The Management of Early Rheumatoid Arthritis

Dr George Hirsch, Specialist Registrar in Rheumatology & Dr Diarmuid Mulherin, Consultant Rheumatologist Mid Staffordshire General Hospitals NHS Trust
Original article: 18/08/2003
Reviewed: 23/07/2012
Next review due: 23/07/2015

Introduction

The word “arthritis” stems from the Greek and literally means joint inflammation. Doctors use the word 'arthritis' to describe diseases affecting joints (for example an infected joint is called a septic arthritis). Rheumatoid arthritis (RA) is one of a number of conditions that causes widespread joint damage and forms the bulk of the work for rheumatologists, who have developed expertise in managing rheumatoid arthritis as well as other musculoskeletal diseases. It is a chronic disease, affecting most commonly the joints in the hands and wrist but can affect almost any joint, and other parts of the body also. Left untreated, rheumatoid arthritis can progress to a disabling disease. However the use of new treatments is changing the outlook for patients diagnosed with this condition.

Doctors have identified that rheumatoid arthritis is an inflammatory arthritis, a separate condition from the so-called wear and tear type arthritis "osteoarthritis". This means that the body’s immune system causes inflammation in the joints and causes them to become hot, red and swollen. Peoples' experiences of RA can be varied, and there can be quite subtle changes in the joints that can indicate inflammation. These can be difficult to detect by an examining doctor.

Rheumatoid arthritis inflammation and the immune system

We rely on our immune system to protect us from infectious diseases such as viruses and bacteria. It’s not surprising that a defective immune system will put us at risk of infection. The immune system has complicated safeguards to allow it to recognize infections that need to be attacked with inflammation and normal parts of the body that need to be left alone and protected. In rheumatoid arthritis, the mechanism of recognising what is part of the body (and therefore should not be attacked) breaks down and the immune system is directed to attack the joints and other parts of the body, in effect attacking the joints as though they were an infection. Despite extensive research into the matter, it's not clear exactly why the disease starts, although there are many theories about this. These include possible links to infection, that some of the affected parts of the body may contain elements that look like germs to some people's immune systems, and that coincidental infection with these germs can cause a mistaken immune response. A second cause may be in our genetic make up. This may explain why rheumatoid arthritis can run through several generations of a family.

The inflammation in rheumatoid arthritis is really an unhelpful response from the immune system. The inflammation is not of benefit (unlike, for example, the immune system in the lungs responding to defeat a pneumonia with inflammation).This unhelpful inflammation can be compared to a defence system that has been triggered ‘in error’.

The problem with all this inflammation is that it can lead to longstanding damage to the joints and to the tissues around them. This damage to joints and their surrounding structures causes limitations in an individual’s activity, making rheumatoid arthritis such a challenge to treat. It also fosters the idea that the earlier you treat rheumatoid arthritis; the joint damage may be reduced, possibly leading to a better long term outcome.

What is early rheumatoid arthritis?

One way of understanding 'early arthritis' is by understanding some of the ways a rheumatologist will actually diagnose rheumatoid arthritis. Some recent guidelines published in 2010 by the American College of Rheumatology (known as ACR) and the European League against Rheumatism (known as EULAR) are now the gold standard internationally for categorizing the condition. These are a little complicated but described as simply as possible in the table below. They should be used in patients who have at least 1 joint with definite swelling and inflammation on clinical examination where this is not better explained by alternative diagnosis.

Criterion	Description	Points scored
A Joint involvement	1 large joint 2-10 large joints 1-3 small joints 4-10 small joints >10 joints	0 1 2 3 5
B Serology (results of rheumatoid factor and anti-CCP antibody tests)	Both negative Both weak positive Both strong positive	0 2 3
C Inflammation tests (results of CRP and ESR blood tests)	Both normal Either raised	0 1
D Duration of symptoms	Less than 6 weeks 6 weeks or longer	0 1

Table 1: Outline of the 2010 ACR/EULAR criteria for classification of rheumatoid arthritis.

The maximum possible score using these criteria is 10 and a score of 6 or more allows a patient to be classified as having definite rheumatoid arthritis. It’s important to recognise these criteria are not set in stone: people can have rheumatoid arthritis without some of these features, or have all of them and have another condition. It is expected that many patients will be diagnosed with rheumatoid arthritis before they meet the criteria above and a lot of energy goes into trying to diagnose patients as early as possible. This has been helped by more accurate blood tests and the expanding use of investigations such as ultrasound scans and MRI, to identify signs of inflammation that are not obvious on clinical examination.

