Rheumatoid arthritis: an update

Dr Badsha presents an overview of diagnostic and treatment advances in the field of rheumatoid arthritis.

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By  Dr Badsha Published  September 27, 2006

Dr Badsha presents an overview of diagnostic and treatment advances in the field of rheumatoid arthritis.

If not treated quickly, as many as 80% of patients will develop erosions in their joints in the first two years after RA begins.

Rheumatoid arthritis (RA) is an autoimmune disorder of unknown etiology, characterised by symmetric, erosive synovitis and, in some cases, extra-articular involvement. Most patients experience a chronic fluctuating course of disease that, despite therapy, may result in progressive joint destruction, deformity, disability, and even premature death. Active and persistent joint inflammation begets joint damage and functional limitation.

If not treated quickly, as many as 80% of patients will develop erosions in their joints in the first two years after RA begins. If the condition is left untreated, over 50% of patients have to stop work within five to ten years of its onset.

RA is estimated to affect 1% of the adult population. It results in more than 9 million physician visits and more than 250,000 hospitalisations per year. Disability from RA causes major economic loss and can have a profound impact on families.

Disability from RA causes major economic loss and can have a profound impact on families. Due to the need to treat patients with rheumatoid arthritis promptly and appropriately, it is crucial to identify patients in the earlier stages of disease.

In the initial stages of disease, patients can test negative for rheumatoid factor in up to 50% of cases and, in established disease, negative tests occur in 20%. The proliferation of ‘early arthritis clinics’ is a response to this need for early detection.

Patients are typically seen with less than 12 months of symptoms and attempts are made to determine whether they are at risk for developing full blown rheumatoid arthritis, based on certain prognostic criteria.

Certain diagnostic modalities, including ultrasound and MRI of small joints, have been useful to detect early bony erosions that have not been apparent on x-rays.

A new blood test called anti-CCP (cyclic citrullinated peptide) is sometimes useful in patients who have rheumatoid factor negative undifferentiated arthritis.

The presence of anti-CCP in these patients predicts a higher likelihood of developing rheumatoid arthritis. In patients with established rheumatoid arthritis, the presence of CCP antibodies can indicate a poorer prognosis, signaling a need for earlier and more aggressive treatments.

To date, the American College of Rheumatology’s criteria has been widely used in the diagnosis of rheumatoid arthritis.

However, rheumatologists now will not wait for patients to have four out of seven criteria to confirm a diagnosis of RA.

There is a push to treat patients earlier and some new criteria have been established to identify those at risk of persistent (erosive) disease who need earlier treatment. The Netherlands model to predict persistent (erosive) disease is an example of this. It’s criteria are:

1. Symptoms > 12 weeks
2. Early morning stiffness > 60 minutes
3. Arthritis > three joints
4. Bilateral compression pain in
metatarsophalageal joints
5. Positive anti-CCP antibody
6. Erosions on hand or feet x-rays.

The more numbers of criteria present in the Netherland model, the greater the need to begin treatment early.

Disease modifying drugs should be used as soon as a diagnosis of rheumatoid arthritis is made.

Disease modifying drugs should be used as soon as a diagnosis of rheumatoid arthritis is made. The traditional drugs have included methotrexate, sulfasalazine, hydroxychloroquine, gold and more recently, leflunomide, but there are several newer treatments now available.

Tumor necrosis factor (TNF) blockers

All three of the available TNF blockers have led to quantum clinical improvement over that obtained with methotrexate alone. However, while high levels of TNF contribute to chronic local or systemic inflammation and joint destruction, low levels increase the risk of infection. Consequently, TNF blockers have been linked to an increased risk of infections, such as tuberculosis, and other medical problems such as low blood counts.

Monitoring with blood counts and TB skin tests is appropriate and should be guided by the physician. However, despite the necessity for caution and increased monitoring, the benefits of these drugs continue to outweigh their risks. Multiple issues, including effectiveness, safety, route of administration, likelihood of compliance, and costs or insurance coverage, need to be considered before prescribing, because important differences exist between these three agents.

Etanercept (Enbrel)

This fusion protein combines two p75 TNF receptors with an Fc receptor to form an immunoglobulin-looking molecule that decoys the pro-inflammatory cytokine TNF.

By doing so, it decreases the binding of TNF to its cellular receptors and thus avoids the downstream development of tissue inflammation and damage. It is both highly effective and, to date, safe. It not only leads to a clinical improvement over that obtained with MTX alone, but it has been shown to be disease-modifying.

Infection risk is increased in those patients who have actively infected skin ulcers or diabetes. No increased risk of tumours or autoimmune disorders has been found.

At this time, it is most commonly employed when patients have not had an excellent response to full-dose MTX. Etanercept is approved by the FDA for use with methotrexate, or may be used alone.

Dose: 25 mg subcutaneously twice weekly.

