Biologic agents in the treatment of inflammatory rheumatic
`diseases
`
`Joachim R. Kalden, MD, and Bernhard Manger, MD
`
`In 1996, experience in treating autoimmune rheumatic
`diseases with biologic agents has further improved. New data
`have been published using different principles directed against
`cell surface antigens or against proinflammatory cytokines or
`applying anti-inflammatory cytokines such as interleukin-10 and
`interleukin-4. In addition, combination therapies with
`anti—tumor necrosis factor-on monoclonal antibody and
`methotrexate have shown sustained long-lasting beneficial
`effects. Undoubtedly, with increasing knowledge of the exact
`mechanisms leading to tissue destruction in autoimmune
`rheumatic diseases, new treatment principles will be devel-
`oped that may be even more specific and may be associated
`with fewer adverse effects than the biologic agents tested thus
`far.
`
`Studies about the clinical efficacy of biologic agents in the
`treatment of autoimmune diseases, including the autoim-
`mune rheumatic diseases, have progressed recently with
`regard to 1) the use of monoclonal antibodies interfering
`with activation processes between antigen-presenting and
`CD4+ helper cells; 2) the application of anti-inflammatory
`cytokines; and 3) treatment principles for inhibiting
`proinflammatory cytokines. The main targets for treat-
`ment are, as in previous years, cell surface molecules of
`CD4* T cells or cytokines as messenger molecules, which
`control cellular function, cell differentiation, and intracel-
`lular cooperation. Cytokines playing a role in the patho-
`genesis of autoimmune diseases can be classified accord-
`ing to their function in three main classes:
`
`Department of Internal Medicine Ill and Institute for Clinical Immunology and
`Rheumatology, University of Erlangen-Ntirnberg, Krankenhausstralie 12,
`D-91054 Erlangen, Germany.
`
`Current Opinion in Rheumatology 1997, 92206-212
`
`Abbreviations
`
`collagen-induced arthritis
`CIA
`ICAM-1 intereellular adhesion molecule-1
`IL
`interleukin
`RA
`rheumatoid arthritis
`Th1.Th2
`T-helper 1 and T-helper 2 (cells)
`TNF-a tumor necrosis factor-a
`
`© 1997 Rapid Science Publishers
`lSSN 1040-8711
`
`206
`
`1) Proinflammatory cytokines produced in excess, such as
`interleukin-1 (IL-1), tumor necrosis factor-0L (TNF-ot),
`granulocyte-macrophage colony-stimulating factor, and
`chemokines such as RANTES and macrophage inflamma-
`tory protein;
`
`2) Anti-inflammatory cytokines, such as IL-4 and IL-10,
`which are sometimes produced in quantities insufficient to
`suppress inflammatory reactions; and
`
`3) Anticytokine molecules, which block the effects of
`proinflammatory cytokines, such as soluble p55 and p75
`TNF-O. receptors, and the soluble IL-1 receptor antago-
`nist.
`
`Our increasing knowledge about the mechanisms underly-
`ing the pathogenesis of autoimmune diseases has
`disclosed the complexities in the treatment of autoim-
`mune diseases, including the autoimmune rheumatic
`diseases. Thus, in a study by Genain et a/. [100] it was
`shown that experimental allergic encephalomyelitis
`induced in marmosets by immunization with myelin oligo-
`dendrocyte glycoprotein can be delayed by intraperitoneal
`treatment with this agent. However, the treated animals
`subsequently developed a hyperacute form of the disease.
`Blanas at al. [20] noted that oral administration of large
`amounts of the antigen ovalbumin can result in the gener-
`ation of CD8* cytotoxic T cells and that, furthermore,
`these T cells can promote the disease process after oral
`administration of ovalbumin in a murine model of insulin-
`
`dependent diabetes mellitus. These two examples clearly
`indicate that immunologic intervention in autoimmune
`diseases may not always alleviate disease activity as
`expected but may rather enhance it, although data
`obtained from autoimmune animal experimental models
`may not be directly transferable to the human situation.
`
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`Biologic agents in inflammatory rheumatic diseases Kalden and Manger 207
`
`Progress in the development of biologic agents for treat-
`ing autoimmune diseases is rapid and promising.
