Inflammatory Arthritis - RA

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Socks Toxicity And Drugs In RA

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TOXICITY AND DRUGS IN RA

 
Until recently most patients with early rheumatoid arthritis (RA) have been treated, initially, with nonsteroidal anti-inflammatory agents or low doses of corticosteroids. Only those patients who had continued synovitis or who had extra-articular manifestations of their rheumatoid disease were treated with one of several disease modifying agents (DMARDS).
 
Because of the potential adverse reactions of the DMARDS, and together with their considerable expense, these agents were usually used alone. However, in the last few years, there has been increasing enthusiasm for the early institution of DMARD therapy and, even more recently, for the use of early combination DMARD therapy.

The rationale for combination DMARD therapy soon after the diagnosis of RA is established is based upon several theoretical considerations and clinical observations:
 
Recent studies of the natural history of rheumatoid arthritis, using a single DMARD, have emphasized the dire prognosis in a subset of RA patients who have a genetic predisposition (best identified at present by the presence of a shared epitope in the variable region of the histocompatibility antigen HLA-DR), are seropositive (rheumatoid factor positive), have early articular erosions, have functional disability early in the course of their disease and who have elevated levels of CRP.
 
In the early stages of RA, patients are generally healthier and, therefore, better able to withstand the potential adverse effects of these drugs.
 
Early in the course of RA, there is less disease mass (i.e., proliferative synovitis) to suppress and less irreversible joint damage.
 
The different DMARDS appear to act at different sites in the immunological and inflammatory cascades. While rheumatologists have been aware of the potential additional efficacy of combination DMARD therapy for some time, large prospective trials to test this therapeutic possibility have been delayed by the success of methotrexate (MTX) as a single DMARD.
 
More than 75% of rheumatoid arthritis patients receiving weekly oral or parenteral MTX achieve a moderate to excellent response with a minimum of adverse reactions requiring discontinuation of the MTX.  However, as is the case with all of the currently used DMARDs, only a few of these patients actually go into a complete remission. Thus, the MTX therapy must be continued and we are beginning to see an increasing number of patients who are relapsing after several years of treatment with MTX.
 
Another reason for the delayed large scale implementation of early combination DMARD therapy has been the hope that the recently introduced monoclonal antibodies to T helper lymphocytes would prove to be significantly better than the current DMARDS in the treatment of RA. Unfortunately, several trials with these products of molecular biology have proved to be rather toxic and not particularly effective.
 
Most of the published trials using more than one DMARD have been confined to patients whose RA had already failed to respond to one or more of these drugs used as single agents.  As might be expected, in this subset of difficult patients with well established disease, the results of these studies were not very promising.
 
Only very recently has combination DMARD therapy been compared with single DMARD therapy in prospective randomized studies of patients who had not failed previous DMARD therapy. Some of these studies have indicated that early combination therapy may be both more effective than single agents.
 
In all of these trials, the toxicity from the combination therapy has been quite low and comparable to that encountered with the single agents alone. No toxicity resulting from interaction between the different DMARDs has been reported and no significant drug interaction has been observed.
 
Three combinations that appear to be promising are sulfasalazine (SSZ) plus MTX, cyclosporine A plus MTX, and SSZ plus MTX plus hydoxychloroquine (HCQ).
 
One of the goals of early combination DMARD therapy is the induction of a remission in the RA in a significant number of patients, thereby permitting all anti-rheumatic therapy to be gradually withdrawn (sometimes referred to as step-down therapy).
 
This goal has clearly not been achieved in the trials reported to date. In view of the encouraging results and the very low order of toxicity that has been observed, it would seem reasonable to study these combinations using increased doses; or the addition of even more agents to the combinations in the hope of achieving early and lasting remissions in these patients -- an approach not unlike that used in the chemotherapy of certain malignancies.
 
While some investigators  ( many do ) may not feel that early combination DMARD therapy is a major break through in the treatment of RA, they  do believe that it is worth trying in some RA patients who have a poor prognosis at the onset of their disease -- objective evidence of persistent proliferative synovitis involving several joints, significant functional disability on a verified test such as the HAQ index, seropositivity and elevated levels of C reactive protein.
 
The goal of therapy in these patients is to eradicate all signs of synovitis and to bring the CRP down to normal. When carefully monitored, these combinations appear to be quite safe and effective in certain patients.

