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Scientists at,University College,London,England have developed the hypothesis that RA is caused by certain B cells. By
chance,these cells make autoantibodies,i.e.,antibodies against the person's own tissues.
The immune system ordinarily would destroy these B cells,but in rare cases these unusual antibodies escape destruction
and actually set up a vicious cycle that triggers the production of many identical copies of themselves,resulting in self-sustained
attatack on joints and tissues seen in RA.
If this hypothesis is correct,it would seem logical that wiping out the B cells might eliminate the very cause of RA.
Because a depletion of B cells is not life threathening,and the B cell population gradually reestablishes itself after several
months,the assumption is that the new B cell population would be unlikely to include any cells that make the unusual antibodies
that lead to RA.
The researchers began preliminary trials in 1998 with five people suffereing from severe RA,and whom no other treatments
had been effective. The volunteers were given rituximab (Mabthera),a monoclonal antibody that destroys B cells,as well as
steriods and an immunosuppresive drug.
Eighteen months later the researchers could report that those five volunteers "....now only have some residual pain from
the damage already done. They have returned to a more or less normal life",according to Dr.J Edwards the lead professor of
rheumatology.
Fifteen more people with severe RA underwent the same procedure. By late 2000,only two of the twenty treated had shown
no benefits,and although several of the responders relapsed,they achieved significant relief after another round of antibody
treatment
Much more people involving couple hundred people with RA in Europe, Australia, and Canada are planned for 2001-2002.
AMERICAN COLLEGE OF RHEUMATOLOGY
Rituximab in the Treatment of Rheumatoid
Arthritis
A number of high-profile media reports heralded a study reported
at the recent ACR annual meeting in Philadelphia as describing a possible cure for rheumatoid arthritis. Many patients and
physicians have understandably expressed interest in the therapy.
News reports were a response to an abstract presented by Edwards
et al.1 regarding the use of rituximab (RituxanŽ in U.S., MabtheraŽ in Europe) in the treatment of rheumatoid arthritis. Rituximab
is an anti-CD 20 chimeric mouse/human monoclonal antibody approved in 1997 for the treatment of B-cell lymphomas and has since
been used in more than 50,000 patients. The monoclonal antibody has been shown to selectively deplete mature and malignant
CD-20 positive pre B-and mature B-cells, and is the first monoclonal agent approved for cancer therapy. Based on their hypothesis
that rheumatoid arthritis may be driven by auto-reactive B-lymphocytes, the authors utilized rituximab to deplete B-cells
in five patients with refractory rheumatoid arthritis.
Five patients with refractory seropositive rheumatoid arthritis
who had failed five or more disease modifying drugs, were treated with a four week course of rituximab in conjunction with
prednisolone (60 mg. daily for 10 days, then 30 mg. daily for 12 days) and cyclophosphamide (750 mg. iv x2). At six months
all patients achieved an ACR 50, and three achieved an ACR 70. Three had still achieved an ACR 70 at one year. The two who
relapsed (at 7 and 9 months) were retreated and achieved an ACR 70. At 18 months all patients were classified as having a
durable ACR 70 response. The effective lowering of rheumatoid factor titers and the number of circulating B-lymphocytes appear
to correlate well with efficacy. These patients were able to discontinue all other DMARD use and no DMARDs were reintroduced.
Despite prolonged B-lymphocyte depletion, no serious infections were encountered. Two patients developed lower respiratory
tract infections requiring antibiotics, one patient developed petecchiae and thrombocytopenia in the second week of therapy
and one patient had a local tissue reaction to cyclophosphamide. The investigators also claimed improvement in some extraarticular
features (e.g., amyloidosis, nodules, anemia).
This novel study has resurrected the notion that RA may be
a B cell driven process in some patients and that therapies aimed at curtailing the humoral response may be efficacious. Nonetheless,
this is a very preliminary and uncontrolled trial in a small number of patients. Moreover, it is not certain to what extent
cyclophosphamide and corticosteroids contributed to the therapeutic responses observed. More clinical research with this combination
regimen is necessary before it can be applied in the clinic.
