A middle-aged woman was referred to a rheumatologist for evaluation of hand and foot pain of two months'duration. She had noticed a gradual increase in pain and swelling in the proximal interphalangeal (PIP ) and metacarphal phalangeal (MCP ) joints of the hands and the metatarsal phangeal (MTP ) joints of the feet. She also experienced a progressive increase in morning stiffness,which now lasted as long as two hours and could be relieved somewhat by taking a warm shower and forcing herself to use her hands (e.g., preparing breakfast). Later in the day,activity made the pain worse. There was occasional discomfort and stiffness in her knees,but substantially less in her hands and feet.

 

The patient worked as a secretary fo many years but was now having difficulty performing her job. She had tried over-the counter ibuprofen and acetaminophen; neither provided significant relief.

 

She had no fever,ulcers,serositis,neurological disorder,renal disease,or photosensitivity. Her family and family history revealed no history of significant disease.

 

Examination of the hands revealed significant warmth and swelling in both wrists and a noticeable reduction in both flexion and extension. There was mild swelling of the PIP and MCP joints in a bilateral and symmetric distribution. Palpation of the forefoot produced a notable tenderness.

 

Laboratory studies showed a white blood count of 6,500/mm^3,with a differential of 59 % polymorphonuclear leukocytes and 31 % lymphocytes; hemocrit,38.3 %;platelet count,275,000/mm^3;blood urea nitrogen (BUN),11 mg/dl;seru creatinine,0.7 mg/dL;aspartate aminotransferase (AST).16 U/L. Assays for antinuclear antibody (ANA) and rheumatoid factor (RF) were negative. The erythrocyte sedimentation rate (ESR) was 39 mm/hr. A urinalysis was normal. This patient has rheumatoid arthritis.

 

Treatment: The patient was treated with oral methotrexate,7.5 mg once a week,and this dosage was titrated to 20 mg during the next three months. Her liver function test remained normal,and she reported no significant side effects. However,she experienced only mild change of symptoms.

 

The rheumatologist considered adding one of the newer antirheumatic agents (leflunomide,etanercept,or infliximab),but the patient's insurance company refused to pay for treatment with these agents until therapy with at least two of the established DMARDs had failed. Consequently,hydroxychoroquine and sufasalazine were added to her regimen. Within three months,she showed substantial improvement.

 

The patient,posed a bit of a diagnostic decision.  In spite of her clinical history and findings on examination,her serum was negative for both rheumatoid factor and antinuclear antibody.and it was not clear whether there were any abnormalities on x-ray.

 

The decision to start MTX at the first call was a judgement call. Another rheumatologist might have tried another ( prescription ) NSAID at full dosage,added a few milligrams of predisone each morning,and checked films of the hands and wrists for at least evidence of some tell-tale juxtra-articular osteoporosis. If the films were normal,a few weeks of a full-dose NSAID or low dose steriod,or both,would probably have been satisfactory.

 

With minimal changes on x-ray (i.e., mild osteoporosis) the rheumatologist might have started with hydroxoychloroquine because of its great safety (eye examinations are really all that is needed for sound follow-up) and relatively minimum side effects. If the films showed any evidence of erosion,or very active,MTX would be the choice,with rapid escalation of doseage as needed.

 

 Had hydroxychloroquine been started and found inadequate,methotrexate could have been added at any time,as could sulfasalazine,but methotrexate appears to be more effective.

 

Many rheumatologists prescribe folic acid whenever treatment with methotrexate is begun. It appears to improve safety with little or no loss of MTX efficacy ( 5 day rather the 7 day treatment proved more effective in research trials-folic acid-dilution concerns of MTX when used with folic acid )

 

The importance of educating the patient cannot be overemphasized,but in reality,limited time is a factor in modern day medicine. Cox-2 inhibitors are not more effective than non-selective NSAIDs,but they are thought to do less damage to the gastric mucosa.

 

One other interim strategy to keep in mind when one or two joints remain troublesome is to inject them with corticosteriods. These injections,which may be given once or twice,can provide excellent relief for many weeks or months.

