Biologic Agents

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Biologic Agents in Rheumatoid Arthritis

http://rheumatology.medscape.com/Medscape/CNO/2000/ACR/ACR%2D01.html

Arthur Kavanaugh, MD

Treatment Update

The development of biologic agents for treatment of patients with

rheumatoid arthritis (RA) has progressed rapidly in the past few years,

especially agents targeting the key proinflammatory cytokine tumor

necrosis factor (TNF). The rationale for this treatment lies in an

understanding that cytokines are critical molecules lying at the heart

of the chronic autoimmune/inflammatory disease process. Investigations

that focused on the major site of the disease, the rheumatoid synovium,

have been essential in understanding that blockade of TNF-alpha might be

an effective treatment. This has resulted in the introduction into the

clinic of 2 inhibitors of TNF, the soluble TNF receptor construct

etanercept and the anti-TNF monoclonal antibody (mAb) infliximab.

Additional inhibitors of TNF, as well as biologic agents targeting other

important inflammatory cytokines (eg, interleukin-1 [iL-1]), have been

assessed in late-phase studies. At this year's annual scientific meeting

of the American College of Rheumatology (ACR), several presentations

provided updated information on progress in this field during the last

year.

The ATTRACT Trial

Lipsky, MD, from the National Institutes of Health in Bethesda,

land, presented 2-year data from the Anti-TNF Trial in Patients With

Rheumatoid Arthritis on Concomitant Therapy (ATTRACT) trial. This

double-blind, placebo-controlled study evaluated the chimeric anti-TNF

antibody infliximab in patients with severe RA who had active disease

despite concurrent use of methotrexate (MTX).[1] One-year follow-up

showed that infliximab had superior clinical efficacy and also resulted

in an apparent arrest in the progression of structural damage assessed

by x-ray. At 2 years, there continued to be significant clinical

efficacy. Using stringent intent-to-treat analysis, ACR20 responses in

the 4 infliximab groups (3 mg/kg every 4 or 8 weeks, 10 mg/kg every 4 or

8 weeks) were 40%, 41%, 42%, and 48%, respectively, compared with 16%

for patients receiving MTX alone. In addition, ACR50 and ACR70 responses

were significantly higher in patients receiving infliximab.

More notably, the ability of treatment with infliximab to essentially

halt radiographic progression was maintained at 2 years. Treatment

continued to be well tolerated during the second year. Thus, this study

provides evidence of longer-term efficacy and tolerability of the

infliximab; it also reaffirms the beneficial effect of infliximab

therapy on progression of bony destruction noted at the 1-year analysis.

ERA Trial

Mark Genovese, MD, of Stanford University School of Medicine in

Stanford, California, presented 2-year follow-up data from the

etanercept in early RA (ERA) trial.[2] In this study, patients with

early (<1 year) but aggressive RA were randomized to receive an

aggressively escalating dose of MTX or 1 of 2 doses of etanercept (10 or

25 mg twice weekly). After a 1-year blinded trial, patients were allowed

to continue into another year of open-label follow-up.

Significantly more patients receiving etanercept 25 mg (75%) remained in

the study at 2 years compared with those receiving MTX (58%). In

addition, clinical responses were superior in patients receiving

etanercept 25 mg. Moreover, patients receiving etanercept 25 mg twice

weekly had less progression of radiological damage than those receiving

MTX (63% of etanercept patients had no progression compared with 52% of

MTX patients); this effect was particularly notable considering joint

erosions. For all the outcome variables, the 10-mg dose of etanercept

was not as effective as the 25-mg dose. Etanercept therapy was well

tolerated, with injection site reactions being the only adverse effect

more common with etanercept; several patients receiving MTX developed

pneumonitis.

The findings from ERA support the longer-term efficacy of etanercept in

this population. Other presentations at this meeting assessed the

long-term efficacy and safety of etanercept in open-label follow-up from

previous studies[3,4] and provided strong additional support for the

value of this agent.

Monoclonal Antibody D2E7

Another inhibitor of TNF, the fully human mAb D2E7, is in advanced-phase

studies. Weisman, MD, of the University of California at San

Diego, and Leo van de Putte, MD, from University Hospital Nijmegen in

The Netherlands, presented the results of 2 trials of this agent in RA

patients with severe, active disease.[5,6] In the first study, D2E7 was

used as monotherapy[6]; in the other, it was used with MTX.[5] Several

doses and dose regimens of the antibody were used in the 2 studies. All

doses tested appeared to be efficacious and well tolerated. These

studies lay the groundwork for ongoing pivotal studies of this agent,

which might be expected to lead to its introduction to the clinic.

