankylosis occurred in 2 control animals. The
experimental animals had hip joints that remained congruous and were free of lips and spurs. Microscopically,
fibrous tissue was present as early as 1 month in the articular defects in all animals but was clearly more exuberant
in the tenotomized animals. After 1 year histologic sections
taken through the weight-bearing portions of the heads and
acetabulae of the tenotomized group showed fibrocartilage
and what appeared to represent transformation of small
focal areas of fibrocartilage into an intermediate stage,
more hyaline than fibrous. T h e chondroid nature of this
tissue was confirmed by Safranin-0 staining. There was no
indication that the small rim of cartilage left in the periphery of the joint contributed to the healing. T h e hips
of the animals with the multiple tenotomies went on to
fibrocartilaginous and chondroid healing of their articular
surfaces and clinically did well. Judged by all criteria the
tenotomized hips were consistently functionally excellent at
month 30 as compared to those of the control animals who
pathologically and clinically had degenerative arthrosis.
Small Airway Disease in Scleroderma
M. Guttadauria, D. Saroja, P. Gopinathan, H. Ellman, G. Emmanuel,
H. Lyons, H. Diamond, and D. Kaplan, Brooklyn, New York
Pulmonary Function Tests (PFTs) were performed
in 46 patients with Progressive Systemic Sclerosis (PSS), 35
women and 11 men. Parameters measured were vital capacity (VC), total lung capacity (TLC), residual volume (RV),
diffusion capacity of the lung for carbon monoxide
(DLCO), midmaximum expiratory Row rate-FEF25%-,5%
(MMFR). and forced expiratory volume in 1 second (FEV,).
The findings were not those that have been considered
typical of PSS.
Twenty-nine patients (63%) were found to have
small airway disease (SAD) as manifested by an abnormally
low MMFR (1.5 f 0.59 liter/sec; 50.5 f 16.8% Pred).
Thirteen of these patients (28%) had frank obstructive lung
disease as evidenced by the finding of a low FEV, (67.83
7.05% of FVC). Smokers comprised only 7/29 (24%) of
+
Arthritis and Rheumatism, Vol. 18, No. 3 (May-June 1975)
the patients with a low MMFR and 14/46 (30%) of the
total. An additional 13 patients (23%) had abnormalities
suggestive of SAD. These patients had an elevated RV
(2.18 -t 0.71 liter; 176.5 -C 29.9% Pred) with normal
MMRF and FEV,. These patients are considered to have
SAD because of the close relationship that has been shown
to exist between RV and closing volume. The latter measurement was not made in our patients. Radiographic evidence of lung cysts was not present. Thus 42 of 46 patients
(91%) manifested some evidence of SAD. Only 3 patients
(7%) had PFTs consistent with classic restrictive lung
disease-decreased RV, TLC, and VC-without evidence of
SAD. One patient had normal PFTs.
Obstructive lung disease had been considered not
only unusual in PSS but also a manifestation of advanced
284
AF2A ABSTRACTS
disease when it occurs. Twenty-two of 42 (52%) of our patients with SAD had PSS for less than 2 years. Twentythree
of 42 (55%) had no dyspnea or other pulmonary symp
toms. Twenty-six of 42 (62%) had normal chest film. T e n
of 42 (24%) had normal chest ratio-gram, no dyspnea, and
disease of less than 2 years duration. Thus, the finding of
SAD is not restricted to patients with advanced disease.
These data suggest that involvement of the small
airways is a frequent finding in PSS.
