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While the etiology of rheumatoid arthritis (RA) is still not known, knowledge of the pathogenesis of rheumatoid joint disease has increased at an accelerated pace in recent years. There is general agreement that the pathologic process is largely, if not entirely, immunologically mediated. There is a postulated rheumatoid arthritis "antigen." It could be viral, bacterial, or a fragment of a bacteria1 agent, most likely sequestered in the chondrocyte lacunae of the articular cartilage. The articular cartilage should be looked upon as the target organ in rheumatoid joint destruction.
The goal, to put it another way, of the immunological process in RA is the total destruction of the articular cartilage. Until that occurs in a particular joint the immune-mediated inflammatory process never becomes quiescent.
The presumed RA antigen (complex protein) is ingested by the antigen presenting cell, macrophages and certain B-cells, Within this cell, the antigenic protein is broken down into small peptide fragments and goes to the cell surface. If the appropriate major histocompatibility molecules (MHC) are present, such as HLA-DR4, this peptide + HLA complex will activate certain T-cells, These activated t-cells will in turn activate macrophages, which elaborate a variety of cytokines particularly I1-1 and tumor necrosis factor (TNF). TNF will be discussed in greater detail subsequently, The activated T-cells also stimulate auto-reactive B-cells, which lead to the production of rheumatoid factors and immune complexes. There is therefore a two pronged attack on the articular cartilage - the T-cell driven cytokines, via macro-phage activation, and B-cell derived immune complexes, The T-cell process occurs primarily in the rheumatoid pannus.
In parallel with this cell-mediated process, the immune complexes are secreted into the joint space, Here, they initiate the complement cascade within the synovial compartment and are chemotactic for polymorphonuclear leukocytes, As these cells ingest the immune complexes, rheumatoid factors and immunoglobulins, the granulocytes are disrupted, This results in the liberation of a variety of proteolytic substances such as neutral proteases and cathepsins within the joint fluid. These contribute significantly to the process of joint destruction.
Clinically we see soft tissue swelling and pain in the involved joints, but radiologically, the marker for destructive disease is the presence of erosions, usually in the sub-chondral region. Many rheumatologists believe that once the erosive process has begun, the disease is no longer reversible. By standard X-ray, erosions may be seem as early concepts rheumatoid arthritis.
Two years after the onset of clinically apparent disease, but utilizing the MRI, erosive changes may be found even at 6 months, while standard radiographs show minimal soft-tissue swelling and little else. These observations are responsible for the more aggressive and earlier use of second and third line drugs in the therapeutic approaches to be discussed, Most rheumatologists believe that therapeutic strategies which result in normalization of the erythrocyte sedimentation rate and the C-reactive protein.
The traditional therapeutic "pyramid" for treatment of RA utilized simple measures and nonsteroidal, antiinflammatory drugs (NSAID)s in an initial effort to afford symptomatic relief, Only if these drugs failed or could not be tolerated, was the next tier of drugs utilized, Thus years might elapse before more definitive therapies were begun, Now the trend is for more aggressive intervention earlier with the so-called disease modifying agents, but since NSAIDs are basic to the entire treatment regimen, their use will be briefly reviewed.
NSAIDs are chosen for clinical trial based Upon their ability to inhibit the enzyme cyclooxygenase or prostaglandin synthetase, now referred to as synthase, When this enzyme is blocked, pro-inflammatory prostaglandins are reduced, hence there is a diminution in the inflammatory response. Unfortunately; production of physiologically important prostaglandins also results: This manifests itself clinically in 3 major areas; the GI tract platelet aggregation and renal blood flow. The GI effect of NSAIDs is not only the so-called gastropathy but involves the small and large bowel as well. These drugs may either induce or, more likely exacerbate, inflammatory bowel disease.