Immunomodulators and the Normal Immune Response -- A Warning

Because biologic immunomodulators may suppress not only the pathogenic

but also the normal immune response, there has always been concern that

therapy with these powerful agents may be associated with the

development of complications, such as infection. Investigators at the US

Food and Drug Administration (FDA) addressed this issue[7] by analyzing

all spontaneous postlicensure reports to its " Adverse Event Reporting

System " related to etanercept and infliximab through August 28, 2000.

Etanercept, licensed in the United States for the treatment of RA in

November 1998 and for juvenile RA in September 1999, generated more than

13,000 safety reports, almost all from the United States. Infliximab,

licensed for treatment of Crohn's disease in the United States in August

1998 and for RA in November 1999, generated more than 1100 reports, many

from outside the United States.

The FDA investigators rightfully brought up numerous caveats that must

be considered when assessing data such as this, including lack of

causality, incomplete data regarding comorbidity (eg, use of other

medications that could cause the same effect), inability to verify data,

factors that might influence reporting of adverse events (eg, " Dear

Doctor " letters sent out by the FDA) and, perhaps most important, the

lack of a clear denominator (ie, the number of patients exposed and the

number of similar events that could be expected to occur in similar

populations of patients not exposed to these drugs).

Infections accounted for approximately 22% of the adverse event reports

and contributed to about 60% of the reported deaths for both agents. A

total of 17 cases of tuberculosis were noted among patients receiving

infliximab, and 3 cases of tuberculosis and 3 cases of atypical

mycobacterial infection were noted among patients treated with

etanercept. Eleven of the 17 cases of tuberculosis reported in patients

receiving infliximab occurred outside the United States, presumably in

areas where it is endemic.

Other infections were noted, including pneumocystis (5 infliximab, 2

etanercept), herpes virus infection (8 infliximab, 108 etanercept), and

candidiasis (7 infliximab, 11 etanercept). Because RA patients are at

greater risk of developing infection (as was shown in a poster from the

Mayo Clinic group),[8] and because patients with severe RA, who have

been those perhaps most likely to receive TNF inhibitors, are not only

at the greatest risk of infection but are also likely to be taking

concurrent medications that by themselves can suppress the immune

response and predispose to infection, it is not clear to what extent

therapy with these agents increases the risk of these serious infectious

outcomes. Clinicians should continue to report such adverse events

occurring in their patients to the FDA's MedWatch (1-800-332-1088).

New Developments and Applications:

Higher-Dose Therapy With TNF Inhibitors

In determining the optimal use of TNF inhibitors, one must consider

patients who are treated with these agents and experience an incomplete

clinical response. From the clinician's standpoint, the key question

that arises is whether larger doses of these agents induce further

clinical benefit, and whether they could do so safely. That issue was

addressed in a study presented by Schiff, MD, from the Denver

Arthritis Clinic in Colorado.[9]

In this double-blind, 6-month study, patients with active RA were

randomized to 25 or 50 mg (1:2 randomization) of etanercept given

subcutaneously twice weekly. In terms of clinical efficacy, improvement

was more rapid with the larger dose of etanercept; however, at 6 months,

all efficacy measures were similar in the 2 groups. Although generally

well tolerated, withdrawal due to adverse effects was more common among

patients receiving the larger dose (8% vs 0%). Serious infections were

not seen in either group, but significantly more patients receiving the

larger dose had symptoms of upper respiratory tract infection (26% vs

4%).

The results from this study argue against the value of the 50-mg

twice-weekly dose of etanercept in patients with RA, particularly given

the potential costs associated with higher-dose therapy. Patients

receiving partial benefit from standard dose etanercept may be

candidates for other types of combination therapy, which may be studied

in the near future.

TNF inhibitors may be of value in a number of other rheumatic conditions

in addition to RA. Etanercept or infliximab has been used to treat

ankylosing spondylitis, psoriatic arthritis, adult-onset Still's

disease, and juvenile RA. Because patients with these conditions can

have synovitis similar to that in RA, it seems to be a natural extension

of the utility of these agents in RA; the clinical efficacy achieved

would seem to support that. Moreover, TNF inhibitors have been tried in

a number of autoimmune conditions without frank synovitis, including

myositis, uveitis, and autoimmune inner ear disease.

B-Cell Depletion

In recent years, biologic agents have been targeting T lymphocytes

(which presumably have a central role in orchestrating the autoimmune

inflammatory response characteristic of RA) and inflammatory cytokines

(eg, TNF and IL-1). However, a body of data suggests that B cells also

play an important role in sustaining the autoimmune process. Among their

myriad immunoregulatory activities, B cells are the only cells capable

of producing antibodies, including rheumatoid factor.

Tremendous media attention surrounded a presentation on B-cell depletion

using a biologic agent in patients with RA.[10] Indeed, at the ACR

meeting, many rheumatologists commented that when they called back to

their offices during the meeting, they had received calls from patients

who had heard about the therapy in the press.