Detection of Antibody to Native DNA(N-DNA):Increased Specificity for Active SLE by Using a
Synthetic N-DNA Antigen Free of Contaminating Single-StrandedDNA (ss-DNA)
Charles R. Steinman, Utis Deesomchok, and Harry Spiera, Mount Sinai School of Medicine, New York
Contamination with ss-DNA of most or all natural
N-DNA antigens used for measuring antibody to N-DNA
may account for recently reported detection of such antibody in non-SLE states. Some denaturation may be virtually
unavoidable during purification and handling of natural
N-DNA. Hence it is proposed that a synthetic, self-complementary, alternating copolymer of deoxyadenylate and deoxythymidylate (dAT) be substituted for natural N-DNA
(KB DNA) in such assays. This substance would, on theoretical grounds, be expected to be free of ss-DNA and other
cellular antigens and should carry the same antigenic determinants as natural N-DNA. Immunochemical comparison
of dAT with KB DNA was carried out. T h e above expectations were confirmed. All natural N-DNA preparations
examined, including those repurified to remove ss-DNA by
MAK chromatography or by treatment with an ss-DNA-
specific nuclease, still contained detectable ss-DNA. Binding of dAT in the ammonium sulfate assay for anti-N-DNA
by sera from patients with SLE and other diseases as well
as from normals was compared with binding of KB DNA.
dAT binding appeared to be more specific for SLE, particularly for active SLE nephritis. Active neurologic disease
was not associated with increased dAT binding. T h e percent dAT binding, when elevated, paralleled disease activity in the same manner as did KB binding. In at least
1 patient the only clinical evidence of diffuse proliferative
nephritis was the elevated dAT binding. Limited data comparing renal biopsies with coincidental dAT binding will
be presented. It is concluded that use of d A T to detect
anti-N-DNA antibody offers theoretical and practical advantages over use of natural N-DNA including greater
specificity, better reproducibility, and lower cost.
Antibodies to DSDNA in Patients with Rheumatic Disease Other than Systemic Lupus (SLE)
C. Bell and P. H. Schur, Robert B. Brigham Hospital, Harvard Medical School, Boston, Massachusetts
Antibodies to double-stranded DNA were detected
by counterimmunoelectrophoresis and measured by radioimmunoassay in sera from patients with certain connective
tissue disorders other than SLE. Precipitins to DSDNA were
found in 40 of 448 sera from patients with rheumatoid
arthritis (RA) and in 25 of 162 sera from patients with
juvenile rheumatoid arthritis (JRA), as well as 5 sera
from patients without RA, JRA, or SLE. Sera and additional clinical information were available on 28 patients
who could then be divided into four groups, based on the
number of criteria each had for RA and SLE. Group I:
5 patients had five or more criteria for RA and four or
more for SLE; Group 11: 13 patients had five or more
criteria for RA and less than four criteria for SLE; Group
111: 5 patients with JRA; and Group IV: 5 patients had
less than five criteria for RA and less than four criteria for
SLE. Patients with RA and anti-DNA antibodies had more
severe disease, particularly extraarticular manifestations,
than did RA patients without anti-DNA antibodies. Nephritis and hypocomplementemia were observed in 4 of 5 patients in Group I. Based on these observations, it was concluded that the presence of anti-DSDNA should not be used
as a sole criterion in establishing the diagnosis of SLE.
Various Types of Antilymphocyte Antibodies in Patients with Systemic
Lupus Erythematosus (SLE)and Their Relationship with Lymphopenia
John B. Winfield, Robert J. Winchester, and Henry J. Kunkel, Rockefeller University, New York, New York
A 12-month prospective study of 30 patients was
performed to define the relationship of antilymphocyte
antibody Ig class and thermal amplitude of binding with
lymphopenia. Sera given high in vitro lympholysis at 25°C
were highly correlated with lymphopenia in paired blood
specimens (r = 0.66, P
0.0001 by linear regression analy-
<
285
ARA ABSTRACTS
sis). A variety of different antibodies were found. IgM
antibodies predominated and appeared to be the only type
active in in vitro cytotoxicity. Different thermal amplitudes
could be demonstrated by indirect immunofluorescence and
cytotoxicity carried out at 15"-37"C for IgM antibodies and
by immunofluorescence for the much less frequent IgG
types, although marked cold enhancement of binding (4'C)
was universally present. Representative clinical courses regarding these different types of antibodies will be presented.
The data suggest that lymphopenia may be directly
related to cold-reactive IgM antibodies, particularly those
exhibiting a relatively higher thermal amplitude of binding.