`Impressive experimental and clinical data are available
`from double-blind, placebo—controlled trials published in
`1996. In addition to the aforementioned major treatment
`targets, new therapeutic approaches concentrate on the
`administration of peptides or antigens; recently, prelimi-
`nary experiments were published describing gene thera-
`peutic approaches.
`
`High-dose intravenous immunoglobuiins
`Although it is expensive, high-dose immunoglobulin
`therapy is still being used for the treatment of autoim-
`mune rheumatic diseases. Interest in the use of
`
`immunoglobulins in these diseases is reflected by two
`published supplements on this subject [3',4°]. Infused
`immunoglobuiins may regulate autoimmunity through
`the idiotype—anti-idiotype network, depending on their
`variable (V) region reactivities with natural and disease-
`related autoantibodies or with surface immunoglobulins
`of B cells, or by inhibiting T cell—dependent B-cell differ-
`entiation [5]. However, placebo—controlled, double-blind
`studies are still lacking. Furthermore, it is still unknown
`whether manipulation of the idiotype network might not
`only generate insights into the pathogenesis of autoim-
`mune diseases but also provide a new avenue for the
`management of autoimmune disorders by modulation
`with antibodies or peptides [60].
`
`Of interest is a recently published pilot study of the use
`of antithymocyte globulin to treat systemic sclerosis
`patients. This study showed that after a single course of
`treatment in a dosage of 10 mg/d on 5 consecutive days,
`two patients still had improvement of skin and pulmonary
`function after 12 months. Five patients were worse and in
`three disease was stable [7]. Although most patients toler-
`ated the treatment well, one patient developed an allergic
`reaction, one showed symptoms of severe serum sickness
`after completion of therapy, and another developed a
`central venous access—related axillary vein thrombosis.
`Two patients died of systemic sclerosis—related complica-
`tions during the follow-up period. Although these data do
`not indicate a breakthrough in the treatment of patients
`with systemic sclerosis, they suggest that for this disease
`entity, for which there are few therapeutic options,
`antithymocyte globulin might be used in severe cases.
`
`Agents directed against cell surface antigens
`Based on the continuing analysis of receptor—ligand
`systems involved in CD4* T-cell activation by antigen-
`presenting macrophages or B cells, new blocking princi-
`ples for the interaction between antigen-presenting and T
`cells have been developed. Most of the data reported in
`the past were obtained with monoclonal antibodies
`directed against the CD4 molecule. Results are also avail-
`able now from clinical studies applying monoclonal anti-
`bodies against CDS, CD7, and CD52 in rheumatoid
`
`arthritis (RA) patients. Furthermore, clinical trials have
`been conducted with diphtheria-IL-2 fusion toxin and
`with monoclonal antibodies against intercellular adhesion
`molecule-1 (ICAM-1) [8].
`
`In a recently published phase I dose-escalation study,
`Moreland at a/. [90] treated 15 patients with moderate to
`severe RA using an intramuscular injection of four differ-
`ent doses of the VB17 T-cell receptor peptide, followed
`by boost injection of the same dose of vaccine 3 weeks
`later. Patients were followed up for 48 weeks. The vacci-
`nation procedure was well tolerated and no.serious
`adverse events were observed. Decreases in patients’
`joint counts were seen starting 4 weeks after the primary
`immunization. In the peripheral blood, decreases in
`VB17* T cells, in lymphocyte proliferation, and in the
`response to the VBI7 peptide were detected 6 weeks or
`longer after the primary inoculation in 40% of the vacci-
`nated patients. This new type of immune intervention in
`RA warrants further controlled studies.