Rheumatoid arthritis is most commonly suspected by general practitioners (GPs) and diagnosed by rheumatologists. Intervals before patients seek medical advice, waiting lists for rheumatology clinics, waiting for investigations, and constraints of follow up clinic appointments all mean that rheumatoid arthritis may not be diagnosed for many months or years after the first symptoms appear, although these delays have been reduced by encouraging GPs to refer patients early and by limits on the times patients are allowed to wait before seeing a rheumatologist.

Although there is no international definition of early rheumatoid arthritis, you could think of it as symptoms before there has been significant damage to the joints from the inflammation. It’s a significant challenge to the NHS as to how to accurately identify and fast track such suspected early arthritis patients, but one that has been recognised as of great importance.

The main advance in drug therapies for arthritis is the distinction between treatments that will improve symptoms and treatments that will alter the course of the disease. Tablets that are thought to slow the progression of rheumatoid arthritis are called ‘disease modifying drugs’ and are often abbreviated to DMARDs. Such treatments are discussed later.

An introduction to drug treatments

The first thing to note is that medications prescribed that are still under patent (only the company that invented them can market them) have two names: for example the tablet “leflunomide” is marketed by the drug company that makes it under the name of “Arava ® ”. Where applicable, both names will be listed with the marketing name in italics. Two ways of determining that drugs work are by experience in its use, or by studying it in clinical trials. For example, experience showed that when penicillin was developed in 1939 and was rushed into use in the Second World War, it is thought to have saved many lives. Clinical trials are another way for doctors to evaluate the effectiveness of treatments. These involve setting up highly controlled conditions in which patients taking study medications can be observed closely for benefits when compared with other treatments or none at all, without being clouded by wishful thinking on behalf of the patients ('the placebo effect') or doctors ('observer bias').

Changing the symptoms or the disease itself

A paracetamol or ibuprofen tablet may help an arthritis pain or a migraine. That does not mean to say that they will prevent further pains or migraines, or reduce the frequency of pains in the future. Anti-inflammatory tablets such as ibuprofen and diclofenac reduce joint symptoms, but do not seem to alter the progression of the rheumatoid arthritis. For example if you took two identical patients and gave one ibuprofen for 10 years and the other nothing, after 10 years they would still have similar levels of joint damage, although you may expect one to have had less symptoms. A disease-modifying drug (commonly called a DMARD) will improve symptoms and reduce the progression of joint damage.

Tablets that target symptoms

Tablets like ibuprofen and diclofenac (known as NSAIDs or non-steroidal anti-inflammatories) have been used successfully to treat symptoms for all sorts of arthritis. They have important side-effects, most importantly the possibility of causing stomach and bowel irritation causing bleeding and ulcers. They need to be used cautiously.

A new group of tablets (cyclo-oxygenase 2 inhibitors or COX-2 inhibitors) work in a similar to the above tablets but have been developed to reduce the risks of stomach bleeding and ulceration. Celecoxib (Celebrex ®) and etoricoxib (Arcoxia ®) are used in the UK for treatment of symptoms in rheumatoid arthritis. However these COX-2 inhibitors have recently been under medical and media scrutiny because of a suspicion of adverse effects. A tablet called rofecoxib (Vioxx ®), one of the ‘family’ of COX-2 inhibitors, was withdrawn in September 2004 because of concerns over an increased risk of heart attacks. As a result of these concerns the European Medicines Agency recommended that patients who have ischaemic heart disease, peripheral vascular disease or stroke disease should not use COX-2 inhibitors. It’s also recommended that they should be used cautiously in patients who have are at a higher-risk of developing side-effects such as high cholesterol. Recent recommendations advise that another tablet to protect your stomach should be prescribed with an NSAID or COX-2. There are potentially additional risks if you have a severe heart problem, or high blood pressure, impaired kidney function or have risks related to bleeding from your gut, such as a
previous stomach ulcer.

Anti-inflammatories are not the only other drugs that can be used to treat symptoms. Paracetamol has been proven to be a very safe and highly effective drug in treating pain symptoms and this is frequently suggested as a first step, although often in combination with other medicines such as codeine or tramadol. Like anti-inflammatories, they will not alter the course of the disease but are useful in reducing any pain symptoms and helping activities to continue as normal.

DMARDs or disease modifying drugs

DMARDs or disease modifying drugs commonly used in the UK include methotrexate, sulphasalazine, leflunomide (Arava ®), hydroxychloroquine, azathioprine, and ciclosporin (Neoral ®). These are all tablet preparations. These drugs have been shown in clinical trials to slow the progression in rheumatoid arthritis (by looking at joint symptoms and x-ray changes). This means that as well as reducing symptoms they slow progression of rheumatoid disease on x-rays. These drugs form the benchmark for treatment of early arthritis, discussed later. They themselves also have important side effects, and all require regular monitoring of blood tests to detect the earliest signs of problems before they become significant enough for patients to develop symptoms. For example, many of the treatments can cause inflammation of the liver and anaemia, but blood tests allow detection of the earliest signs, allowing any changes in treatment that are required to be made.