ACR position on cost-new medications: Several new medications used to treat both inflammatory and degenerative arthritis have been recently approved by the U.S. Food and Drug Administration.
 
 The need to balance the potential benefit of rational and appropriate use of these newer therapies with their increased cost is of significant importance to people with rheumatic diseases, their physicians, health insurance purchasers and third party payers.
 
Following double-digit health care inflation in the late 1980s and early 1990s health care premiums have been stable over the past few years. However, despite the flat to declining health care premiums, the cost of providing medications has risen 15-18 percent a year during this period. If this trend continues, it is estimated that over the next few years pharmaceutical costs will overtake those associated with hospitalization.
 
Several new arthritis therapies have been introduced, including cyclo-oxygenase 2 (COX-2) inhibitors and new biologic and immuno suppressive  agents. More new therapies, perhaps new classes of drugs, are on the horizon.

Early studies suggest that some of these agents may surpass currently available treatments either due to improved efficacy or a better side effect profile.
 
COX-2 inhibitors may provide comparable relief to other non-steroidal anti-inflammatory drugs (NSAIDs) with potentially less gastrointestinal toxicity.
 
The new biologic and immunosuppressive agents provide new or improved mechanisms to control inflammatory arthritis. These advances, however, are not without increased costs. The new COX-2 inhibiting NSAIDs, may be several times more expensive than non-selective generic NSAIDs. New biologic agents can cost $10,000 per year or more.
 
Insurers, health delivery systems, and self-funded employers have tried to control pharmacy costs by: Using formularies and other prescribing rules and restrictions. Increasing medication copayments and creating differential pricing between generic and brand medications. Outsourcing management to pharmacy benefit companies. Providing clinician feedback on prescribing patterns and associated costs. Creating treatment guidelines. Placing the pharmacist or clinician at financial risk for medication costs
 
Despite these efforts, medication costs continue to rise. In our multifaceted system of private and public insurance coverage, both the cost burden and the potential benefit of access to these new medications is often unevenly distributed.
 
Fully capitated large multispecialty groups may place the provider at risk for pharmacy costs. In contrast, in delivery systems where providers accept risk only for professional services, the insurer or managed care organization (MCO) is primarily at risk for medication costs.  Self-funded employers and preferred provider organizations (PPOs) may be at risk for medication costs or may shift part or all of that risk by contracting with a pharmacy benefit management company. 
 
Medicare beneficiaries are disproportionately impacted by rising pharmacy costs. Medicare has generally not provided outpatient medication coverage, resulting in many Medicare patients purchasing Medigap insurance to provide that coverage. In areas of significant managed care penetration and relatively high Medicare reimbursement rates, however, MCOs have offered generous pharmacy benefits as a way of attracting new enrollment into Medicare HMOs.
 
Rising pharmacy costs and declining reimbursement rates have forced many MCOs to drop those plans entirely or cut pharmacy benefits. Complicating this situation has been legislation in several states mandating the offering of comprehensive pharmacy benefits for Medicare patients and subsequent court reversal of this legislation in some of those states. Societys challenge is to balance the obligation to provide optimal treatment for individual patients with sensible cost considerations. Unfortunately, this often pits the provider against the insurer.
 
The American College of Rheumatology supports placing treatment decisions in the hands of those providers most knowledgeable about both the diseases and the newer therapies. The rheumatologist as an expert in both inflammatory and degenerative arthritis is best qualified to triage and promote the rational use of these treatments.  Strict external rules and restrictions imposed by payors may result in the denial of these agents to those most in need of treatment, leading to increased pain and disability. Differential rules and regulations on access to these medications can be a subtle way of encouraging chronically ill patients to switch to other insurers or health plans.
 
There has been a great deal of enthusiasm for disease management for chronic diseases such as asthma, congestive heart failure and diabetes, as these programs have resulted in rapid cost containment from decreased hospital and emergency room use. This same enthusiasm should be extended to chronic diseases such as rheumatoid arthritis, which often requires less hospital care and has a longer and less certain financial payoff.  For those still working, gains can be measured in longer and more productive work lives, and for those no longer in the workforce, these gains can be measured in improved quality of life.
 