Cost factor may influence choice of therapy:
Depending on the health care setting,the majority of the care of patients with RA may be provided by a single physician
(primary care physician,internist or rheumatologist who also provides primary care) or the responsibility might be shared.
The role of the primary care physician is to recognize and diagnose RA at its onset and to ensure that the patients receives
timely treatment before permanent ,irreversible damage occurs.
They should provide support and consultation to the patient in the diagnosis and treatment of RA. Since the level of
training and experience in diagnosing and treatment RA varies among primary care physicians. The responsibility for accurate
diagnosis and monitoring of RA activity and/or drug toxicity may appropriately be assigned to a rheumatologist.
If the care of a patient with RA is to be shared,an explicit plan for monitoring disease activity and or/drug toxicity
needs to be formulated. The patient's preference may be the most important factor in deciding which physician(s) assume responsibilty
for care.
A general health maintenance strategy should be developed,and responsibility for this strategy should be coordinated
among the patient's health care providers. Routine prevention measures,such as screening for hypertension or cancer,should
be recommended and risk factors modified.
RA has significant economic implications for the individual patient as welll as for society. Individuals with RA have
3 times the direct medical costs,twice the hospitalization rate and 10 times the work disability and work disability rate
of an age and sex-matched population.
A recent study has shown annual medical costs for a patient with RA to be approximately $8,500. Annual costs rise as
the duration of disease increases and as function measured by the Health Assessment Questionnaire,declines. Indirect costs
related to disability and work loss have been estimated to be 3 times higher than the direct costs associated with the disease.
Responsibilty for the direct medical costs often falls to the third party payor and in part to the patient,whereas the
majority of indirect costs are borne by the government or employers. In a variety of health care financing systems,the fragmentation
of these financial risks and incentives,the frequent turnover of patients into different risk pools and health care delivery
systems,and to the relatively slow disease course may all adversely affect access to appropiate care.
For many years,relatively low-cost options have been available for the treatment of RA. However,the advent of COX-2 inhibitors,newer
DMARDs,including biologic agents,and the increasing use of combination therapy have all brought cost considerations to the
forefront. The majority of guidlines have generally ignored,cost issues by limiting their scope to an optimum treatment recommendations.
However, ignoring financial considerations would inadequately reflect the impact on daily treatment decisions.
Despite promising short-term results for newer DMARDs that have demonstrated significant effects on functional status
and radiographic progression,there are,at present,insufficient longitudinal data to fully,determine whether such an increased
expenditure will eventually be offset by lower costs of the disease.
A recent analysis has examined the relative cost-effectiveness of 6 different treatment options for RA patients in whom
MTX therapy has failed:etanercept nonotherapy,etanercept plus MTX,cyclosporine plus MTX,triple therapy with HCQ,SSZ,and MTX,continued
MTX nonotherapy,and no second-line agent. Triple therapy was the most cost-effective option,as determined by the ACR 20 improvement
criteria or a weighted proportion of patients achieving ACR 20,ACR 50,and ACR 70 improvement.
However,as with all cost-effective analyses,there were assumptions,which may limit the applicability of the results.
For example,the time horizon for this model was limited to the first 6 months of therapy. In addition,only a limited number
of treatment options were considered in the model. Neither leflunomide nor infliximab were considered. More data about the
impact of newer DMARDs on outcomes such as work capacity and radiographic progression are also needed.
In today's cost-contrained environment,whenever the efficacy and toxicity of treatment options are equivalent,the lower-cost
agent is likely to be used. However,practitioners are increasing facing situations in which therapies are no longer equivalent,there
is only a partial treatment to response,treatment toxicity or comorbid conditions contraindictate the use of more traditional
agents,or high-risk or severe disease requires the use of newer aagents,either alone or in combination.
Providers with sufficient numbers of RA patients in their practice and with longatudinal experience in treating this
disease will,in consultation with their patients,be the best qualified to balance thes delicate cost issues with diagnosis
and timely initiation of disease-modifying agents.
The goal of treatment is to arrest the disease and to achieve remission. Although remission occurs infrequently,patients
may benefit from nonpharmacologic,pharmacologic,and if necessary,surgical interventions. Optimal longitudinal treatment requires
comprehensive coordinated care and the expertise of a number of health care providers.