Infliximab (Remicade)

This chimeric monoclonal molecule is composed of 3/4 human and 1/4 mouse proteins and is an antibody to TNF itself. Thus, it either binds TNF in the blood or as it attaches to its receptor. By doing so, it stops its downstream pro-inflammatory and tissue damaging actions.

Infliximab leads to both clinical improvement and, according to a recent trial, a halting of erosion development and joint space narrowing. At this time, infliximab is approved only for use in combination with MTX.

More than 80 cases of Mycobacterium tuberculosis have been reported worldwide in patients who have been treated with infliximab. The infection appears to occur soon after the institution of infliximab, and some patients have developed disseminated disease.

Thus, a PPD must be performed prior to starting infliximab and, if positive, a chest x-ray. If the chest x-ray is normal, then infliximab can be used along with a nine month course of isoniazid and Vitamin B6. To date, the reported infection and tumour risk is not greater in patients treated with infliximab than in RA patients not treated with this medication.

Dose: The usual starting dosing schedule is an infusion at weeks zero, two, six and then every eight weeks. While the usual starting dose is 3 mg/kg in 250 cc of saline over two hours, in those patients who have not responded optimally to this dose, it has been increased to 5 to 10 mg/kg and the frequency of infusions to monthly or every six-weeks.

Adalimumab (Humira)

Created with phage display technology, adalimumab is the first fully human anti-TNF-alpha monoclonal antibody (IgG1). It therefore has low immunogenicity and may have greater therapeutic potential than infliximab or etanercept.

It has been approved both for reducing signs and symptoms of RA, and inhibiting the progression of structural damage in adults with moderately to severely active disease, who have had insufficient response to one or more DMARDs.

Dose: As the latest option, adalimumab offers a much more practical, patient-friendly dosing regimen of one subcutaneous injection of 40 mg every other week.

Interleukin-1 (IL-1) blocker - Anakinra (Kineret)

The FDA has approved this interleukin-1 (IL-1) receptor antagonist for the reduction of signs and symptoms of moderate to severely active RA in adult patients who have failed to achieve a significant clinical improvement from one or more DMARDs.

IL-1 is an important pro-inflammatory cytokine that plays a significant role in the development and progression of RA, both with regard to inflammation and joint damage.

Unfortunately, in RA, too much IL-1 is produced and too little IL-1ra is available to counter its activity. Anakinra was developed as a recombinant form of the human IL-1 receptor antagonist to reset the inflammatory thermostat and inhibit inflammation, pain and joint damage. The most common side effect was a reaction at the site of injection, usually mild and characterised by redness, swelling and pain.

There was a risk of serious infection (2% in the anakinra

treated patients and less than 1% in the patients treated with placebo). Consequently, the drug should not be started when an active infection is present and should be stopped in the setting of an active infection.

Dose and route of administration: Daily subcutaneous injections that contain 100 mgm of anakinra.


As the first from a novel class of agents to block co-stimulatory molecules and T cell activation, the ultimate place for abatacept in the rheumatologist’s armamentarium remains to be defined.

Abatacept in combination with methotrexate has demonstrated efficacy and is approved for use in RA patients who are partially or poorly responsive to methotrexate or TNF antagonists.

In studies of efficacy, abatacept in combination with methotrexate has been associated with a slight increase in infections but no opportunistic infections. Abatacept is infused over approximately 30 minutes and is usually associated with only mild infusion reactions.


Rituximab is currently approved only for patients who have failed TNF antagonists and who are receiving concomitant methotrexate. Whether or not the indications will be expanded in the future remains uncertain, and long term data regarding safety, radiographic effects, and when to re-treat will be important.

It will also be important to establish in patients who receive rituximab and do not respond, whether or not they can be treated with alternative agents while remaining B cell depleted.

Rituximab in combination with methotrexate has demonstrated efficacy and is approved for RA patients who have failed or been intolerant to TNF antagonists.

In the studies in RA patients demonstrating efficacy, rituximab has been associated with a slightly higher incidence in infections compared to placebo. Rituximab can be associated with infusion reactions, particularly with the initial infusion.

Pretreatment corticosteroids can decrease the incidence of infusion reactions by about a third. About 4 ½ hours are required for the first infusion; if the first infusion is well tolerated the second infusion may be given over a shorter time period, e.g., three to four hours.

It is very difficult to predict the outlook in any given individual with rheumatoid arthritis. Overall we know that the disease will go into remission in perhaps 15% of people.

At the other extreme, some 10% have it in a severe form with persistent joint inflammation leading to joint damage, deformity and the need for orthopaedic operations.

The remaining 75% have persistent joint problems, which will vary in severity from time to time over the years, but with gradual deterioration in joint function and quality of life.

Early aggressive management is vital to prevent joint deformities, disability, morbidity and mortality, especially in those patients with poor prognostic features. Our aim, with the help of new diagnostic criteria and more effective medications, should not only be to improve joint function and quality of life for patients, but also increase their lifespan.

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