`
`Besides influencing the interaction between antigen-
`presenting cells or B and T cells, the manipulation of T-
`helper 1 and T-helper 2 (Th1 and Th2) cell subsets has
`increasingly been discussed as targets for treatment in
`human autoimmune diseases. This discussion is based on
`
`the differential involvement of Th1 and Th2 cytokines in
`autoimmune diseases [I00]. Although a strict compart-
`mentalization ofT cells into Th1 and Th2 seems to be an
`
`oversimplification, studies of different experimental
`models of autoimmune diseases suggest that Th1 cells
`contribute to the pathogenesis of several organ-specific
`autoimmune diseases, whereas Th2 cells may inhibit
`disease development [I10]. Although the Th]/Th2
`dichotomy is not as clear in the human as in the mouse,
`discussion has begun about immune intervention based
`on the manipulation of Th1 or Th2 type cells by
`cytokines. Antagonists of IL-12 and inducers of IL-4 or
`IL-10 offer the possibility of selectively manipulating
`Th1 and Th2 cell induction as a potential base for treat-
`ing autoimmune diseases. Based on experimental animal
`studies, the most effective approach for the manipulation
`of Th1 and Th2 cells, however, most likely consists of a
`combination application of cytokines and their respective
`autoantigens. Cytokines appropriately administered in
`association with known autoantigens could be used to
`target specific autoreactive T cells, diverting them from
`autoaggression by changing their lymphokine profile.
`
`Anti-CD4 monoclonal antibodies
`
`Previously published data on double-blind, placebo-
`controlled trials applying chimeric anti-CD4 monoclonal
`antibodies in patients with RA failed to show a significant
`therapeutic effect. Even when a chimerized anti-CD4
`monoclonal antibody was combined with methotrexate,
`no significant clinical efficacy was observed. Interestingly,
`no enhanced toxicity from infectious complications was
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`208 Clinical therapeutics
`
`recorded either, despite a significant peripheral CD4* T-
`cell depletion [I20]. With regard to CD4 treatment, two
`recently published communications are of interest, indi-
`cating—in contrast to previous studies with depleting
`anti-CD4 monoclonal antibodies—that a non—T cell
`
`depleting anti-CD4 monoclonal antibody was well toler-
`ated, clinically active in reducing RA disease activity, and
`capable of suppressing acute—phase
`responses.
`Multicenter placebo—controlled trials are presently under-
`way to further explore the clinical efficacy of nondeplet-
`ing anti-CD4 monoclonal antibodies for the treatment of
`RA [13,14]. With regard to the possible action of nonde-
`pleting anti-CD4 monoclonal antibodies, recently
`published data indicate a shift from a Th1- to a Th2-like
`immune response as shown in the animal model for colla-
`gen II—induced arthritis (CIA). Investigating the effect of
`the nondepleting anti-CD4 monoclonal antibody (KT6)
`including an adoptive transfer of CIA into mice with
`severe combined immunodeficiency, Chu and Londei
`[150] demonstrated that only 20% of KT6-treated mice
`developed arthritis as compared with 100% of mice
`treated with the control isotype. Furthermore, KT6 was
`capable of reversing the profile of cytokine release of in
`vivo primed and pathogenic collagen II—specific T cells.
`These data suggest that the use of nondepleting anti-
`CD4 antibody prevents CIA, probably by switching the
`functional profile from Th1 to Th2 cells. From these
`experiments it can be deduced by this shift not only that
`the disease be prevented, but also that established CIA
`can also be controlled. Similarly, using CTLA4
`immunoglobulin for treatment of the BXSB autoimmune
`disease—prone mouse strain, Chu et a/. [160] elegantly
`demonstrated that a marked shift from predominantly
`naive CD4‘ cells to a prevalence of activated/memory
`subsets could completely reverse autoantibody produc-
`tion and increase longevity. From this experimental
`animal model it is tempting to speculate that therapeutic
`interventions designed to recover a normal Th1/Th2
`balance will provide a useful therapeutic strategy for
`autoimmune diseases.
`
`Monoclonal antibodies against cell surface antigens
`In addition to anti-CD4 monoclonal antibodies, other
`
`antibodies against various T—helper surface molecules
`have been studied in RA and other autoimmune
`
`rheumatic diseases. The use of CAMPATH-ll-I, a
`humanized monoclonal antibody, which induces a
`pronounced lymphocyte depletion, has been studied for
`several years [8]. In an open, multicenter, single-dose-
`escalation study treating 40 patients with active refractory
`RA, a clinical response with a mean duration response of2
`weeks was induced in 65% of subjects. All immediately
`observed adverse side effects resolved within 24 hours.
