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Updates II - RA

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The American College of Rheumatology have recenty added updates to RA---first since 1992.  6/7/08.

Rheumatology update

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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.

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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.