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1191
SPECIAL ARTICLE
REVIEW O F THE NATIONAL ARTHRITIS ADVISORY BOARD
SYMPOSIUM, “MOLECULAR BIOLOGY: ITS POTENTIAL FOR
ADVANCING RHEUMATOLOGY RESEARCH”
RALPH SNYDERMAN, WILLIAM J. KOOPMAN, and DARWIN J. PROCKOP
During the last decade, there has been explosive
progress in biomedical research, due, to a major degree, to
the application of new technologies. The benefits which can
be derived from the application of molecular biology to the
field of rheumatology can clearly be illustrated by its potential impact on early diagnosis, a better understanding of
pathogenesis, and more effective treatment.
The National Arthritis Advisory Board and the National Institute of Arthritis and Musculoskeletal and Skin
Diseases have recognized the great potential for applying
molecular biology techniques toward resolution of many of
the current perplexities regarding arthritis-related diseases.
It was believed that, although many investigators are already
applying state-of-the-art technology toward rheumatic disease research, it would benefit our field to alert a broader
range of researchers and physicians about the many untapped potential techniques for further research into these
diseases. For this reason, a major symposium was organized
to address the topic “Molecular Biology: Its Potential for
Enhancing Rheumatology Research.” New investigators in
the field of rheumatic disease research were invited, and
support for their attendance was generously provided by a
number of sources (see Acknowledgments). Three hundred
seventy-four investigators attended the conference, which
was held October 19 and 20, 1986, in Bethesda, MD.
On the evening prior to the meeting, a basic review of
the principles of molecular biology was presented by Drs.
John D. Stobo and Darwin J. Prockop. During the next 2
days, leading researchers in the fields of molecular biology
and rheumatic disease discussed their work. The presentations are summarized below. In addition, an ad hoc committee consisting of Drs. Ralph Snyderman (Chair), Bevra
Ralph Snyderman, MD: Professor of Medicine, Duke University Medical Center, Durham, North Carolina, and Chair, National Arthritis Advisory Board; William J. Koopman, MD: Professor of Medicine and Director, Division of Clinical Immunology and
Rheumatology, The University of Alabama at Birmingham; Darwin
J. Prockop, MD: Professor and Chairman, Department of Biochemistry and Molecular Biology, Jefferson Medical College, and Director, Jefferson Institute of Molecular Medicine, Philadelphia, Pennsylvania.
Submitted for publication June 16, 1987; accepted June 18,
1987.
Arthritis and Rheumatism, Vol. 30, No. 10 (October 1987)
Hahn, Hugo Jasin, William Kelley, William Koopman,
Henry Mankin, Neil Otchin, Darwin J. Prockop, Lawrence
Shulman, Allen Steere, and John Stobo convened immediately following the meeting. This committee made recommendations to the National Arthritis Advisory Board concerning mechanisms to best enhance the applications of
molecular biology to rheumatic disease research. These are
also summarized below. The National Arthritis Advisory
Board will, in turn, submit a request to Congress regarding
specific funding that would be required to implement the
committee’s recommendations.
Session I: Immune-Mediated Diseases (Dr. Ralph
Snyderman, Chairperson). Presentations highlighted several
research areas in which application of molecular biology
approaches should enhance progress toward ultimate understanding of the etiology and pathogenesis of rheumatoid
arthritis (RA).
AII overview of the field, presented by Dr. J. Claude
Bennett (Birmingham, AL), focused on several areas of
current inquiry that would be particularly likely to benefit
from molecular biology approaches. He pointed out that the
major question in RA research is “What are the initiating
events of this complex process?” or, in molecular terms,
“What are the events at the gene level that initiate cell
responses with subsequent elaboration of a variety of mediators, enzymes, immunoglobulins, and growth factors which
presumably contribute to cell proliferation?” Researchers to
date have pursued several possibilities, including an infection etiology, persistent antigenic stimulation (e.g., bacterial
cell wall debris), molecular.mimicry, and true autoimmunity.