`
`These effects included fever, headache, nausea, vomiting,
`and hypertension [I70]. In addition, there was a profound
`and sustained reduction in peripheral lymphocyte counts.
`This intravenous dose escalation study with CAMPATH-
`
`1H warrants further exploration. Use of CAMPATH-1H,
`however, which is directed against the surface antigen
`CD52, may be associated——-at least after repeated applica-
`tion—-with severe side effects, because the target mole-
`cule is not only expressed on lymphocytes.
`
`The finding that adhesion molecules undoubtedly play a
`pivotal role in synovial pannus formation in RA has
`inspired trials using a monoclonal antibody against the
`adhesion molecule ICAM-1 (CD54) [18]. Examining
`adhesion molecule expression during the progression of
`inflammation in the RA model of adjuvant-induced arthri-
`tis in rats, an upregulation of CD44 expression on
`macrophages and lymphocytes during the early phase was
`obvious, whereas expression of lymphocyte function
`antigen-1 was shown to be upregulated later in the course
`of the disease. The upregulation of CD44 and of lympho-
`cyte function antigen-1 at different times in the develop-
`ment of adjuvant-induced arthritis suggests an important
`role of these adhesion molecules in establishing and
`sustaining an inflammatory response, at least in this
`disease model [19]. Interestingly, no differences were
`noted in ICAM-1 expression on endothelial cells between
`rats with adjuvant-induced arthritis and control animals.
`Working with the same model, Bullard et a/. [20]
`concluded that naturally occurring genetic variations in
`the expression of ICAM-1 or related adhesion cell mole-
`cules may influence susceptibility to RA in humans. They
`suggest that pharmacologic approaches based on these
`genetic variations might be of therapeutic Value by reduc-
`ing the expression and function of ICAM-1.
`
`Continuing work on the potential utility of a monoclonal
`antibody against ICAM-1 in patients with long-standing
`RA, Kavanaugh at al. [210] showed that a single course of
`therapy was associated with clinical improvement in a
`group of patients with early or indolent RA to an extent
`apparently greater than previously observed in patients
`with long-standing aggressive RA. In this open-label
`study, a 5-day infusion of anti-ICAM-1 monoclonal anti-
`body was performed in 10 patients with early or indolent
`RA. Seven of 10 patients showed marked or moderate
`responses to the treatment at 1 month of follow-up.
`Clinical benefit was sustained through 2 months for five
`of 10 patients, and for three of 10 patients the benefit
`extended for more than 7 months. This phase I and II
`open-label study was conducted with a murine IgG2a
`monoclonal antibody. Although these data are promising,
`studies with a chimerized or humanized monoclonal anti-
`
`body applied in a double-blind, placebo—controlled
`fashion are necessary to fully assess the value of this treat-
`ment principle in the repertoire of anti-RA treatment
`modalities.
`
`Although the clinical efficacy of monoclonal antibodies
`against cell surface antigens in the treatment of RA has
`shown extreme variability, individual clinical studies have
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`Biologic agents in inflammatory rheumatic diseases Kalden and Manger 209
`
`nevertheless yielded new and important findings about
`the tolerability and efficacy of monoclonal antibodies.
`Furthermore (and even more important), the interference
`of monoclonal antibodies with specific surface molecules
`has provided new insights into the pathogenic mecha-
`nisms leading to tissue destruction. In the majority of the
`reported studies adverse effects were minor and transient.
`Thus, further clinical trials must be conducted to evaluate
`the clinical efficacy of monoclonal antibodies directed
`against cell surface molecules involved in macrophage
`and B- and T-cell cooperation, including cell adhesion
`molecules.
`
`Anticytokine treatment principles
`Reports are steadily increasing about the possibility of
`blocking IL-1 and TNF-ot as an effective treatment in
`RA. Although it has been emphasized that IL-1 and
`TNF-(X may have overlapping biologic properties, each of
`these two proinflammatory cytokines may exhibit distinct
`effects on the mechanisms leading to joint destruction.