Essential components of management include systematic and regular evaluations of disease activity,patient education/rehabilitation
intervensions,use of DMARDs,possible use of local or low-dose oral glucocorticoids, minimization of the impact on the individual's
function,assessment of the adequacy of the treatment program,and general health maintenance.
Clinical studies:
There were only a limited number of presentations directly concerning MTX other than as an anchor
drug for trials of combination therapy. A retrospective evaluation of 442 patients with RA receiving MTX from the practices
of 7 community rheumatologists examined the frequency of liver function test abnormalities for a mean 4.05 years of follow-up.
The purpose of the study was to validate the present ACR recommendations for liver function test monitoring in a larger patient
cohort. Throughout the 4-year study, the percentage of patients at risk by ACR criteria was relatively constant, and the frequency
of serum glutamate pyruvate transaminase (8.8%) and serum glutamic oxaloacetic transaminase (7.4%) elevations was similar.
Regardless of the frequency of liver function testing, monthly or every 6 or 8 weeks, the percent of patients at risk per
ACR criteria for having to undergo liver biopsy were similar, suggesting that laboratory tests 6 times per year may be sufficient.
Confirmation in other patient cohorts is needed before altering the present recommendation for monitoring.
Lambert and colleagues evaluated the potential benefit of MTX doses up to 45 mg/wk in patients with active disease who
were taking MTX, 15 mg/wk. Compared with the placebo control group, no additional benefit was seen with high-dose MTX as measured
by the Disease Activity Score (DAS) 28, suggesting that patients with poor response to 15 mg/wk of MTX will be less likely
to respond to dose increase.
On a personal note,I am on MTX: For 5 years I was on the drug (oral). Working up from 7.5 mg/weekly to 20 mg. For 4
years I was on 19 to 20 mg but I still had unaccetable inflammation,ESR was 50+mm/h. I tried leflunomide after 4 months it
worked poorly,and my ESR rose,it was discontinued. The rheumatologist suggested subcutaneous injection. I had read study literature
stating 19 mg or a higher dose of MTX does not make a difference,and that there was little difference between subcutaneous
injection or taking the medication orally. One patient of RA also said there was no difference in efficacy or side effects,in
her case.
At first I resisted the idea,but after the leflunomide experience and diarrhea,I asked to be given subcutaaneous injection.
I went on a regimen of 25 mg injection (folic acid 5 days/wk). After a month I began feeling better,my ESR came down with
no side effects. I am on 25 mg currently and my ESR went down to 10 mm/h at one point. The ESR fluctuates between 30 mm/h
at the high end and averages 20 mm/h. The bottom line is I feel good! MY conclusion is that there is a big difference between
19 mg orally and 25 mg subcutaneous injection.
A study of RA patients from a Medicaid database was performed to evaluate the incidence of lymphoma. No increase in incidence
of lymphoma was seen in RA patients compared with a control group of non-RA patients. Additionally, no increase in lymphoma
was seen in MTX-treated patients.
Leflunomide: During the last 2 years, issues relating to hepatic safety of leflunomide have been raised. A thorough review
of this issue by the European Medicines Evaluation Agency has determined that a favorable benefit-risk ratio exists for leflunomide,
and the US Food and Drug Administration (FDA) investigated this issue and gave a green light assessment on leflunomide.
Cannon and associates presented data evaluating a large managed care claims database containing information on more than
10 million patients followed up for 3.3 years. They evaluated the rate of adverse events (AEs) per patient year for all events,
including hepatic events. Their results demonstrated a similar rate of AEs for leflunomide as monotherapy or in combination
with MTX compared with MTX or other DMARDs even after adjustment for comorbid conditions. An evaluation of 14,997 patients
receiving leflunomide or MTX from the National Data Bank for Rheumatic Diseases demonstrated more self-reported hepatic AEs
with leflunomide or MTX than with other DMARDs, but serious hepatic AEs were uncommon.