Efforts must be directed at defining the control(s) of
cell proliferation and immune regulation that are defective in
RA. This process will undoubtedly require studies of events
at the gene level that govern the elaboration of biologically
active products in rheumatoid synovial tissue. Infectious
agents in the genetically susceptible host could activate
specific “rheumagenes” (as suggested by Dr. Ralph Williams), inducing cells to proliferate, triggering T cell activation, and resulting in elaboration of cytokines and elicitation
of the inflammatory process. A vast amount of work has
gone into the study of immune responses in RA and of
enzymes involved in tissue breakdown, but these studies
have not yet elucidated the etiologic events that give rise to
1192
these various processes. One would hope that an approach
at the gene level would allow a clearer understanding of
these events.
Presentations by 3 investigators exemplified the impact of molecular approaches on complex problems currently being pursued in RA research. Dr. Dennis Carson (La
Jolla, CA) summarized recent progress in defining the molecular basis of rheumatoid factor (RF) expression in humans. A germline k gene that encodes the primary structure
of a human RF light chain has been isolated and sequenced.
Genes related to the primary structure of RF light chains are
widely distributed in the human population. Products of
these genes may be recognized with antiidiotypic antibodies
raised against synthetic peptides derived from the individual
hypervariable regions of RF light chains. Such reagents will
be important tools in the analysis of the genetics of
autoantibody expression in outbred populations.
Efforts have also been directed toward defining the
molecular mechanisms that underlie RF expression in mice.
These studies were reviewed by Dr. William Koopman
(Birmingham, AL). RNA dot-blot hybridization and limited
complementary DNA (cDNA) sequencing studies have
clearly indicated that murine RFs (present in autoimmune
MRL mice or induced by lipopolysaccharide [LPS]) are not
encoded by a unique group of “autoimmune” genes, but
rather, are derived from the same germline gene pool used in
response to environmental antigens. Restriction of VH gene
family utilization in encoding for RF has been suggested in
some studies but not in others. A restriction of VL gene use
(reflecting conservation of framework sequences) has been
observed in RFs elicited by LPS stimulation in vivo, but not
in spontaneously elaborated RFs from autoimmune MRL
mice. These data suggest the possibility that at least some
RFs may be triggered by antigens unrelated to IgG Fc and
may exhibit binding specificity for more than one antigen.
There is considerable interest in retroviruses, not
only as potential etiologic agents for RA, but also as “shuttles” for oncogenes among different cells. Dr. Stuart
Aaronson (Bethesda, MD) surveyed advances in this area of
intensive study. Of particular interest is evidence that
caprine retroviruses are capable of inducing an arthritis in
goats that has some features of RA. Interestingly, only a
small fraction of cells in involved synovial tissue express the
virus. Retroviral infection of cells may result in autonomous
expression of an associated oncogene or in disrupted function of important gene regulatory sites (e.g., promoters,
enhancers) in the cell. Implications of these studies with
regard to the proliferative lesion in RA synovium are obvious and warrant efforts to search for evidence that
retroviruses are etiologic agents in this disease.
Dr. Bevra H. Hahn (Los Angeles, CA) summarized
recent work on the immune disorder underlying systemic
lupus erythematosus (SLE). She stressed that molecular
biology will provide the tools to elaborate on preliminary
findings which suggest that selected genetic information participates in autoantibody formation, that T cell help is critical to
expansion and selection of pathogenic subpopulations. and that
yome of the suppressive mechanisms to abort this process are
absent in autoimmune diseases of the SLE type.
Dr. Michael B. Matthews (Cold Spring Harbor, NY)
reported on the isolation and characterization of the cellular
SNYDERMAN ET AL
antigens reacting with the autoantibodies found in patients
with rheumatic diseases. One of the surprising results was
that of the 10,000 or more proteins found in a human cell,
only 30 or 40 are common targets of the autoimmune
response. Among the most intriguing are 3 autoantibody
system5 that react with aminoacyl-transfer RNA synthetases found in patients with myositis. One current hypothesis is that these autoantigens are triggered by RNAs from
viruses that infect muscle, bind to the synthetase enzyme,
and cause it to be recognized as foreign.