`Thus, it was demonstrated in an animal model that anti-
`TNF-0L treatment primarily prevents synovitis whereas
`blocking TL-1 may be more effective in preventing carti-
`lage destruction [Z200].
`
`Anti-tumor necrosis factor-a treatment principles
`Studies have continued on the clinical efficacy of anti-
`TNF—ot treatment in RA. Whereas little is known about
`the mode of action of anti-CD4-directed monoclonal anti-
`
`bodies, data have been published elucidating at least
`some mechanisms of anti-TNF-on treatment. In our own
`
`experiments [23-], we were able to demonstrate that
`serum concentrations of IL-1B, IL-6, and soluble CD14
`were significantly diminished in RA patients after in vivo
`TNF-0L blockade. In addition, a significant decrease was
`observed in soluble ICAM-1 molecules in the serum of
`
`treated patients. No relevant changes were found in gran-
`ulocyte function or T-cell proliferation. Absolute numbers
`of T cells increased only slightly and transiently after the
`infusion of the monoclonal antibody. These data were
`confirmed by Paleolog et 52/. [240], who also demonstrated
`decreased serum levels of adhesion molecules after TNF-
`
`on treatment. Based on these findings, the hypothesis
`might be proposed that a diminished activation of
`endothelial cells by anti-TNF—0L interferes with migration
`of leukocytes into inflamed joints. In further support of
`this hypothesis are observations by Tak el :21. [Z50], who
`reported a reduced expression of adhesion molecules and
`a decrease in cellularity in RA synovial tissue after TNF-
`oz blockade. This finding again suggests that the anti-
`inflammatory effect of TNF-0t therapy may be explained
`partly by a downregulation of cytokine-induced vascular
`adhesion molecules, which would thereby interfere with
`cell trafficking. Edwards 62‘ (I/. [26] reported data suggest-
`ing that staphylococcal endotoxin B—an extremely potent
`macrophage-activating factor both in vitro and in vivo—
`enhances several aspects of autoimmune diseases in
`
`MRL//pr mice. Applying a transcriptional inhibitor of
`TNF-oc, they showed that anti-TNF therapy may have a
`use in the treatment of this arthritis model. In this context
`
`it is of interest, however, that anti-TNF-on treatment in
`the NZB >< NZW mouse model for systemic lupus erythe-
`matosus is known to enhance the clinical appearance of
`autoimmune nephritis.
`
`Combining methotrexate and repeated application of an
`anti—TNF—0t monoclonal antibody, Kavanaugh at al. [27]
`demonstrated that this type of therapy was especially
`effective in RA patients in whom disease control with
`methotrexate alone is incomplete. The clinical response
`achieved using this combination therapy was sustained for
`more than 12 weeks.
`
`Using a TNF-on receptor (p80) fusion protein in a multi-
`center double—blind controlled trial enrolling 180 patients
`with active arthritis, a 20% response according to the
`American College of Rheumatology criteria was observed
`in 14%, 33%, 46%, and 75% of RA patients in different
`dose groups, respectively. These response rates were in
`striking contrast to rates in the placebo-treated groups.
`The most common adverse events were mild injection
`site reactions and upper respiratory signs and symptoms,
`which did not require withdrawal from the study. No anti-
`bodies to the TNF-0t receptor construct were detected
`[Z80]. In this context, an interesting report shows in mice
`deficient in the TNF receptor type 1 with a CIA-suscep-
`tible genetic background that TNF plays an important
`role in the late initiation phase of the arthritic process,
`and that TNF receptor type 1
`is the main transducer of
`proinflammatory TNF effects, but also that the progres-
`sion of arthritis-to-tissue destruction and ankylosis is
`independent of TNF receptor type 1 [Z90].
`
`Anti-interleukin-1 principles and anti-inflammatory
`cytokines
`Recently, an international double-blind, placebo-
`controlled trial has been completed using a recombinant
`human IL-1 receptor antagonist in RA patients [30-,31].