 

 The main concern is to be sure that no infection is in the joint. Sometimes, the second injection may prove less effective,but often,its a trial decision. Larger joint involve larger doses than smaller joints,and less frequency of repeat injection in the larger joints (i.e.,hip-knee vs fingers).

 

During the last 5 years,our therapeutic options increased significantly. The introduction of leflunomide (Arava).a pyrimidine synthesis inhibitor (suppresses cells that are rapidly dividing),has provided an alternative for patients who cannot tolerate methotrexate or provide another option.

 

Etanercept (Enbrel),a fusion protein that interrupts the inflammatory cascade by binding to tumour necrosis factor (TNF)-alpha,can be used in early disease or when conventional therapy do not work (limited by cost factor and insurance coverage). Another TNF-alpha inhibitor,infliximab (Remicade), would probably work very well in early disease,but currently its use is limited to refractory (people who do not respond to conventional therapy) cases,in which it is given in combination with traditional medications such as MTX (high cost).

 

Recently (2003)another TNF-alpha inhibitor Formerly known as DE27,now called Humira has been approved by the FDA for RA therapy. In the U.S.,the manufacturer,Abott Laboratory has introduced a promotional aspect to senior citizens on medicare whereby the drug is offered,free of charge. The manufacturer  estimates it will cost them 30 million per annum. Early clinical trial were conducted by Dr.Edward Keystone,researcher,scientist and rheumatologist of MT.Sinai  hospital,rheumatology division (Adelimumab). 

 

Kineret is a Il-1ra (interleukin family)inhibitor introduced in early 2002. It can be used with MTX,but currently,combination with other TNF inhibitor is not recommended because of recent clinical trials. Researchers believe the serious side effects may be dose related and they are working on the problem.

 

Both Remicade and Enbrel improve function,and there is good evidence they slow radiographic progression of RA(Arava also,but Arava might be more suitable for patients that cannot tolerate MTX). This would argue for their use early in the disease,especially in patients who seem likely to have a aggressive or a destructive course.

 

Traditional disease-modifying agents can also slow radioraphic progression,

however,and they are much less expensive then the newer agents. Consequenty,governments (provincial health plans have different guidelines in different provinces in Canada) and thrd-party payers impose restrictions on the use of the new biologic drugs. They may stipulate that patients must first be unresposive to as many as three traditional agents before they will pay for treatment with a TNF-alpha inhibitor.

 

These restrictions are being relaxed somewhat,slowly,as evidence of the new agents,efficacy and safety accumulates. Enbrel recently released a 5 year safety data,but drugs like methotrexate (what to expect-side effects-safety)-has a long track record.

 

For physicians whose choice of initial therapy is limited to traditional agents,the first question is whether to start with a single agent or combination therapy. Possible combinations include HCQ with SSZ or MTX,SSZ with MTX,or all three together.

 

The choice of initial therapy can be a difficult one. They do not want to administer more medication than is necessary,yet they want to be aggressive enough to improve function and prevent the development of radiographic destruction,therby ultimately minimzing functional impairement and keeping down the long-term cost of care.

 

At present the most common strategy is to start with methotrexate alone. However,to minimize the risk of hepatoxicity,the patient must agree not to consume alcohol (or to do so only very modestly). If a patient is not tolerant to MTX,Arava can be tried.

 

Most rheumatologists choose not to start treatment with HCQ monotheraphy (single),except perhaps in patients with mild disease. Physicians are beginnining to use,more and more,use of HCQ in combination with MTX or SSZ,then in the past. Another alternative would be to start with SSZ alone,but the approach is less common (increasing) in North America than in Europe.

 

In the past a typical RA patient's MTX doseage (7.5 mg orally once a week) would have been titrated up slowly over six months or even a year. Now rheumatologists tend to move much faster,starting with up to 10 mg per week and taking dose to as 20-25 mg a week within the first two to three months. In 1998 a clinical trial was conducted with subcutaneous MTX injection with a equivalent dose of 25 mg and they found it more efficacious on patients with less side effects.

 

Faster dose escalation requires more frequent follow-up. Some physicians will try another approach. But they all look for abnormalities on liver function tests,mouth sores or ulcerations,significant fatigue,nausea,or discomfort during the first 24 hours after taking the drug.