Twin Studies in Systemic Lupus Erythematosus (SLE)
Sidney R. Block, John B. Winfield, Michael D. Lockshin, William A. D'Angelo,
Marc E. Weksler, Marilena Fotino, and Charles L. Christian, New York, New York
Clinical and serologic characteristics and certain cellmediated immune functions were studied in 12 sets of twins
(7 monozygotic, by erythrocyte and leukocyte antigens) of
which one or both twins had SLE. Four of 7 monozygotic
pairs were concordant for overt SLE (ARA criteria); 5 for
ANF, 6 for hypergammaglobulinemia. (Similar data of 17
previously reported sets will be reviewed.) In other firstdegree relatives the prevalence of ANF was 28 percent and
hypergammaglobulinemia 33 percent.
Lymphocytes of 6 monozygotic pairs, including the
3 clinically discordant sets, failed to demonstrate stimulation in mixed leukocyte cultures (twin versus twin) but
stimulated and were stimulated by unrelated leukocytes.
Sera of 2 of 3 SLE twins (whose lymphocytes exhibited poor
mitogen-induced blastogenesis) did not suppress the normal
responses of their discordant twin's lymphocytes; nor did
the SLE twin's leukocytes recover in the well twin's serum.
Cold-reactive IgM lymphocytotoxic antibodies were present
in the sera of most SLE twins, but only in 1 well twin.
Each lymphocytotoxic serum was equally reactive with normal and SLE peripheral blood lymphocytes.
The data suggest a strong genetic component in the
pathogenesis of SLE and an acquired defect in leukocyte
function. Evidence for neoantigens on SLE lymphocytes,
foreign to the well twin of clinically discordant monozygotic pairs, was not obtained.
Distribution of HLA Antigens in Patients with Juvenile Rheumatoid Arthritis (JRA)
D. Gibson, P. H. Schur, C. B. Carpenter, J. S. Stillman, Robert B. Brigham Hospital,
Peter Bent Brigham Hospital, Harvard Medical School, Boston, Massachusetts
The recent demonstration of an association between
certain HL-A phenotypes and JRA stimulated us to reexamine whether a similar relationship could be demonstrated in our patients. Thirty HL-A antigens were examined in 126 normal Caucasian controls and 122 patients
with JRA. W-17 was found in 7% of JRA patients and in
0.01); HL-A, was found in
18% of controls (a' 6.72, P
597" of JRA patients and in 41% of the controls (a' 7.11,
P
0.01). Although there was no evident difference in the
frequency of these phenotypes in JRA patients with or
without nodules, lymphadenopathy, serositis, uveitis, ANA,
<
<
rheumatoid factors, type of onset, or a family history of
arthritis, HL-A was found in 69% of JRA patients with
hepatomegaly, as compared to 23% of JRA patients with0.005). W27 was found in
out hepatomegaly (a* 9.01, P
16% of JRA patients and in 6% of the normal controls
(a' 3.14, P
0.1). Of those JRA patients with W27 only 1
of 13 had radiologic evidence of sacroilitis. Although trends
are noted between HL-A phenotypes and aspects of JRA,
these studies fail to confirm the observations of others reporting a relationship of W27 and JRA.
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Connective Tissue Proteins Synthesized by Scleroderma Fibroblasts in Cell Culture
Roy Fleischmann and E. Carwile LeRoy, College of Physicians and Surgeons of Columbia University, New York, New York
Soluble precursors of collagen in the culture medium
of fibroblasts obtained by skin biopsy from 5 patients with
scleroderma (SD) were characterized by SDS-acrylamide gel
electrophoresis and compared to the medium of normal
human fibroblasts (NL) matched for age, sex, race, and
biopsy site. By using the parameters of molecular size,
patterns of dual isotope incorporation (3H tryptophan and
14C proline), sensitivity to pepsin and bacterial collagenase,
and of reduction and alkylation, both SD and NL medium
contained newly synthesized proteins that were character-
286
ARA ABSTRACTS
ized as polymers of procollagen and monomers of collagen
and procollagen. Electrophoretic patterns of NL and SD
medium were qualitatively similar. T h e ratio of collagenous
protein synthesis as demonstrated by collagenase sensitivity
was 1.8 (SD:NL, five culture pairs); using hydroxyproline
analysis the ratio was 2.2 (collagen/flask) and 1.3 (collagen/
cell) in three culture pairs. A previously unrecognized, noncollagenous protein (or proteins) in the gel region of procollagen polymers was characterized as pepsin sensitive, bacterial collagenase resistant, nonreducible, and possibly glycoprotein or glycosaminoglycan in nature. These noncolla-
gcnous materials represent a substantial proportion of the
NL and SD fibroblasts synthetic output (s 50% of incorporated label) and can be mistaken for procollagen polymers by electrophoretic mobility and isotope incorporation.