Remarkable progress in cloning and characterizing
several of the autoantigens found in patients with rheumatic
disorders was reported by Dr. Jack D. Keene (Durham,
NC). Clones were obtained for both the La and the Ro
proteins that are antigenic in many connective tissue diseases. ‘The La clone was used to generate protein in an
expressing host-vector system. About one-third of the La+
patients tested had antibodies that were strongly reactive
with the carboxyl portion of the La molecule, while in
two-thirds, the antibodies were strongly reactive with the
middle portion. The La protein is a n RNA-binding protein,
and the RNA-binding domain appears to overlap with the
middle portion that is strongly antigenic. The purified recombinant DNA-derived La protein was used to develop a rapid
dipstick method for serum analyses.
Clones were also obtained for the 70-kd RNA protein, which is antigenic in mixed connective tissue disease.
Sequence analysis revealed a region of very strong hydrophobicity near the middle of the molecule that has a strong
homology to the C-terminus of the p30 gag protein of
Moloney murine leukemia virus. Also, antibodies specific
for the p30 gag protein are reactive with the cloned 70-kd
protein. These recent results, as well as earlier findings by
other investigators, strongly implicate a viral etiology for the
autoimmunity in patients with lupus nephritis.
Studies by Dr. Robert S. Schwartz (Boston, MA)
indicate that the autoantibodies found in lupus may be
closely related to the natural autoantibodies found in the sera
of all normal animals. Studies by Dr. Betty Diamond (New
York, NY) demonstrate how examination of antiidiotypes
can begin to reveal the structural and genetic basis for
autoantibody production and perhaps provide a means for
identifying disease-prone individuals.
Session 11: Metabolic Diseases (Dr. William N. Kelley,
Chairperson). Of the many ways molecular biology can
influence medicine, the potential of human gene therapy is
certainly among the most dramatic. In the next century, gene
therapy may have an impact on the prevention of genetic
diseases, which would be similar to the impact of vaccination in the past century. Such possibilities, however, will
clearly not occur in the immediate future, since the realistic
prospects for gene therapy within the next decade are far
more restricted. Drs. William N . Kelley (Ann Arbor, MI)
and C. Thomas Caskey (Houston, TX) discussed current
strategies.
Dr. Kelley observed that, at present, all discussions
relevant to humans assume that genetic material is introduced into somatic cells, thereby affecting a single individual
rather than future progeny. lntroduction of DNA into a
fertilized ovum could be used to alter all cells in the
developing animal and the alterations would be transmitted
MOLECULAR BIOLOGY SYMPOSIUM
to its offspring, but this use of gene manipulation will remain
exclusively in the realm of experimental animal research for
the foreseeable future. On the other hand, the results of
somatic gene therapy would not be passed on to subsequent
generations, and this therapy could be administered both in
vitro and in vivo. With in vitro gene therapy, the gene is
introduced into cell? obtained from the individual, whereas
with in vivo gene therapy, the genetic material in an expression vector is introduced directly into the individual. In the
former case, most approaches have entailed the use of bone
marrow stem cells followed by autologous bone marrow
transplantation.
The 3 diseases in which human gene therapy is most
likely to be useful are adenosine deaminase deficiency,
purine nucleoside phosphorylase deficiency, and hypoxanthine-guanine phosphoribosyl transferase (HPRT) deficiency. These diseases are excellent candidates for gene
therapy, since they are caused by single enzyme deficiencies
and could potentially be corrected by in vitro gene therapy
with bone marrow stem cells.
Most researchers are addressing adenosine deaminase deficiency by introducing the gene for this enzyme into
a retrovirus, transfecting the expression vector into stem
cells, and, for the time being, readministering the stem cells
to experimental animals. Unexpected difficulty in obtaining
high levels of expression of the adenosine deaminase gene
has slowed progress in this area. Treatment of Lesch-Nyhan
syndrome has also proven to be unexpectedly difficult since
a cure for the disease will require targeting of sufficient
HPRT expression in the central nervous system (CNS). Dr.
Kelley and his colleagues are currently attempting to obtain
HPRT expression in a neurotropic virus capable of directly
infecting the CNS.