`As early as 2 weeks after the initiation of treatment, 172
`patients with active RA demonstrated clinical improve-
`ment in a decrease in tender joints, morning stiffness, and
`pain. In an intention-to-treat analysis, significant improve-
`ment was observed according to American College of
`Rheumatology response criteria in 43% in the group
`treated with 150 mg for 28 weeks compared with 27% in
`the placebo-treated group. This study demonstrates that
`recombinant human IL-1 receptor antagonist therapy is
`safe and that it produces clinical improvement in patients
`with severe active RA.
`
`In a comparative study of the effect of anti-TNF-0t, anti-
`IL-1-(X and -[3 and IL-1 receptor antagonist in CIA in
`DBA/1 mice, anti-TNF-ot treatment was efficacious
`shortly after onset of disease but had little effect on fully
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`210 Clinical therapeutics
`
`established disease. Histologic analysis revealed that anti-
`TNF-OL significantly reduced joint pathology as deter-
`mined by infiltration of inflammatory cells and cartilage
`damage. In contrast, anti-IL-1-0L and -[3 treatment
`decreased both early and fully established CIA. The
`suppression of established disease was also observed after
`the administration of high doses of IL-1 receptor antago-
`nists. Histologic analysis showed markedly reduced carti-
`lage destruction in both knee and ankle joints. These
`data indicate that blocking of TNF-on does not necessarily
`eliminate IL-1 effects with regard to cartilage destruction
`[3Z°]. Extrapolating from these data, it could be specu-
`lated that combination therapy with blocking agents for
`TNF—0t as well as for IL-1 would be more effective than
`
`monotherapy using either anti-TNF-ot or IL-1 receptor
`antagonist.
`
`Of interest are recent in vitro studies about the action of
`
`IL-10 and IL-4 on mononuclear cells from the synovial
`fluid and peripheral blood of RA patients stimulated
`with bacterial antigens. As demonstrated in these exper-
`iments, IL-10 reverses the cartilage degradation
`induced by antigen-stimulated mononuclear cells, and
`IL-4 has an additive effect. Furthermore, IL-10 was
`shown to have a direct stimulatory effect on
`prostaglandin synthesis and on IL-4 as a growth factor
`for CD4‘ Th2 cells. These data are an argument for the
`use of these anti-inflammatory cytokines alone or in
`combination as treatment for RA [330]. Also in favor of
`this hypothesis are data demonstrating that IL-4
`inhibits prostaglandin production by freshly prepared
`adherent rheumatoid synovial cells via inhibition of
`biosynthesis and gene expression of cyclooxygenase II
`but not of cyclooxygenase I [34].
`
`The demonstration that IL-13 is consistently present in
`rheumatoid synovium, and that exogenous IL-13 has the
`ability to decrease the production of proinflammatory
`cytokines by synovial fluid mononuclear cells, suggests
`that IL-13 might have therapeutic potential for the treat-
`ment of RA [350] This possibility is supported by obser-
`vations of CIA in mice, showing that the systemic admin-
`istration of IL-13 as well as IL-4, using vector cells
`engineered to secrete these proteins, is a powerful
`method for delivering the cytokines in vivo and for atten-
`uating significantly the progression of joint inflammation
`both clinically and histologically [36°]. Additional experi-
`ments suggest that IL-13 may exert its beneficial effects
`by a downregulation of the expression of the TNF-(X
`gene.
`
`Other treatment approaches
`In a recent study 90 patients were enrolled in a double-
`blind, placebo-controlled, randomized trial to investigate
`the efficacy of oral type II collagen in treating RA [37].
`No significant differences were seen in response to treat-
`ment between three groups having received different
`
`amounts of type II collagen; however, a higher prevalence
`of responses was observed in the groups treated with type
`II collagen compared with groups receiving placebo. Side
`effects were rare. Because a minority of patients did
`respond to treatment with oral type II collagen, the
`authors argue in favor of further efforts to identify a
`subgroup of patients who might respond to this type of
`therapy. When 10 patients with juvenile RA were
`enrolled in a pilot trial using oral type II collagen, eight
`patients had a reduction in both swollen and tender joint
`counts after 3 months of treatment [38]. Although the
`data were not impressive, the authors conclude that the
`administration of oral type II collagen might be safe and
`effective in juvenile RA. However, further investigations
`including controlled double-blind trials are necessary to
`substantiate the reported treatment effects. Furthermore,
`when treating autoimmune diseases by oral administra-
`tion of the respective autoantigen, it must be taken into
`consideration that autoimmune disease activity might also
`be enhanced [Z00].