Biologic therapies (“anti-TNF” or “cytokine inhibitors”): No license yet in early arthritis

There have been recent advances in attempting to modify the way the immune system targets the joints by affecting the function of small proteins in the blood and joints that attract cells of the immune system to joints and cause inflammation. These treatments are called biologic drugs.

Biologics are not currently licensed for use in early rheumatoid arthritis: i.e. they cannot be prescribed on the National Health Service (NHS). Their use is currently reserved for patients who have active disease that has not responded to treatment with other DMARDs.

Treating early RA in the future

Recent research has shown very promising results in treating patients with very early arthritis and has led to suggestions that in future it may even be possible to make inflammation undetectable for very long periods without the use of medication (drug free remission) or even cure the disease (currently the disease can go into remission, but this is 'drug induced' and in most cases patients need to stay on medication to keep the disease in a state of remission). This has led to the idea of 'the therapeutic window', an early period in disease in which more intensive treatment can make major differences to the disease, where similar treatment later on may have less impressive results. This might be likened to putting the handbrake on a car that has just begun to roll backwards, rather than waiting until it has gained speed and is harder to stop.

How to manage early rheumatoid arthritis?

It is a fact that there is no accepted “gold standard” treatment for early rheumatoid arthritis. In general, however, just as the consensus among rheumatologists has changed over the last decades towards using more powerful treatments at higher doses earlier in disease, consensus is now also steadily swinging in favour of using several treatments at once, often in combination with steroids. This has been encouraged both by the idea of the therapeutic window and also by successful trials that used combination treatments in early arthritis.

Two approaches to combining treatments begin either with several DMARDs at once and can reduce down over time if disease is controlled (so called step down therapy) or by starting a single DMARD and rapidly increasing treatment if disease is not controlled. Each approach has its advantages and disadvantages, but expert opinion probably now favours starting combination treatment immediately on diagnosis, with methotrexate being a key part of any combination.

Recently released guidelines for managing rheumatoid arthritis from the National Institute for Health and Clinical Excellence (NICE) has set out some standards for services that rheumatology units should offer patients. This included a recommendation for the early use of combination treatments as well as encouraging regular review in early arthritis.

What happens when my rheumatologist starts these treatments?

Whichever approach is used, patients with early rheumatoid arthritis should be reviewed regularly and the intensity of their treatments increased if signs of uncontrolled disease are found. This review can be conducted by rheumatologists, but also by specialist nurses who have expertise in rheumatoid arthritis and its management. Specialist nurses are usually the member of the team that patients see most often and with whom they are in closest contact. As well as reviewing how effectively medication is working, specialist nurses give patients information about their condition and treatments. Written information is provided about treatments and different aspects of living with arthritis. Many rheumatology units now have a telephone service run by the specialist nurses too.

Blood tests are taken every few weeks for most therapies, and can be taken at the hospital or in your GP surgery, depending on local agreements. If you have significant
problems with any of the tablets, there may be other treatment options you can discuss with your management team. All rheumatology teams would agree that patients who experience increased joint pain or swelling (known as a 'flare' of arthritis) which is not settling quickly should let the rheumatology team know as soon as possible. This is normally through contacting their nurse specialist by telephone or telephone helpline.

It is understood that access to other areas of the multi-disciplinary team is important. This includes physiotherapists, who can advise patients about the best forms of exercise and give treatments that can help improve joint movements and muscle strength after 'flares' or injury to joints. Occupational therapists (OTs) help patients in a large number of ways. A few of these are advising patients about the best way to protect their joints during flares, the way in which everyday tasks that might be difficult can be achieved most easily and provide any devices or 'gadgets' that might make difficult jobs easier, such as devices to help open tight lids or stiff taps for patients with reduced hand strength.

As rheumatoid arthritis can frequently affect the feet, patients should see a podiatrist (previously known as a chiropodist) early on to advise on footwear and care of their feet, as well as identifying and treating any developing problems early on.

Summary

With support from your local rheumatologist, specialist nurses, your general practitioner and the other members of the rheumatology team, early arthritis can be tackled in the most effective fashion. In time, with more research, the role of biologics and the best use of DMARDs and steroids will become clearer. The management of early rheumatoid arthritis is not yet perfected, but the agreed expert opinion is that early use of DMARDs is the best management course. With regular monitoring and follow up, serious side effects can be minimised. The future for patients currently being diagnosed with rheumatoid arthritis promises improved responses to tried and tested treatments.