Dr. Caskey focused attention on the Lesch-Nyhan
syndrome. The HPRT gene is 45 kb in size, consists of 9
exonr, and has a 1,650-bp transcript that is expressed in all
tissues. He and his colleagues have demonstrated that, in the
65 Lesch-Nyhan syndrome patients studied thus far, there
are 20 independent molecular defects, many of which are
point mutations. Other mutations have included complete or
partial gene deletion, exon duplication, gene disruption by
insertion, and splicing errors. Regulation of HPRT gene
expression is of considerable interest and has been found to
be fifteenfold higher in basal ganglia of the CNS. The
regulation of this gene has been found to be governed by
regulatory sequences in the 5’-untranslated region. Dr.
Caskey and coworkers are developing neurotrophic retroviruses as expression vectors, and they are trying to develop
a transgenic mouse model for Lesch-Nyhan syndrome, using
antisense sequences of the HPRT gene driven by the
adenovirus major late promoter and the chicken beta-actin
promoter.
Session 111: Gene Expression in Connective Tissue
Diseases (Dr. Darwin J. Prockop, Chairperson). The numerous areas of investigation now under way to gain insight into
osteoarthritis (OA) and osteoporosis were reviewed by Dr.
Lawrence E. Shulman (Bethesda, MD). Other discussions
led to the development of a major theme for current research, in which one first isolates the human genes for
important structural macromolecules of connective tissues
and then uses the normal structures of the macromolecules
1193
to explore basic questions of both connective tissue biology
and connective tissue disease.
One application of this strategy was illustrated by a
discussion of heritable disorders of connective tissue, by Dr.
Darwin J. Prockop (Philadelphia, PA). Because cloned genes
for type I procollagen are available, it has been possible to
search for mutations in these genes in patients with heritable
forms of connective tissue disease. About a dozen specific
mutations in the genes that produce either osteogenesis
imperfecta or Ehlers-Danlos syndrome have now been identified. The results indicate that similar mutations in different
parts of the same gene can produce remarkably different
clinical manifestations. In some patients, the primary effect
of a mutation i s the looseness of joints characteristic of
Ehlers-Danlos syndrome, whereas in others, the major manifestation of a similar mutation in another part of the same
gene is the marked brittleness of bone characteristic of
osteogenesis imperfecta.
Moreover, studies on several families indicate that
the effects of some of the mutations are so mild that they are
not apparent until late in life. In 1 family, for example, a
child who was homozygous for a defect had osteogenesis
imperfecta. His parents were heterozygous for the same
defect and had no evidence of brittle bones, but while still in
their thirties, they were found to have radiologic evidence of
osteopenia. Therefore, there may be considerable overlap
between the brittleness of bone that is manifested as
osteogenesis imperfecta in childhood and the brittleness of
bone recognized as osteoporosis later in life.
The potential contribution of molecular biology to
general structural information about the macromolecules of
connective tissue was illustrated by Dr. George R. Martin
(Bethesda, MD). Over the last several years, human cDNA
clones have been generated for the major constituents of
cartilage, such as type I1 procollagen and cartilage proteoglycans. In addition, several glycoproteins that bind to type
I1 collagen have been isolated and characterized-in particular, a 54-kd matrix protein, a 77-kd protein (called chondronectin), and a 34-kd protein (called anchorin). These
binding proteins appear to have important functions in
regulating the size of collagen fibrils, cellular proliferation,
and the rate of collagen synthesis. Preliminary studies show
that the genes for type I1 procollagen, proteoglycan, and link
protein are transcribed coordinately during differentiation
and dedifferentiation of chondrocytes. The results suggest
that it should soon be possible to identify the factors that
control the entire cartilage phenotype.
The structure of 2 new collagens found in cartilage
was reported by Dr. Bjorn R. Olsen (Boston, MA), who
cloned the genes for type IX and type X collagen. The
structure of these genes is distinctly different from that of the
fibrillar collagens, types I , 11, 111, and V. Studies with
monospecific antibodies suggest that type IX collagen is
found in areas of cartilage matrix where type I1 collagen
fibrils intersect. Type IX collagen is, therefore, a potential
bridge molecule between type I1 fibrils. This observation
raises the intriguing question of whether “loosening” of the
collagen fibril structure seen in the cartilage of patients with
early OA may be associated with, or caused by, changes in
the structure in or distribution of type IX collagen. Type X
collagen is found in hypertrophic chondrocytes and, there-
SNYDERMAN ET AL
1194
fore, is limited to tissue that undergoes physiologic destruction. Therefore, type X collagen may be associated with the
abnormal destruction of cartilage that occurs in conditions
such as OA.