In 1993, it was shown that Synthase is an isoenzyme, with the form responsible for physiological prostaglandin functions referred to as synthase I or cyclo-oxygenase (cox) I, and the pro-inflammatory isoenzyme, COX II. currently available NSAIDs vary in there inhibitory effect oh the 2 forms, but this correlates only partially with clinical experience with respect to adverse effects. The effort is now underway to synthesize specific COX II inhibitors, thereby achieving the desired antiinflammatory effect, while not Upsetting physiologically dependent prostaglandin functions.
The "therapeutic pyramid" of 1995 is no longer a pyramid. NSAIDs tend to be used throughout, but either Azulfidine or hydroxychloroquine may be implemented well within the first year of disease; If the RA activity is persistent, methotrexate will be introduced early, This drug has largely revolutionized the approach to RA, It has an extremely favorable benefit/risk ratio, and is less likely to result in secondary failures.
Methotrexate is given once weekly, in dosages between 7.5 Up to 25 mg, orally or by injection, as the level of disease activity requires, Onset of action is usually between the 3rd and 6th week. Some patients wi11 require higher doses with time, but in others, a lower maintenance dose may suffice after optimum disease control has been obtained, Complete blood counts with platelets and chemistry, with hepatic enzymes should be done monthly, Those at greatest risk for toxicity are patients with impaired renal function, folic acid deficiency or concomitant administration of other drugs with an antifolate effect, ie, Bactrim, and liver disease or heavy alcohol ingestion.
Methotrexate toxicities are many, but often discontinuance of treatment can be avoided. Anorexia., and nausea and vomiting are common; the only manifestation being a subtle loss of Weight. Modest elevations in liver enzymes are often found, and can be corrected with daily administration of 1.0 mg of folic acid, provided it is not given on the treatment day. The necessity for periodic liver biopsy is still not resolved; most rheumatologists do not routinely have biopsies done, although hepatic fibrosis may occur even with normal transaminase levels. Oral mucositis may also respond to folic acid supplementation, but alopecia, headache, sedation, and howe1 disturbances, do not, Methotrexate-induced lung disease is a serious complication, which may be manifest as dyspnea and interstitial pneumonitis, mandating cessation of therapy, Despite the potential for these adverse effects, most patients tolerate the drug remarkably well.
It must be emphasized that methotrexate is an antiinflammatory drug, and disease flares usually follow its withdrawal, It probably works in RA by the same mechanism that it works in malignancy, psoriasis, and other chronic inflammatory diseases; the inhibition of the enzyme dihydrofolate reductase, This decreases the availability of reduced folates needed for purine biosynthesis in rapidly replicating cell systems, such as one finds in the inflammatory response in RA. Unique to this drug in RA is the accelerated growth of rheumatoid nodules, often in sites where they would hot Usually occur. The mechanism for methotrexate nodulosis is unknown.
Immunosuppressive drugs such as azathioprine and cyclosporine are Used in resistant RA with some success in a subset of patients, Cyclosporin is limited in part by its nephrotoxicity and proclivity to induce hypertension, particularly when accompanied with NSAIDs. Cyclophosphamide is used only in life threatening complications of RA, such as vasculitis.
A new class of compounds are called the biologicals, as they have been designed to interfere With the immunopathogenic mechanisms outlined earlier. Unfortunately) most of these, including monoclonal antibodies (Mab) to CD4 lymphocytes, have largely failed in the clinic. The most promising of this group is the Mab to TNF (tumor necrosis factor), which is a cytokine discussed earlier, TNF appears to play a major role in cytokine regulation, and its inhibition by Mab has resulted in significant improvement in RA in appropriately conducted trials. Furthermore retreatment continues to result in improvement as relapse ensued. However, the remittive period appears to shorten with multiple treatments. Although this Mab to TNF may not become widely Used in therapy for a variety of reasons, it has pointed to TNF as a major target for cytokine inhibition.