Three papers evaluated the durability of response to leflunomide. The patient demographics of the studies were different
but predominantly consisted of patients with longstanding disease and previous multiple DMARD failures. Kaplan-Meier plots
of treatment discontinuation demonstrated that 42% to 57% of patients were no longer undergoing therapy at 12 months. One
study demonstrated an increased risk of treatment discontinuation associated with the standard loading dose of 100 mg for
3 days (odds ratio, 2). Wolfe and coworkers compared the time to treatment discontinuation in 1431 patients initiating leflunomide
or MTX therapy. Time to treatment discontinuation was defined as actual discontinuation or addition of a second DMARD. Failure
rates using this definition were similar for leflunomide and MTX, and median failure time for leflunomide was 15 and 14 months
for MTX.
Previously, Kremer and associates reported benefit of leflunomide in combination with MTX in patients with partial or
no response to MTX alone. Data were presented on the addition of MTX to patients with a partial response to leflunomide. Using
a stringent ACR 20 responder at end point as a primary efficacy variable, 65% of patient undergoing leflunomide monotherapy
at week 16 and 44% patients at week 40 achieved this response. At week 16, patients whom physicians believed had an inadequate
response had MTX added to their regimens. Of interest, 32.6% of patients whom physicians believed were nonresponders achieved
an ACR 20 response. After the addition of MTX, 52% of patients at week 40 achieved an ACR 20 response.
The dosage of MTX used to achieve this additional benefit was low, with 29 of 46 patients receiving 10 mg or less and
only 6 patients taking doses greater than 15 mg. Frequency of liver function test elevations was greater in patients undergoing
combination therapy but either responded to dose reduction or resolved without alteration in the treatment regimen.
Etanercept: Several papers presented longer-term follow-up of RA patient cohorts receiving etanercept. These were patients
who elected to continue taking open-label etanercept after completion of their randomized clinical trial. By definition, patients
remaining in the long-term trials have demonstrated clinical efficacy and safety and therefore are a selected group and the
data should be evaluated cautiously. The information is important in that it provides data on the persistence of benefit and
long-term toxic effects.
In 64 patients continuing with etanercept-MTX combination therapy, persistence of clinical response similar to that seen
at the end point of the initial study was reported. At a median of 48 months, 74% achieved ACR 20 response, 45% achieved ACR
50 response, and 12% achieved ACR 70 response. Improvement in disability was maintained. Sixty-nine percent of patients discontinued
use of corticosteroids, and 24% discontinued use of MTX. No increase in AEs over time was seen, including infectious AEs.
Similar results were seen in a cohort of patients receiving etanercept monotherapy followed up now for more than 5 years.
Data were available for 562 of 629 patients from the original cohort, with more than half of the patients completing 4 years
of therapy. Persistence of effect, as measured by ACR response, was seen and similar to the combination trial. Seventy-three
percent of patients were able to decrease or lower their dose of corticosteroids. No increase in AEs was reported, and the
incidence of malignancies was similar to that expected.
An analysis of the impact of etanercept on patient-reported outcomes involving patients from the etanercept clinical
trials (n = 921) demonstrated greater impact on patients with early disease compared with patients with longstanding disease.
Zero Health Assessment Questionnaire scores were exhibited by 23% of patients with early RA and 16% of those with longstanding
RA at 4 years.
Results from the Etanercept (Enbrel) in Early Erosive Rheumatoid Arthritis (ERA) trial of patients receiving open-label
etanercept demonstrated persistence of impact on radiographic progression as measured by total Sharp score at year 3 follow-up
in patients with available radiographs. Radiographic progression measured by total Sharp score in year 3 in patients who continued
to receive etanercept was only 0.37 compared with an increase of 1.47 during the previous 24 months.
In addition, in patients receiving MTX who had etanercept added to their regimens at 24 months, radiographic progression
was only 0.28 as measured by total Sharp score compared with an increase of 1.77 in the previous 24 months.