Dr. Erkki Ruoslahti (La Jolla, CA) reported that 3
amino acids found in several matrix proteins, in 1 specific
sequence, are critical binding sites for matrix cells. The
sequence, Arg-Gly-Asp (RGD), was found first in fibronectin
and subsequently in a series of other matrix proteins, including collagens, vitronectin, osteopontin, von Willebrand factor, fibrinogen, and thrombospondin. The RGD sequences in
different proteins are recognized by cell surface receptors
that are capable of distinguishing between these sequences
because of differences in their 3-dimensional conformation.
Four receptors for RGD sequences have been identified:
receptors for fibronectin, for vitronectin, and for type I
collagen, and a receptor from platelets that recognize several
RGD proteins. Recognition through the RGD system appears to impart positional cues to cells and, perhaps, signals
for growth and locomotion.
Session IV: New Frontiers (Dr. Arnold Levine, Chairperson). Dr. Edward W. Holmes (Durham, NC) reported on
the use of vectors that allow expression of cloned cDNAs in
host cells. Of special importance is an expanding class of
vectors, derived from retroviruses, in which the gag-pol and
envelope genes have been removed. The vectors are capable
of infecting a wide range of host cells and achieving high
levels of expression-cultured cells.
Dr. Sidney Pestka (Piscataway, NJ) reported on
experiments in which antisense RNA was used to inhibit
translation of a prokaryotic protein, beta-galactosidase of
Escherichia coli. The gene was inserted in an antisense
direction behind a temperature-sensitive phage lambda PL
promoter, so that expression of the gene as antisense RNA
could be controlled by maintaining the cells at 42°C or 30°C.
For total inhibition of beta-galactosidase synthesis, it was
found that anti-messenger RNA (anti-mRNA) must be generated in an anti-mRNA:mRNA ratio of 100: 1. Targeting of
the anti-RNA for 3'-coding sequences was ineffective,
whereas targeting the anti-RNA for the ribosomal binding
site andlor the 5'-coding region near the translation initiation
site was most effective. In studies of animal cells, several
researchers have shown an inhibition of synthesis of several
proteins by antisense RNAs complementary to the translational initiation sites and intron-exon splicing junctions, but
some constructs of antisense RNA complementary to the
splice junctions were ineffective.
Dr. Arnold Levine (Princeton, NJ) described experiments in which transgenic mice carrying the simian virus 40
(SV40) early control region and early genes encoding the
viral tumor T antigens were produced. The mice consistently
developed tumors of the choroid plexus. The tumor tissue
selectively expresses the viral T antigen, and this is required
for production of the tumors. T antigen was first detected
about 14 days after birth, but the initial pathologic change,
anaplastic focus of cells, was not detected until 3 6 4 2 days
after birth. The mice died at age 104 % 12 days (mean SD).
The long lag period between the onset of T antigenic
expression and the appearance of pathologic changes sug-
*
gests that expression of the viral tumor antigen, although
required for tumorigenesis, is not sufficient to produce the
initial tumor focus. Transgenic mice provide an important
new model system for studying genetic regulation.
Ad hoc committee recommendations to the National
Arthritis Advisory Board. Techniques of molecular biology
are now being applied, with great success, to the study of a
number of diseases. This science has dramatic and exciting
implications for the study of arthritis and musculoskeletal
diseases, and the committee identified the following as areas
of research that would benefit rapidly from the application of
molecular biology techniques:
1. Identification of possible genetic markers
for connective tissue diseases that would enable early
diagnosis and treatment.
2. Anrrlysis of substances that are produced or
inhibited at the site of disease-related tissue destruction and their relationship to gene activity.
3. Investigation of the genetic structure and
regulation of collagens (because abnormalities in these
connective tissues may be an early sign of disease).
4. Investigation of human growth factors and
cytokines as mediators, and their possible link to
arthritis-related diseases.