These data confirm the initial impression of increased collagen synthesis by SD fibroblasts in vitro and are consistent
with an orderly assembly and maturation from procollagen
to collagen in SD fibroblasts as shown with NL fibroblasts.
Increased collagen synthesis by SD fibroblasts is consistent
with an activated or incompletely regulated state of the
SD fibroblast in vitro.
Release of RNA Virus from Human Rheumatoid Synovial Fibroblast-Mouse Fibroblast Hybrids
Olaniyi Kehinde and Robert Poss, hlassachusetts Institute of Technology,
Harvard Medical School, and Robert Breck Brigham Hospital
Somatic cell hybridization has proved a useful tool
for studying mechanisms of genetic control. Using these
techniques, cell functions ordinarily not expressed can be
“turned on”; conversely, a gene usually expressed in one
of the parent cells may not be expressed in the hybrid.
We have utilized a human-mouse hybrid to study
certain properties of the rheumatoid synovial fibroblast.
Rheumatoid synovial tissue obtained at the time of surgery
was grown in tissue culture until confluent monolayers were
established. These cells were then cocultivated with mouse
fibroblasts in the presence of inactivated Sendai virus.
Clones were selected after growing the cell populations
in selective HAT media. Six clones have been isolated,
grown in quantity, and carried in HAT media.
Each clone differs in growth characteristics and in
karyotype. We have tested these clones for their ability to
express RNA tumor virus; particularly, we have studied the
contribution of the human rheumatoid synovial cell genome to virus release from the mouse-human hybrid.
Although a viral etiology of rheumatoid arthritis is
suspected, no virus has been previously isolated from rheumatoid tissues. T h e implications of our finding that RNA
tumor virus is released from human rheumatoid-mouse
fibroblast hybrids are discussed.
Desensitized Human Synoviocytes: A Model for
Investigating the Interaction Between Prostaglandins and Other Hormones
D. S. Newcombe, C. P. Ciosek, Jr., J. V. Fahey, and R. W. Ortel
Human synoviocytes in culture exposed to prostaglandin (PG) El and E, demonstrate a dramatic increment
in intracellular cyclic AMP (ICAMP) concentration. Synoviocytes, after preincubation in serum-free media, have an
ICAMP concentration (pmoles per milligram of protein)
of 79.3 (+ 17.5), whereas synoviocytes exposed to 3 pg per
milliliter of PGE, or PGE,, for 15 minutes, have concentrations of 1890.5 (& 248) and 393.5 (+ 9.6), respectively.
PGA,, PGA,, PGB,, PGB,, and PGF,, at concentrations u p
to 10 r g per milliliter do not significantly increase synoviocyte ICAMP concentrations; 7-oxa-13-prostynoic acid inhibits the PGE, response. A maximum ICAMP response
to PGE, or PGE, occurs in 15 minutes and returns to approximately basal ICAMP levels 2 to 4 hours later. PGE,or PGE,-stimulated ( 3pg per milliliter) synoviocytes re-
spond minimally to rechallenge with PGE, or PGE2 (desensitization) after ICAMP concentrations have returned to basal
levels. PGE,-containing media from desensitized cells transferred to untreated synoviocytes elicit an ICAMP response
similar to primary PGE, treatment. Desensitized synoviocytes when retested with PGE, remain unresponsive for at
least 72 hours after initial PGE, treatment. Desensitized
synoviocytes require 36 hours in the presence of PGE,free media to regenerate full PGE, responsiveness. PGE,desensitized synoviocytes are also unresponsive to PGE, and
epinephrine. Epinephrine (1.8 rcg per milliliter) alone results in a doubling of ICAMP as compared to untreated
synoviocytes. Massive doses of PGE, (30 pg per milliliter)
added to PGE,-desensitized synoviocytes are unable to overcome the desensitization.