The FDA reported on 25 cases of tuberculosis in patients receiving etanercept through March 2002. The primary findings
were that 60% of patients were also taking other immunosuppressives and 52% had extrapulmonary disease, suggesting that physicians
should be alert for extrapulmonary disease. The FDA group also reported 28 cases of leukocytoclastic vasculitis occurring
in patients while receiving biologics, of which the agency was notified from August 1998 to April 2002. Sixteen patients were
taking etanercept and 12 were taking infliximab. The vasculitis resolved with discontinuation of the tumor necrosis factor
(TNF)-alpha inhibitor and/or corticosteroid treatment.
One paper from the University of Arizona and Immunex presented a cost-effectiveness analysis of etanercept and infliximab
from 125 rheumatology practices. The primary outcome was the cost to achieve an ACR 50 response using published data from
the clinical trials. The cost per patient for achieving an ACR 50 response was $31,108 for etanercept and $54,525 for infliximab.
In 254 patients evaluated in a European randomized clinical trial, etanercept monotherapy or etanercept in combination
with sulfasalazine was found to be superior to continuing sulfasalazine in patients previously treated with sulfasalazine
alone. Three presentations evaluated intra-articular etanercept in RA. One randomized trial of 26 patients suggested
benefit clinically and by ultrasound.
Infliximab: Investigators presented data from the randomized clinical trials of infliximab in RA and Crohn's disease
throughout 54-102 weeks of treatment. Infusion reactions were noted in 5% of patients, leading to treatment discontinuation
in 2.5%. Thirty-one percent of patients developed antibodies to infliximab, which did not seem to affect efficacy. Serious
infections were not seen more frequently with infliximab than in placebo-treated patients, and the incidence of overall malignancies
was similar in the 2 groups.
An evaluation of overall safety of biologics compared with DMARDs was reported from Wolfe's National Data Bank. Only
prednisone treatment was found to be associated with an increased risk for hospitalization for infection. Neither infliximab
nor etanercept was associated with an increased risk of infection.
A follow-up evaluation of the ATTRACT trial, stratifying patients by prestudy annual rate of radiographic progression,
was presented. The results demonstrated that patients with the highest rate of progression (Sharp score > 10.2) demonstrated
the greatest benefit from infliximab, although clinical benefit was seen for all patients regardless of baseline radiographic
progression.
A study from the Swedish RA registry examined patients who had increases in infliximab dose up to 5-6 mg/kg and compared
these patients to 2 control groups: patients continuing infliximab use without dose increase and patients receiving a stable
dose of etanercept. Patients receiving infliximab dose increases had a higher DAS at the time of increase compared with the
previous best attained level (4.04 vs 3.46; P < .001). Of interest, the improvement in DAS with increased infliximab dose
was similar over time to that of the patients continuing stable-dose infliximab or etanercept when their response was compared
with a reference time point of an increase in DAS while receiving treatment in their registry. The authors concluded that
these findings may be due to regression to the mean and suggested that the use of infliximab at higher doses needs to be further
evaluated.
Two presentations evaluated the impact of short-term infliximab on bone. Twenty patients with less than 1 year of RA
were treated with MTX and the addition of infliximab or placebo for 54 weeks. Bone mineral density was evaluated at the hand,
spine, and hip. Infliximab prevented bone loss at the hip and lesser so at the spine but not at the hand. The difference reached
statistical significance only at the hip.
The effect of infliximab on magnetic resonance imaging (MRI) progression of joint damage was evaluated in the same patient
cohort. Infliximab was statistically superior to MTX in retarding MRI evidence of synovitis (P < .05). Bone erosion score
at 54 weeks improved from 7.1 at baseline to 2.8 in patients receiving infliximab, compared with MTX-only treated patients'
improvement of 7-5.8. Neither treatment altered bone edema scores during the study, with no change for those receiving infliximab
and MTX and worsening on MTX alone throughout 54 weeks.
The results of an early RA cohort treated with infliximab in addition to methotrexate was reported as a late-breaking
abstract. This study evaluated 20 patients with a mean of 6 months' RA and compared the response to patients treated with
MTX alone. The ACR 50 and 70 responses at 54 weeks were statistically superior for the infliximab/MTX patients compared with
MTX treatment alone. At 54 weeks the infliximab was discontinued, and 19 patients have been followed for a mean of 81 weeks.