5. Development of more efficient chromosomal mapping techniques to speed efforts to locate
disease-related genetic defects. These techniques are
particularly important when more than one gene is
involved in a disease process, as may be the case with
rheumatic diseases.
6. Investigation into additional ways to apply
molecular biology approaches in understanding
autoimmunity.
To enable researchers to fully utilize these new
molecular biology techniques, the committee recommended
that the National Institute for Arthritis and Musculoskeletal
and Skin Diseases receive additional funds to implement:
1. Fellowships and career development awards
designed to teach beginning investigators in rheumatology and orthopedics the latest techniques of molecular
biology and biotechnology .
2 . A special training program for established
investigators in rheumatology and musculoskeletal diseases, to enable them to adapt their research to the latest
techniques in molecular biology and biotechnology .
3. Special grants to medical schools for research by medical students in rheumatology and
musculoskeletal diseases, with special emphasis on
molecular biology and biotechnology techniques.
Acknowledgments. The National Arthritis Advisory Board
and the National Institute of Arthritis and Musculoskeletal and Skin
Diseases thank the following companies and organizations for their
support of the conference: Burroughs Wellcome Company (Research Triangle Park, NC), Merck Sharp and Dohme (West Point,
PA), Smith Kline and French Laboratories (Columbia, MO), The
Upjohn Company (Washington, DC), American Rheumatism Association (Atlanta, GA), Arthritis Foundation (Atlanta, GA), Orthopaedic Research and Education Foundation (Chicago, 1L).
1195
k-APRILt-
LETTERS
Methotrexate therapy for severe systemic
lupus erythematosus
To the Editor:
In the treatment of severe systemic lupus erythematosus (SLE), corticosteroids are used in combination with
antimetabolites or alkylating agents. These agents are associated with risks of oncogenicity, teratogenicity, and sterility
(1). In young women who wish to bear children, these risks
are of particular concern. Methotrexate (MTX) has not been
associated with permanent sterility, nor is it associated with
oncogenicity (1). Because MTX has been successfully used
in the treatment of other connective tissue diseases (2), we
considered whether this drug would be of benefit to an SLE
patient whose disease was resistant to, or who was not
tolerant of, other modalities of therapy.
The patient, a 32-year-old white woman, had presented to her local physician because of multiple oral ulcers
and a rash. She had a history of the development of seizures
at age 11. Within months, pancytopenia was noted. She had
an antinuclear antibody titer of 1:320 and positive test results
for anti-double-stranded DNA, anti-RNP, anti-Sm, and
cryoglobulins. A direct Coombs’ test result was positive.
CH5O was undetectable, C3 was 32 mgldl, C4 was 8 mgldl.
She was treated with prednisone (10 mg, orally, 4 times a
day), and there was a modest improvement in her symptoms.
Within 3 months, however, she experienced lowgrade fevers, fatigue, arthralgias, and myalgias. A left-sided
pleural effusion contained many L E cells, and a pericardial
effusion was noted. A kidney biopsy revealed diffuse proliferative glomerulonephritis. She was treated with cyclophosphamide, 1.5 mg/kg/day, orally, after a 3-day regimen of
methylprednisolone (1 gm intravenously per day). Prednisone treatment was continued at a dosage of 60 mglday. Her
serum creatinine level fell from 1.8 mg/dl to 1.3 mg/dl. Her
symptoms were controlled for the next 2 months, but then
daily fevers, lethargy, ataxia, and dyspnea occurred. She
had a recurrence of oral ulcers and pancytopenia, and
hypoxemia was present. There was no clinical response to 3
days of pulse methylprednisolone therapy (1 gm intravenously per day). Cyclophosphamide treatment was discontinued, and azathioprine, 75 mglday, orally, was begun.
Clinical deterioration occurred, and she was transferred to
the University of Wisconsin Hospital.
On admission, she was found to have oral ulcers, a
pericardial effusion, and pitting edema. She was disoriented
and diffusely weak. The following laboratory values
were noted: hematocrit 29 mgldl, white blood cell count
6,100/mm3, platelet count 174,000/mm3,creatinine 1.3 mgldl,
serum glutamic oxaloacetic transaminase 54 unitsfliter (normal W O ) , alkaline phosphatase 307 unitdliter (normal
35-1301, bilirubin 0.3 mgldl, and urinalysis 3+ proteinuria,
with 6-10 red blood cellshigh power field and granular casts.