ARA ABSTRACTS
287
Bence Jones Protein (BJP) from a Patient with Primary Amyloidosis Identical to the Amyloid Fibril
Paul J. Block, Martha Skinner, Merrill D. Benson, and Alan S. Cohen
Serum M-components may be found in patients with
primary amyloidosis. We recently studied such a patient
(AC 72-168) with an IgG M-component who had a nephrotic
syndrome and ascites. An M-component was also demonstrated in the peritoneal fluid and found by agarose electrophoresis to be identical with that of her serum. The peritoneal fluid M-component was extracted by ammonium
sulfate precipitation and isolated by starch block electrophoresis. The protein was reduced, alkylated, and chromatographed on Sephadex G-100 into its heavy- and lightchain components. The resulting light chain reacted by
immunodiffusion with anti-kappa BJP.
Amyloid fibrils were isolated from the patient’s liver
by exhaustive saline washes, denatured in 5 M guanidine,
and fractionated by Sepharose 6B chromatography. The
major retarded fraction amounted to approximately 70%
of the amyloid fibrils.
Amino acid sequence determination was performed
on both the isolated light chain from the peritoneal fluid
to 30 residues and on the amyloid fibril protein from the
patient’s liver to 18 residues. Both began as Asp-Ile-GlnMet-Thr and were identical throughout to one another and
to a typical Kappa I type BJB. These results lend support
to the hypothesis that light chains of circulating monoclonal immunoglobulins may be precursors of amyloid fibril
protein in primary amyloidosis. However, this study cannot
rule out the possibility that the circulating immunoglobulins and the amyloid fibrils are produced by separate but
similar mechanisms.
In Vivo Mechanisms of BCG Immunosuppression
R. 1. L. Sutherland, M. A. Spadaro, and F. Quagliata, Rheumatic Disease Study Group,
New York University School of Medicine, New York, New York
We reported (J Rheumatol 1:26, 1974 [suppl 13)
the suppression of adjuvant disease by BCG. I n clarifying
these mechanisms, we noted the following. BCG given to
rats with florid disease significantly suppressed the arthritis
within hours. Delayed hypersensitivity to PPD in rats
treated with BCG either before or after the adjuvant injection was positive. BCG also suppressed disease induced
by Corynebacterium rubrum instead of M tuberculosis in
the adjuvant mixture. When SXr-labeled thoracic duct cells
from normal and BCG-treated rats were transferred into
syngeneic normal, BCG-treated, adjuvant-injected, and
BCG-treated and adjuvant-injected recipients, a marked
increase in counts (P
0.001) was found in the thymi of
<
ERRATUM
Levinson DJ, Silcox DC, Rippon JW, and Thomsen
S: Septic Arthritis Due to Nonencapsulated C q p t o coccus neoformans with Coexisting Sarcoidosis. Arthritis Rheum 17:1037-1047,1974
rats receiving BCG and/or adjuvant. Concurrently reduced
bone marrow localization was noted. Blood, spleen, and
liver counts were unchanged. Nodes draining the site of
adjuvant injection showed higher counts. Increased homing
in thymi of rats receiving BCG was also noted when cells
from BCG-treated donors were used. The altered homing
pattern probably reflects a structural modification of the
plasma membrane of these cells. Our results exclude tolerance, paralysis, antigenic competition, or cross-reactivity as
major factors in the suppression and, with our previous
data, imply that BCG influences the activity of suppressor
T cells, perhaps working in a direct pharmacologic fashion.
On page 1043 of the above article the illustration
labeled Fig 6 Lower should instead appear above the
caption for Fig 7 on page 1044. The illustration on
page 1044 is that for Fig 6 Lower.
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