 

Patients are asked to return two weeks (more or less)after first taking the drug,at which point the dose may be increased to 12.5 mg. Then they usually,return within four weeks. If they have had not a good response,the dose might be increased to 15 mg-17.5 mg. Four weeks after that,if patients still have not responded well enough,the dose may be increased to 20 to 25mg. But at that point,more than likely, subcutaneous injection of MTX will be introduced.

 

Clinical trials suggest that about 50 % of patients respond to methotrexate monotheraphy. Unfortunately,the average degree of improvement tends to be about 25 %. For example,the number of tender or swollen joints may decrease from 20 to 16,but there are always exceptions to the rule.

 

A few years ago,monotherapy was usually continued for six months to a year,and patients who had not responded might be switched to another drug. Today,if patients do not respond sufficiently to a adequate dose of medication, another DMARDs-HCQ,SSZ,or (if possible) Enbrel,Remicade,or Arava.

 

Arava is the least-cost wise of the new drugs,but is less efficacious of the other two-Enbrel and Remicade. Arava can stay in the body for up to 2 years after discontinuation of the drug A loading dose of 300 mg is given,100 mg for the first three day,at the start,and given in 10 or 20 mg ,tablet form,therafter.

The physician might consider switching to one of the newer agents,but if the patient has shown some improvement and has not been troubled by side effects,most rheumatologists will add rather then switch.

 

HCQ can be added at a doseage of 400 mg once a day or 200 mg twice a day. SSZ is usually added at a doseage of 500 mg once or twice a day, escalating to a total dose of 1 gm twice a day.

 

The escalation schedule traditionally recommended is for the patient to take one tablet a day for the first week,one tablet twice a day for the second week,one in the morning and two in the evening during the third week,one in the morning and two in the evening during the third week,and two tablets twice a day during the fourth week and thereafter.

 

For patients on combination therapy,physicians generally follow the same schedule for toxicity monitoring as with methotrexate.

 

They obtain a complete blood count and liver function test and look for myelosuppression. The other medications do not need to be monitored as frequently as methotrexate,but since the patient is in the office anyway,all the monitoring can be done at the same time.

 

If combination therapy does not produce substantial impprovement within three months,the physician has a good clinical basis to move to biologic (anticytokine) therapy,and hope there should be little difficulty in convincing a third party payer of the necessity of using these agents.

 

If a patient responds well to DMARD treatment,the physician should eventually think about reducing doseage or withdrawing the agents one by one. The goal is to provide just enough therapy to keep the disease under control,which drug is kept for maintenance purposes will depend on the rheumatologist and the patient.

 

Patients must undestand that current treatments can provide significant improvement,but complete relief is unlikely. Patients need to learn the importance of avoiding trauma or stress in involved joints and of physical and occupational therapy to improve structures around the joints to decrease pain and improve function.

 

Education about the disease and medication is also vital. Patients need to know the potential complications and toxicities of the drugs they are taking. They must be aware that some DMARDs take time to display their benefits,and be aware of a drug ,once efficacious,has become less effective. The bridge is usually low-dose glucocorticoid therapy (e.g.,up to 7.5 mg of predisone/daily).

 

Many RA patients are at risk of gastrointestinal complications from standard non-steriod drugs (NSAIDs). These patients tend to be older,have existing diseases such as diabetes,kidney,liver etc., and take glucocortoids and they may or may not have a history of coronary artery disease.

 

The cyclooxygenase (Cox-2) inhibitors ,since they appear to have a lower risk of gastrointestinal toxicity. The improved safety of these drugs shoud not be assuned to imply improved efficacy. No NSAID alone can alter the course of RA,they do not change radiographic progression or slow joint destruction.

 

For that reason,they should be used as adjuncts,never as monotheraphy. If a patient has heart problems,selection of NSAID may be important and that also applies to others, existing disease present,must be fully recognized and adjustments made in therapy.

 

With chronic treatment with aspirin or an regular NSAID (in some existing disease conditions,it may be wiser to use a standard NSAID like Naproxen), and add a gastroprotective agent (e.g.,misoprostol cytotec or a proton pump inhibitor).