A pain in the joint

Some 20 million people in the UK suffer from arthritis. This is a painful and debilitating condition which is characterised by inflammation and stiffness in one or more joints. For a long time treatments for arthritis have been fairly primitive. Herbal remedies can reduce pain in arthritis patients, and up until about 150 years ago the disease was treated by draining patients’ blood, a practice first endorsed in the 5th century BC by Hippocrates, considered the ‘father of modern medicine’. In recent years however, chemists have focused on the underlying causes of arthritis to design specific drugs that offer more effective relief to sufferers. 

Arthritis – in various guises 

There are several different types of arthritis. The most inflammatory form is rheumatoid arthritis (RA). In RA white blood cells accumulate in the joints, causing inflammation, ie swelling, and eventually bone damage. Osteoarthritis (OA) involves wear and tear of the joints over many years, again causing swelling and bone degeneration. Other forms of the disease include gout – where crystals of uric acid build up in joints – and ankylosing spondylitis, which is inflammation in the spine. 

Rheumatoid arthritis is probably the best understood of all the different forms of the disease. Iain McInnes, professor of experimental medicine and rheumatology at the Royal Glasgow Infirmary, Scotland, told Infochem that RA is an autoimmune disease, which means the body’s defence mechanism (the immune system) mistakenly attacks the body itself. The reasons for this are still not known, but the processes occurring in the affected joint are becoming increasingly understood. There are three main stages in RA. The first, inflammation, occurs when the joint cavity fills with white blood cells of the immune system and inflammation-causing proteins (cytokines) by some, as yet, unknown trigger. At this point patients feel pain and stiffness. The second stage is proliferation. As the condition worsens the thin filmy material lining the joints of the skeleton (the synovium) becomes inflamed and together with nearby proteins and white blood cells, builds up to form a new ball of tissue, the pannus. Over time the pannus pushes into neighbouring bone and cartilage, eroding it away. In the third stage of RA – destruction – the joints become unstable and dislocate, leading to deformity and disability. 

Drugs and therapies 

A broad variety of medicines has emerged during recent decades which treat the disease at various stages. The mode of action of these drugs varies from giving simple pain relief through to working on the possible causes of the underlying autoimmune response. 

Some of the oldest RA therapies are based on the ‘non-steroidal anti-inflammatory drugs’ (NSAIDs), which reduce inflammation and minimise pain and stiffness. These drugs work by stopping the synthesis of prostaglandins (1), ie  long-chain fatty acid molecules that take part in inflammation.

 

Aspirin (2), the oldest of the NSAIDs, does this by deactivating the enzyme responsible for making prostaglandins in the body, ie cyclooxygenase, (COX). When dissolved in the body, the ethanoyl group (–C(O)CH₃) on the aspirin molecule is hydrolysed (reacts with water) and then binds to a specific site on COX, stopping the enzyme from producing prostaglandins, and reducing inflammation. Alternative NSAIDs include diclofenac (3) and ibuprofen (4). These have a similar chemical structure to aspirin and work in the same way. However, a major side effect of NSAIDs is that they can produce severe stomach pains and internal bleeding. This is because prostaglandins also protect the lining of the gut, as well as other vital organs, and when production of these molecules is suppressed these organs become vulnerable to damage. 

 

Another class of RA medicines – the ‘disease modifying anti-rheumatic drugs’ (DMARDs) – work by slowing down the immune system, thus limiting the damage to the bones and cartilage. There are several types of DMARDs on the market, including methotrexate (5) and sulfasalazine (6). Methotrexate is widely known as an anticancer drug and its anti-arthritic properties were only stumbled upon. Sulfasalazine is made up of two different components; a sulfapyridine group and 5-aminosalicylic acid. The latter is anti-inflammatory (it has a salicylicate ‘core’ similar to aspirin) and the former acts as an antibacterial agent. The combination of the two groups is effective against RA, but as with methotrexate, scientists’ understanding of sulfasalazine’s mechanism of action is still hazy at best. Since the specific link between DMARDs and the immune system is not well understood, chemists, who design medicines based on structural relationships between disease targets and drug candidates, are essentially shooting in the dark, meaning that improved DMARDs are hard to develop. 

In addition, DMARDs can produce several unpleasant side effects. Because they slow down the immune system, the body becomes vulnerable to infections and, in severe cases, bone marrow poisoning. DMARDs are also fairly slow to act, sometimes taking several months to show any benefit. 

In the past 10–15 years an exciting new range of ‘biologic’ medicines (essentially synthetic proteins which mimic natural proteins in the body) have emerged that try to stop the disease before it enters the proliferative and destructive stages. During these stages the immune system releases cytokines into the blood stream. Cytokines are small protein molecules that enhance the growth of destructive pannus tissue. Biologic, protein-based drugs are therefore designed to stop the release of cytokines. One of the most important members of the cytokine family is tumour necrosis factor alpha (TNF-alpha). TNF-alpha is secreted by white blood cells and plays an important role in treating infections in a variety of organs. In terms of RA, however, TNF-alpha is a major promoter of inflammation, controlling several other molecules in the joints that contribute to bone destruction. 

The importance of TNF-alpha in controlling the inflammation process was brought into the spotlight in the early 1990s by Marc Feldman, professor at the Kennedy Institute for Rheumatology, London. Since his pioneering work was first published, considerable progress has been made in making anti-TNF-alpha drugs. Two of the most successful are licensed under the names Infliximab and Etanercept. Infliximab is a hybrid protein made from mouse and human components. The drug works by binding to TNF-alpha and essentially removing it from circulation. Etanercept works in a similar way but has the advantage of producing fewer side effects than Infliximab, such as fatigue and skin rashes. 

Light at the end of the tunnel? 

Despite some success with anti-TNF-alpha drugs, there is still much to be done to find a cure for RA. There are lots of cytokines involved in joint inflammation, and specific drugs are being developed for each of them. Some are in the middle of clinical trials but, as McInnes points out, not everyone taking anti-TNF-alpha drugs and the other biological anti-inflammatories respond positively. He thinks the problem lies in that not enough is known about the role of the immune system in RA. ‘We don’t know the causes of the disease, we don’t know when it starts, and we don’t know how to change it before damage is already done’. If scientists could discover what triggers the autoimmune response in the first place then patients could be screened for RA before it takes hold. Gene therapy might hold the key to this, and a considerable amount of research is being devoted into understanding how a person’s genetic make-up influences their chances of getting RA.  Gaetano Mancino