`
`Gene therapeutic approaches have not yet reached the
`level of clinical studies. A recent report noted that one of
`the problems with direct gene delivery to the synovium is
`the identification of suitable vectors for in vivo gene
`delivery [39].
`
`Finally, another interesting approach for immune inter-
`vention in autoimmune diseases is the treatment of anti-
`
`CD4O ligand antibody. In a subset of NZB X NZW mice,
`it was shown that an anti-CD40 ligand antibody
`prevented the development of lupuslike nephritis associ-
`ated with a reduced anti-DNA-antibody production and a
`significantly prolonged survival compared with control
`mice [40"]. Pathologic examinations confirmed the
`absence of significant renal damage or immune deposition
`in responding mice. Whether this interesting approach
`could also be utilized for the treatment of systemic lupus
`erythematosus or other autoimmune disease entities in
`humans remains an open question.
`
`Conclusions
`
`Due to our increasing knowledge about the pathogenic
`mechanisms of autoimmune rheumatic diseases, biologic
`agents have been explored and tested in open and
`controlled clinical trials. Based on the results of placebo-
`controlled trials, two major targets for immune interven-
`tion in this group of diseases are promising or have
`already shown efficacy: 1) the use of nondepleting anti-
`CD4 monoclonal antibodies and 2) the application of
`blocking agents for proinflammatory cytokines or the
`administration of anti-inflammatory cytokines such as IL-
`10, IL-4, and IL-13.
`
`Combination therapies with different cytokine-blocking
`agents or combinations of anti—T cell and anti-proinflam-
`matory cytokine treatment modalities seem the most
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`Biologic agents in inflammatory rheumatic diseases Kalden and Manger 211
`
`promising, inasmuch as the experimental animal data and
`preliminary data in human diseases demonstrate an
`obvious synergistic effect of these agents. Undoubtedly,
`progress will continue steadily in the development of
`biologic agents. New treatment approaches that will be
`developed in the next few years include the application
`of anti-CD40 ligand antibodies, the use of peptides in
`situations in which the autoantigen is known, or even the
`delivery of genes for anti-inflammatory purposes.
`
`References and recommended reading
`Papers of particular interest, published within the annual period of review,
`have been highlighted as:
`
`-
`-°
`
`Of special interest
`Of outstanding interest
`
`1.
`--
`
`Genain CP, Abel K, Belmar N, Villinger F, Rosenberg DP, Linington C,
`Raine CS, Hauser SL: Late complications of immune deviation therapy
`in a nonhuman primate. Science 1996, 274:2054—2057.
`Although the onset of experimental allergic encephalomyelitis was demonstrated
`to be delayed by treatment with myelin oligondendrocite glycoprotein, treated
`animals subsequently developed a hyperacute form of the disease.
`2.
`Blanas E, Carbone FR, Allison J, Miller JFAP, Heath WR: Induction of
`-°
`autoimmune diabetes by oral administration of autoantigen. Science
`1996, 274:1707-1709.
`In an animal model it was shown that the oral administration of autoantigenes
`could induce a cytotoxic T-lymphocyte response, which could lead to the onset
`of autoimmune diabetes.
`
`3.
`-
`
`Thompson RA, Lachmann PJ, Winchester RJ, eds: Intravenous immune
`globulin: mechanisms of action and model disease states. Clin Exp
`Immunol1996, 104(supp| 1):1—97.
`A supplemental volume summarizing the proceedings of a symposium on
`immunoglobulin therapy in a variety of autoimmune diseases.
`
`8.
`
`Kahaly GJ (ed): lmmunoglobulins in autoimmunity: fundamentals and
`4.
`clinical applications. Clin Exp Rheumatol 1996, 14(suppI 15):S3—S1 19.
`0
`A supplement volume summarizing the proceedings of a symposium on
`immunoglobulin therapy in a variety of autoimmune diseases.