Of interest, none of the patients receiving infliximab who achieved ACR 50 response at 54 weeks had flared on MTX alone.
The investigators suggested that early complete suppression of the disease may provide "optimal outcome." There has been
great interest in the phenomenon of induction-remission in RA but no evidence-based medicine to support the hypothesis. The
results from this small study are intriguing, but longer-term follow-up is necessary. In addition, large randomized clinical
trials evaluating the response to early intervention with infliximab and adalimumab are in progress.
One of 2 retrospective studies of clinical practice experience demonstrated that infliximab may be more effective in
improvement of rheumatoid nodules than etanercept, and both demonstrated that patients with partial response to etanercept
may respond when switched to infliximab. Confirmation of these observations in larger databases is necessary.
Anakinra: Further evaluation of anakinra safety in the previously presented "all comers" study was presented. That study
included patients with longstanding disease, most of whom were receiving corticosteroids and DMARDs. A total of 1396 patients
were divided into groups of high risk or low risk for infection based on comorbidities such as diabetes, chronic obstructive
pulmonary disease, chronic heart failure, and recurrent infections.
There was no significant difference in the frequency of overall infections between the 2 groups, although serious infections
were more common in both groups for patients receiving anakinra compared with placebo-treated patients (low-risk group, 2.4%
vs 0%; high-risk group, 1.9% vs 0.6%). The conclusion of the authors was that except for injection site reactions, no significant
difference in safety profiles was seen in patients receiving anakinra compared with placebo-treated patients.
A presentation on an interim analysis of combination therapy with anakinra and PEGylated soluble TNF receptor type 1
in 6 patients with RA demonstrated clinical efficacy at 4 weeks. Of interest, synovial biopsy specimen evaluation of these
patients demonstrated no difference between responders and nonresponders. Additionally, no significant changes were noted
on 4-week synovial biopsy specimens compared with baseline. A cautionary note on combination cytokine inhibition was reported
at an Amgen-sponsored symposium.
A larger trial evaluating etanercept and anakinra in combination demonstrated a significant increase in infections compared
with etanercept alone, confirming an observation reported previously in a small pilot study presented at last year's ACR meeting.
The results of a large multicenter trial of 906 patients evaluating the impact of anakinra (100 mg/d) on radiographic
progression in patients with longstanding RA on background MTX and with baseline erosive disease was presented.
Patients receiving anakinra had a statistically significant reduction in radiographic progression as measured by modified
Sharp score compared with placebo patients (P = .002). Of interest, the rate of progression in the placebo group throughout
12 months was a Sharp score of only 2.6 less than reported in the placebo group from the ATTRACT trial, where the Sharp score
increased by 7. Although one must be careful to compare studies, the demographics of the patients entered into these trials
were similar, suggesting that patients presently being recruited into trials may differ in their disease from those recruited
in the prebiologic era.
Switching from etanercept to infliximab, and possibly the reverse, may improve symptoms of rheumatoid arthritis in nonresponders
or partial responders, a new study suggests. Karen E. Hansen, MD, with the University of Wisconsin, Madison, and colleagues
presented the findings at the 66th annual meeting of the American College of Rheumatology.
The researchers previously reported the safety and efficacy of leflunomide and infliximab in 93 subjects with RA. They
then analyzed data from the 20 patients in this study who had previously taken etanercept to see how they fared. "Indications
for switching therapy to infliximab included lack of efficacy (17 subjects), shortage of etanercept (1 subject), low platelet
count (1 subject), and patient concern regarding risk of infection (1 subject)," the authors note.
Swollen and tender joint counts were reported for 17 subjects immediately before patients started taking infliximab.
During the study period, the tender joint count decreased from 15 to 4 (72% decline), swollen joint count decreased from 13
to 4 (72% decline), and morning stiffness decreased from 70 to 39 minutes (30% decline).
Similarly, patient global assessment improved by 30%, while physician global assessment improved by 20%, pain diminished
by 84%, and mean prednisone requirement decreased by about 50%. The effect may also work when patients switch from infliximab
to etanercept, When researchers administered etanercept to one patient who had previously been taking infliximab,the patient
with severe arthritis went into remission.