The CHSO value was 148 units (normal 400-600), C3 was 45
mgldl, and C4 was 11 mgldl. During inhalation of 30%
oxygen, the Po2 was 61 mm Hg. Results of a direct Coombs’
test were positive.
The patient’s subsequent course is shown in Figure
Arthritis and Rheumatism, Vol. 30, No. 10 (October 1987)
MAV+JUNE--CJULY--tAUG.f-SEPT+OCl--I
CUTANEOUS
VASCULlTlS
SEIZURE
ACTIVITY
ORAL ULCERS
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PLASMAPHEUESlS
m
26 r
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Figure 1. Course of systemic lupus eryiri,matosus after the patient
was admitted to our hospital in mid-April and treatment was begun,
on admission, with 1 gm of methylprednisolone given intravenously,
each day, for 3 days. AZA = azathioprine; CTX = cyclophosphamide; qw = each week; plasmapheresis = average 2.5-liter exchange; 0 = leukocytes; 0 = platelets; 0 = C4; dotted vertical line
= the initiation of methotrexate therapy; arrowheads = dates of
plasmapheresis treatment.
1. A skin biopsy revealed leukocytoclastic vasculitis. On the
day after admission to our unit in mid-April, pericardial
tamponade developed, and pericardiocentesis was required.
Azathioprine treatment was discontinued, and 3 daily pulses
of methylprednisolone (1 gm intravenously) were given,
followed by 60 mg of prednisone per day in divided doses.
No response was noted. She experienced respiratory arrest
on the fourth day of hospitalization, and she was resuscitated. She experienced episodes of bacterial septicemia, and
1 episode of Candida septicemia occurred.
During the second and third months of hospitalization, her fever persisted, and recurrent seizure activity was
noted, despite negative findings in blood, spinal fluid, and
urine cultures. Cardiac tamponade recurred, requiring a
pericardial window. Oral ulcers, seizures, hypocomplementemia, and pancytopenia persisted. Her symptoms did not
improve with cyclophosphamide treatment (1.5 mg/kg/day),
and her leukopenia worsened. Despite 10 courses of plasmapheresis over a 1-month period, no improvement in the
patient’s course was noted.
At that time, treatment with methotrexate was instituted, and it resulted in a dramatic response. Within 1 week,
the patient became afebrile, and the pancytopenia began to
resolve. Over a period of 4 weeks, the oral ulcers healed and
the cutaneous vasculitis resolved. Four months later, mild
arthralgias persisted as the only manifestation of her disease.
The MTX dosage was increased to 10 mglweek, and the
arthralgias ceased. Subsequently, the patient has noted
occasional oral ulcers and brief episodes of paresthesias in
her feet, but no major organ dysfunction. She has resumed
full-time employment.
1196
High doses of steroids, azathioprine treatment, and
plasmapheresis failed to rapidly control the manifestations of
SLE activity in this critically ill patient, and cyclophosphamide caused severe leukopenia. A marked improvement
occurred within 1 week of starting MTX therapy, and was
sustained over 4 months. This result contrasts with the
relapses she had had with previous treatments. The effectiveness of MTX in the treatment of such diseases as
rheumatoid arthritis, polymyositis, and Reiter’s syndrome
has been previously documented (2). Although this drug is
associated with teratogenesis during treatment, it has not
been associated with permanent sterility, nor has it been
shown to cause cancer in humans (3,4). Drugs such as
cyclophosphamide have been associated with sterility and
oncogenic effects (1). MTX can cause hepatic toxicity, but
the clinical significance of the abnormalities found in liver
biopsy material remains uncertain (5).