One of the most fascinating areas for the future is the study of HLA-DRB1 alleles as markers of severity in RA, Patients who are positive for HLA-DRBI*0401/0401 are at high risk for rheumatoid organ disease and ultimate need for joint replacement, Those with HLA-DR B1*0401/0404, HLA-DRB1* 04/01, and the group with HLA-DRB1*04/x, are at progressively reduced risk, Prospective studies with these markers are now underway to determine if the subset at greatest risk can be identified and subjected to the more aggressive therapies before significant joint damage has developed; Gene therapy may well be the definitive treatment for this disease.
In early rheumatoid we see interphalangeal joint swelling. In the other hand we see exactly the same finding, illustrating symmetry. And this is classical, early RA. After a given number of years, almost invariably this is what we have to show for our therapeutic efforts. Considerable deformity, a relatively functionless pair of hands and yet still synovial thickening, edema, pain and tenderness. So that even after many years the disease continues to destroy what’s left of the articular structure. There is no disease in all of internal medicine which has such chronic persistent and sustained inflammation as the disease of rheumatoid arthritis. We know the etiology of this disease but we haven’t really good knowledge of its pathogenesis and its pathogenesis is largely immunological. The first contribution to this - which in fact is the definition of the first of the so-called autoimmune diseases.
The cytokines, particular two in the necrosis factor alpha, and to a lesser extent interleukin 1, will thread their way back and forth as this talk evolves because this is the year of the cytokine therapy for rheumatoid arthritis and I’ll be coming to that shortly. Suffice it to say, tumor necrosis factor alpha is a fundamental cytokine which regularly upgrades the inflammatory response of the synovia as well as, parenthetically, as the intestinal lining in Crohn’s disease. Both of those lesions are exquisitely TNF dependent for their regulatory response. More TNF, more bad disease. You inhibit TNF or get rid of it, the disease and the inflammation become quiescent. Hold that thought because I will be coming back to it in a few minutes.
Treatment involves giving nonsteroidals throughout therapy, but the big difference in early intervention in rheumatoid arthritis has been the use of methotrexate, which I am going to talk about in detail in just a moment. For patients that were smoldering along and not too bad, we would tend to use hydroxychloroquine, but increasingly one is going directly from nonsteroidal.
We now have two such agents and I’m going to talk to you about them briefly because this is information you need to know. Celebrex was the first one introduced late last fall. And the FDA allows the maker to say that this inhibits prostaglandins and primarily inhibition of COX-2, and in therapeutic concentrations in humans it does not inhibit COX-1. As you will see in a moment, the second COX-2 specific is allowed to make the identical claim and this is the truth. I could show you numerous slides on this. But I think we will just concentrate on this. Placebo, celecoxib in terms of dyspepsia, abdominal pain, diarrhea, the same as background and more importantly but not shown on this slide, if we look at serious GI complications - PUBs - perforations, ulcers and bleed, same as placebo. This is an extraordinary advance and it happens because the COX-2 specifics do not produce the peptic disease in the mucosa and do not inhibit platelet aggregation, so these people are not under a double jeopardy threat.
Very quickly, on this particular one, they claim that it has no interaction with methotrexate, which is true. It claims that it has no action with warfarin, which is not true. INRs go up about 8%, or may go up about 8% in the presence of this drug, so the usual monitoring has to be done. But I will tell you that for the most part, this drug and the other one called Vioxx, which we’ll talk about in a moment. The methotrexate story I emphasize because that represents one of the subtle differences between the two.
Here we talk about platelet aggregation. This is the placebo, this is celecoxib, this is naproxen, this is ibuprofen, this is dipropionate. And once again, in terms of inhibition of platelet aggregation, no effect. These people are not anticoagulant. In fact if you use these nonsteroidals and you have a patient who needs cardiac or stroke prophylaxis, you must give them a baby aspirin a day along with this in order to get an antiplatelet effect and that’s done. No effect on platelet aggregation, what I just showed you. The specific indication labeled by the FDA for this product, is for osteoarthritis and rheumatoid arthritis with their respective doses.