`5.
`Stohl W, Elliot JE: In vitro inhibition by intravenous immunoglobulin of
`human T cell-dependent B cell differentiation induced by staphylococ-
`cal superantigens. Clin Immunol Immunopathol 1996, 79:122-133.
`Zouali M, lsenberg DA, Morrow WJW: ldiotype manipulation for autoim-
`6.
`mune diseases: where are we going? Autoimmunity 1996, 24:55-63.
`°
`Links between idiotypes and certain autoimmune diseases are discussed, includ-
`ing the possibility that autoimmune diseases could be managed by modulation
`with antibodies or peptides targeted to these structures.
`7.
`Matteson EL, Shbeeb MI, McCarthy TG, Calamia KT, Mertz LE, Goronzy
`JJ: Pilot study of antithymocyte globulin in systemic sclerosis. Arthritis
`Rheum 1996, 39:1132—1137.
`Kalden JR, Manger B: Biologic agents in the treatment of inflammatory
`rheumatic diseases. Curr Opin Rheumatol 1996, 8:195-200.
`Moreland LW, Heck LW Jr, Koopman WJ, Saway PA, Adamson TC,
`Fronek Z, O'Connor RD, Morgan EE, Diveley JP, Richieri SP, et a/.: V317 T
`cell receptor peptide vaccination in rheumatoid arthritis: results of
`phase I dose escalation study. J Rheumatol 1996, 23:1353—1362.
`First report of a phase I open-vaccination trial using V617 T-cell receptor
`peptides. Data on lymphocyte and clinical responses are presented.
`10. Kroemer G, Hirsch F, Gonzalez-Garcia A, Martinez AC: Differential
`-
`involvement of Th1 and Th2 cytokines in autoimmune diseases.
`Autoimmunity 1996, 24:25-33.
`The differential involvement .of Th1 and Th2 cytokines in autoimmune diseases is
`discussed as a potential base for the development of therapeutic interventions
`by the recovery of a normal Th1 and Th2 balance.
`11. Adorini L, Guery JC, Trembleau S: Manipulationrof the Th1/Th2 cell
`-
`balance: an approach to treat human autoimmune diseases?
`Autoimmunity 1996, 23:53-68.
`A good review paper on the implications of the Th1/Th2 concept for the patho-
`genesis and potential treatment of autoimmune diseases.
`
`9.
`°
`
`12. Moreland LW, Pratt PW, Mayes MD, Postlethwaite A, Weisman MH,
`0
`Schnitzer T, Lightfoot R, Calabrese L, Zelinger DJ, Woody JN, Koopman
`WJ: Double-blind. placebo-controlled multicenter trial using chimeric
`monoclonal anti-CD4 antibody, cM-T412, in rheumatoid arthritis
`patients receiving concomitant methotrexate. Arthritis Rheum 1995,
`38:1581—1588.
`
`Despite significant peripheral CD4* T-cell depletion, no clinical efficacy was
`reported for anti-CD4 treatment in combination with methotrexate.
`13.
`Panayi GS, Choy EHS, Conolly DJA, Regan T, Manna VK, Rapson N,
`Kingsley GH, Johnston JM: T cell hypothesis in rheumatoid arthritis
`tested by humanized non-depleting anti-CD4 monoclonal antibody
`(mAB) treatment I: suppression of disease activity and acute phase
`response [abstract]. Arthritis Rheum 1996, 39(suppl 9):243.
`14. Choy EHS, Conollay DJA, Regan T, Mann VK, Rapson N, Kingles GH,
`Panavi GS, Johnston JM: T cell hypothesis in rheumatoid arthritis
`tested by humanized non-depleting anti-CD4 monoclonal antibody
`(mAB) treatment II: clinical activity is related to pharmacodynamic
`effects [abstract]. Arthritis Rheum 1996, 39(suppl 9):244.
`Chu CO, Londei M: Induction of Th2 cytokines and control of collagen-
`induced arthritis by nondepleting anti-CD4 Abs. J Immunol 1996,
`157:2685—2689.
`
`15.
`-
`
`Data are reported demonstrating that CIA no