Investigative scientists said,"We might be able to use three different TNF-alpha inhibitors," (infliximab, etanercept,
and the investigational drug adalimumab [Humera) They recommend that physicians try this approach in their patients. Importantly,
side effects appeared to be no different in patients who switched.
A professor in rheumatology with the University of Leeds,England who researches the efficacy of TNF-alpha antagonists,said
he has also seen improvements in patients who have switched. "These agents differentially inhibit cytokines, such as interleukin-6
and are not just anti-TNF," he said. "Patients also show inter-individual variation in the way they express cytokines, which
may also account for these improvements." 'It's not that infliximab is a better product than etanercept or the other way around,"
he continued, and he added that switching to Humira is likely to have a similar effect.
Note that some research papers indicated that if a patient did not respond to one TNF inhibitor trying another is a waste
of time. Sounds like the note I put in about MTX at 19 and 25 mg. RA patients different in medication response.
Charts,trials amd graphs are very important,but they don't always tell the true story when analyzed from different situations
and angles.
VIOXX WAS TAKEN OFF THE MARKET BY THE FDA A FEW YEARS AGO- PLEASE DISREGARD ANY REFERENCE TO THE-NSAID.
Rituximab (Rituxan/MabThera) targets and depletes CD20 positive B cells. In Phase III trials, a single treatment
(two infusions) of rituximab, combined with methotrexate, produced symptom improvement in patients with moderate to severe
RA who had failed to respond to anti-TNF therapies.
CTLA4-Ig (Abatacept) is the first drug in a new class known as selective T-cell co-stimulation modulators. The
drug blocks T-cell activation. Phase III trials of patients who have failed to response to methotrexate have yielded positive
results.
New Rheumatoid Arthritis Drugs
Cimzia. In people with RA who do not respond well to treatment with an older drug called methotrexate, adding the experimental
TNF-blocker Cimzia may do the trick, says Edward Keystone, MD, a rheumatologist at the University of Toronto in Ontario.
People in the study who took the Cimzia with methotrexate were more likely to feel better than those who took methotrexate
alone. What’s more, people taking Cimzia improved quicker than what has traditionally been seen with the other TNF-blockers
on the market such as Enbrel, Remicade, or Humira.
This drug has a different chemical structure than the currently available anti-TNF drugs, which allows it to remain active
in the body for longer periods of time and may allow it to go directly to the inflamed joint.
Among other potential perks, it may be cheaper to manufacture than other TNF-blockers. It also works faster and appears to
be safer for women of childbearing age, which could put it ahead of the pack, he says.
Denosumab. This drug works differently than TNF-blockers. Denosumab targets a protein involved in the destruction of joints
known as RANK ligand. But it doesn’t have any effect on the symptoms of RA.
“It is just affecting RANK ligand, and RANK ligand is involved in the bony erosions, not the overall process that leads
to signs and symptoms,” explains Desiree van der Heijde, MD, a rheumatologist at the Leiden University Medical Center
in the Netherlands.
Ofatamumab (HuMax-CD20). Another new agent, ofatamumab, targets B-cells, which are cells of the immune system that are believed
to play a role in causing inflammation in rheumatoid arthritis. This drug binds to the surface of B-cells, effectively killing
them off.
New research presented here shows that people with RA who received the drug did better than those who received a placebo or
dummy pill. People with RA who were also taking methotrexate in combination with ofatamumab responded better than those taking
the ofatamumab alone, says researcher Mikkel Ostergaard, MD, of Copenhagen University Hospital in Denmark.
Tocilizumab. This drug blocks another inflammatory chemical known as interleukin-6 (IL-6). New research presented here showed
that it significantly reduces inflammation in RA within about two weeks' time. When given at the highest dose used in the
study, it normalized levels of C-reactive protein, which is an indicator of inflammation in the body.
There were some side effects, however, including infections and an increase in levels of blood cholesterol and liver enzymes,
reports Josef Smolen, MD, a rheumatologist at the Medical University of Vienna in Austria.
But “there was a rapid and significant improvement in the signs and symptoms of RA,” he says.
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