In an open study, reported by , MD, of the University

College Hospital London, United Kingdom, 5 patients with longstanding RA

who had been refractory to standard disease-modifying antirheumatic

drugs were treated with a regimen consisting of high-dose prednisone (60

mg/day for 10 days, then a tapering dose), intravenous cyclophosphamide

at a high rheumatologic dose (750 mg given twice), and the anti-CD20 mAb

rituximab. This antibody, which is licensed in the United States for the

treatment of lymphoma, specifically targets B lymphocytes.

Treatment with this regimen yielded notable clinical efficacy. All 5

patients achieved the very impressive level of an ACR70 response at 18

months' posttreatment initiation, although 2 of the 5 required a second

course of treatment during the first year of therapy due to relapse.

Therapy was well tolerated, with minor infections and transient

thrombocytopenia the only adverse effects. As expected, the number of

circulating B cells fell dramatically and remained low for a number of

months. Interestingly, levels of immunoglobulins (IgG, IgM, IgA) were

not significantly suppressed by therapy. More than 10 additional

patients have been treated in a further open study with this regimen in

a slightly modified version, and the results have been similar.

Several important caveats are relevant to the interpretation of this

study. First and perhaps most important, the study was open; both

patients and physicians were aware of the treatment regimen and all

laboratory results, and the study was not controlled. There is an

extensive and unfortunate history in RA treatment -- particularly, it

seems, for biologic agents -- of seeing spectacular results in open

trials that cannot be reproduced in more stringent double-blind,

controlled trials. Indeed, some of the therapies that have not lived up

to their initial promise have targeted B cells (eg, anti-CD52), albeit

nonspecifically. In addition, patients in this study received 2 other

therapies that may have contributed substantially to the clinical

efficacy (high-dose prednisone and cyclophosphamide), and in the long

term may contribute to toxicity. Longer-term follow-up, particularly

regarding safety, and controlled trials are awaited.

Reactivity to gp39 in Rheumatoid Arthritis

For many years, investigators have suspected that the pathophysiology of

RA relates to the presentation of some relevant antigen to a genetically

susceptible host. A large component of the genetic predisposition to RA

comes from class II molecules of the major histocompatibility complex

(MHC), particularly HLA-DR4. While no single etiologic antigen has been

implicated in RA, analysis of patients has shown that reactivity to

certain antigens, such as human cartilage glycoprotein gp39, appears to

be relevant. In animal models of autoimmune disease, interruption of

this key interaction of T-cell receptor/antigen/MHC molecule can result

in disease control or remission. Therefore, a similar approach has

always been hypothetically attractive for the treatment of patients with

RA.

Arthur Kavanaugh, MD, from the University of California, San Diego,

addressed this approach to therapy.[11] A total of 31 patients who had

the proper HLA-DR4 subtype (beta1*0401) were entered into a dose

escalation study that called for vaccination with AG4263 (a complex of

beta 1*0401 with a fragment of gp39). The primary goal of the study was

to demonstrate safety, and treatment did seem to be free of any adverse

effects. From an immunologic standpoint, patients' cells retained their

ability to respond to common environmental antigens, and no patient

developed autoantibodies or other evidence of immunosuppression. More

patients treated with AG4263 did, however, decrease their reactivity to

gp39, a potentially desirable outcome. There was also a suggestion of

some clinical efficacy at the larger doses used. Further studies should

clarify the value of this approach.

T Cells in the Rheumatoid Synovium

A basic science study on T cells in the rheumatoid synovium, which could

have important implications for future biologic therapy, was presented

by Cornelia Weyand, MD, from the Mayo Clinic in Rochester,

Minnesota.[12] Using human synovium transplanted into an immunodeficient

(SCID) mouse, investigators assessed the contribution of various cell

types to the immunologic inflammation in RA. Of interest, when CD8 cells

were depleted, levels of the cytokines interferon-gamma and TNF-alpha

decreased substantially. This implicates CD8 T cells in the production

of, or regulation of production of, these cytokines. Furthermore, CD8 T

cells appeared to have a central role in the formation of lymphoid

germinal centers within the synovium. The data from this study suggest

that CD8 T cells might be important targets for future biologic

interventions.

Clinical Implications for Practice

The new biologics are powerful immunomodulatory agents, and patients

with RA must be monitored assiduously for adverse effects, such as

infections. Patients should understand this when therapy is initiated.

If the tolerability and safety of these and other anticipated

anticytokine agents continue over the long term, treatment of patients

with RA will become safer and more effective.

*****References snipped for space but available at website given

above*****

The materials presented here were prepared by independent authors under

the editorial supervision of Medscape, Inc., and do not represent a

publication of the American College of Rheumatology.