The results in the patient described here suggest that
MTX is useful as an antiinflammatory agent in severe cases
of SLE. Twenty years ago, Miescher and Riethmiiller (6)
described a series of 10 patients with SLE who were treated
with MTX (50 mg intravenously each week). They also noted
a rapid response, with signs of SLE activity diminishing or
disappearing within a few weeks. Dubois (7) observed no
benefits from MTX therapy in SLE, but the method of
administration was different from that currently used in the
treatment of rheumatoid arthritis. A maximum dosage of 7.5
mg/day, for 6-week periods, was administered over the
course of 1 year in those patients (7). In view of the potential
beneficial effects of MTX in SLE, and the relatively less
severe long-term side effects when compared with cyclophosphamide therapy, we believe that a further evaluation of
MTX in the treatment of severe SLE is warranted.
James R. Davidson, MD
Frank M. Graziano, MD, PhD
Ralph J. Rothenberg, MD
William S. Middleton Memorial
Veterans Administration Hospital
University of Wisconsin
Madison, WI
I . Decker JL, Steinberg AL: Immunoregulatory drugs, Arthritis
and Allied Conditions. Tenth edition. Edited by DJ McCarty.
Philadelphia, Lea & Febiger, 1985, pp 525-540
2. Bookbinder SA, Espinoza LR, Fenske NA, Germain BF, Vasey
FB: Methotrexate: its use in the rheumatic diseases. Clin Exp
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LETTERS
The relationship between ocular and articular disease
activity in juvenile rheumatoid arthritis complicated
by chronic anterior uveitis
To the Editor:
We read with interest the report by Rosenberg and
Oen (1) on the relationship between uveitis and articular
disease activity in children with juvenile rheumatoid arthritis
(JRA). We have studied a selected group of 100 children with
JRA, all with at least 5 years disease duration; 94 of them
were antinuclear antibody (ANA)-positive (2).
Seventy-three children, with a mean age at disease
onset of 3.1 years (range 1-9 years), developed chronic
anterior uveitis at an average age of 5.8 years. There was a
trend toward relatively mild involvement in those with a late
onset of uveitis (2).
We have categorized these children into 2 groups
according to the time of onset of uveitis in relation to their
arthritis. in a manner similar to that described by Rosenberg
and Oen. Thirty-three children (45%) had early-onset
uveitis: 3 presented with eye disease, 17 were found to have
uveitis at the time of, or within 6 months after, JRA onset,
and another 13 were diagnosed as having uveitis within 12
months after JRA onset. Twenty of them have severe uveitis
complicated by cataracts or glaucoma; all but 2 have bilateral involvement. Thirteen of these 33 children (39%) had
significantly impaired vision at their last clinic visit (8 were
blind in 1 or both eyes, and 5 had vision of 20/80 to 20/200).
compared with only 5 visually impaired children (12.5%) in
the group of 40 who developed uveitis more than 12 months
after they developed arthritis ( P = 0.013, Fisher’s 2-tailed
test).
We can thus confirm that early onset of uveitis in
relation to arthritis appears to be associated with a poor
prognosis. Chronic iridocyclitis is usually asymptomatic (3),
and the exact time of onset is therefore difficult to ascertain.
Because slit-lamp examination of the eyes would not be
undertaken before the child presented with arthritis, the
diagnosis of chronic iridocyclitis might have been delayed in
children in the early-onset group.
Antinuclear antibodies are associated with earlyonset arthritis and chronic iridocyclitis (4), and we have
shown that ANA titers correlate with active arthritis ( P =
0.03 x lo-’) and correlate weakly with active uveitis ( P =
0.01) ( 2 ) .However, we would agree with Rosenberg and Oen
that eye disease activity and joint disease activity are often
discordant. Eye disease and joint disease were both active at
175 of 568 clinic visits studied and were both inactive at 96 of
568 visits (total both active or both inactive = 271, 47.7%).
In 52.3% of the 568 visits, either one or the other was active.
We would also note that the overall severity of eye
inflammation and joint inflammation tends to differ. Although most of these patients present with pauciarticular
arthritis. the disease progresses to a polyarticular course in
many (2). Among the 94 ANA-positive children, the likelihood of having severe iridocyclitis was almost equal to the
likelihood of having no iridocyclitis, regardless of the degree
of severity of their arthritis. Of 24 children with only
pauciarticular arthritis (never more than 4 joints involved),
14 (58%) developed uveitis, with 8 (33%) of the 24 having
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