The new medications becoming available for arthritis must be examined in terms of both their potential additional benefits and greater costs. Potential benefits include increased effectiveness, a better quality of life, increased work productivity, decreased disability, and possibly a reduction in hospitalization and joint replacement surgery. Increased costs include considerably higher prices than those for currently existing medications and any differential cost of toxicity monitoring and the delivery of treatment.
 
Rheumatologists, the clinicians with the most experience and expertise in diagnosing, evaluating and treating arthritis, are uniquely qualified to determine the appropriate use of these new therapies, especially the biologic and immunosuppressive agents. This is particularly true in the case of juvenile rheumatic diseases where small populations make it impractical for manufacturers to conduct extensive testing. In these cases, clinician experience rather than scientific data becomes the primary factor in determining clinical pathways.
 
Restrictions requiring the failure of an arbitrary number of other therapies prior to use of newer agents are inappropriate. Since these new medications have shown promise of being more effective early in the course of arthritis, the time and expense spent trying serial medications may result in increased joint damage and disability.
 
Providers and insurers alike need to consider both the effectiveness and cost of medications when making or paying for treatment choices. This has very significant implications for society as the purchasers of health care (employers, government and individual patients) decide how best to finance health care in the future

Factors Involved In Therapy:
 
Despite promising short-term results for newer DMARDs that have significantly demonstrated effects on functional status and radiographic progression,there are,at present,insufficient longatudial data to determine whether such a 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 patientients in whom MTX therapy has failed:etanercept monotherapy,etanercept plus MTX,cyclosporine plus MTX,triple therapy with HCQ,SSZ,and MTX,continued MTX monotherapy,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-effectiveness 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 was considered.
 
More data about the impact of newer DMARDs on outcomes such as work capacity and radiographic progression are needed.
 
In to-days cost-constrained environment,whenever the efficacy and toxicity of treatment options are equivalent,the lower-cost agent is likely to be used. However,practisioners are increasingly facing situations in which therapies are no longer equivalent,there is only a partial response to treatment,treatment toxicity or comorbid conditions contraindicate the use of more traditional agents,or high-risk or severe disease requires the use of newer agents,either alone or in combination.
 
Providers with sufficient numbers of RA patients in their practise and with longitudinal experence in treating this disease will,in consultation with their patients,be the best qualified to balance these 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 evaluation of disease activity,patient education/rehabillitation interventions,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.
 
In patients who have unacceptable levels of pain,loss of range of motion,or limitation of function because of structural joint damage,surgical procedures should be considered.
 
Surgical procedures for Ra include,carpel tunnel release synovectomy , resection of the  metarsal heads,total joint arthroplasty,and joint fusion. New prosthetic materials and cements for fixing joint prostheses have greatly advanced the prevention of aseptic loosening and have increased the longetivity of total joint prostheses in patients with RA.
 
Preoperative functional status is an important determinant of the rate of recovery of functional independence after surgery. strategies for increasing functional recovery include optimization of preoperative functional status and early surgical intervention.
 
The pre- and postoperative team should include health care professionals who have performed large numbers of the particular surgical procedures and are experienced in the care of RA patients.

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 or rheumatologist who also provides primary care ) or the responsibility may be shared. The role of the primary care physician is to recognize and diagnose RA at its onset and to ensure the patient receives timely treatment before permanent damage results
 
The rheumatologist should provide support and consultation to the patient and his or her primary care physician in the diagnosis and treatment of the RA.
 
Since the level of training and experience in diagnosing and manageing 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 the patient is to be shared,an explicit plan for monitoring RA disease activity and/or drug toxicity needs to be formulated. The patient's preferences may be the most important factor in decideing which physician(s) assume responsibility 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 preventive measures,such as screening for hypertension or cancer,should be recommended and risk factors modified.
 
RA has significant economic implications for the individual patients as well as for society. Individuals with RA have 3 times the direct medical costs,twice the hospitalization rate,and 10 times the work disability rate of an age sex-matched population
 
A recent study has shown annual medical costs for a patient with RA to be approximately $8,500 (U.S.) 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.
 
Reposibility 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 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 the COX-2 inhibitors,newer DMARDs,including biological agents,and the increasing use of combination therapy have all brought cost considerations to the forefront. The majority of guidelines have generally avoided cost issues by limiting their scope to an optimum treatment recommendations. However, ignoring financial considerations would inadequately reflect the impact on daily treatment decisions.