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Rheumatoid arthritis is a systemic disease of unknown cause which is mainly manifested by chronic inflammation of synovial membranes leads to a deforming arthropathy. It affects 1-3% of the population, and is twice as common in women as in men. The peak age at onset is 20-40 years.
Clinical Features
This condition usually has an insidious onset. Patients initially describe stiffness of the joints, mainly affecting the small joints of the hands but also affecting the toes and larger joints, such as the wrists, elbows and knees. The patient then goes on to develop a symmetrical polyarthritis with pain and stiffness, which is worse in the morning. They may also have constitutional symptoms, such as fatigue, reduced appetite and general malaise. On clinical examination during the acute inflammatory phase, the joints are swollen, hot to the touch, tender, and have limitation of movement. As the disease progresses there is destruction of the synovial structures, the ligaments and the tendons around the joint, and a deforming arthritis results, with atrophy of the muscles surrounding the inflamed joints. Extra-articular features include skin ulcers, digital ischaemia, pleural effusions, pulmonary fibrosis and splenomegaly. Patients often develop rheumatoid nodules, which are most commonly found on the extensor aspects of the elbow joints over the olecranon process, but may also be found around the wrist joint or on the dorsum of the hand. The presence of rheumatoid nodules indicates that the patient has a rheumatoid factor-positive condition, and is associated with a poor prognosis.
Investigations
There is often a mild normochromic normocytic anaemia. The erythrocyte sedimentation rate (ESR) is elevated, as is the level of C-reactive protein, during acute acute episodes of inflammation of the joints. The main diagnostic test is the detection of rheumatoid factor in the blood. Aspiration of synovial fluid shows the presence of increased levels of protein, a slight reduction in glucose concentration, and polymorphonuclear leucocytes present in the fluid.
The diagnosis is based on the presence of four or more of the following criteria:
1. hand involvement in an inflammatory arthritis
2. symmetrical joint involvement
3. arthritis of three or more joints that lasts for six or more weeks
4. morning stiffness
5. the presence of rheumatoid factor
6. the presence of rheumatoid nodules
7. The presence of erosions on X-ray of the small joints of the hands and/or feet.
Treatment
In the early stages, during the acute inflammatory process, the patient should be advised to rest their joints, and this sometimes involves splinting the joints. The specific drug therapy is described below.
Analgesics
Analgesics are given in the form of either simple paracetamol or more commonly non-steroidal anti-inflammatory drugs, which not only reduce the pain and discomfort but are also effective in reducing the inflammatory process.
Disease-modifying drugs
These drugs are designed to suppress or modulate the autoimmune process. They do not have an immediate therapeutic effect, and up to 4-6 months of treatment may be necessary to obtain a full response. Drug in this group include D-Penicillamine, gold and antimalarial drugs such as hydroxyxhloroquine.
Steroid Drugs
These drugs have a potent anti-inflammatory action, and are generally used for patients whose condition is not well controlled by non-steroidal anti-inflammatory drugs, or in whom there is evidence of extra-articullar involvement, such as neuropathy, renal disease or lung disease. Initially, hogh does of steroids are used. These does are then gradually reduced while monitoring the activity of the disease process and inflammatory markers as ESR and C-reactive protein.
Immunosuppressive drugs
These drugs are used to suppress rheumatoid factor production and thus reduce the circulating levels of the immune complexes that cause the inflammatory reaction to occur. This group of drug includes methotrexate, azathioprine and cyclophosphamide.
Specific anticytokine drugs
'With the development of agents that can inhibit the actions of interleukins and tumor necrosis factor, a number of drugs now available necrosis factor, a number of drugs b hat inhibit the cytokines which trigger inflammatory reaction in this condition Monoclonal antibodies and recombinant DNA technology have resulted in the development of a whole range of drugs which can inhibit the action of cytokines or block the receptors to which they normally attach. The potential for the use of these drugs in suppressing the disease activity of rheumatoid arthritis has been demonstrated. However, the potential for increasing the risk of infection and the development of malignancy as a consequence of long-term therapy must also be considered.
Rheumatoid arthritis can affect nearly every part of the body. Complications may include:
Damage to the lung tissue (rheumatoid lung)
Increased risk of hardenign of the arteries
Spinal injury when the neck bones become damaged
Inflammation of the blood vessels (rheumatoid vasculitis), which can lead to skin, nerve, heart, and brain problems
Swelling and inflammation of the outer lining of the heart (pericarditis) and of the heart muscle (myocarditis), which can lead to congestive heart failure
Prevention
There is no known prevention. Proper early treatment can help prevent further joint damage.
"It is possible that yoga may have important physical and psychological benefits for patients with rheumatoid arthritis."
New type of fruit juice interaction
Grapefruit juice is well known to affect the metabolism of several drugs, including felodipine and other dihydropyridine calcium channel blockers, buspirone, ciclosporin, simvastatin and atorvastatin. It has the potential to increase blood levels of these drugs by inhibiting the intestinal cytochrome-P450 enzyme CYP3A4 and the intestinal drug efflux pump P-glycoprotein.
Another way in which fruit juices alter bioavailability of oral drugs has now been identified. According to a review in the British Journal of Pharmacology (November 2010) the discovery was based on an unexpected finding when assessing the possibility of grapefruit juice increasing oral fexofenadine bioavailability. In follow-up studies, grapefruit or orange juice at low concentrations inhibited a drug uptake transporter, organic anion-transporting polypeptide OATP 1 A2, while high volumes of juice dramatically depressed oral fexofenadine bioavailability.
Grapefruit juice has been found to lower the bioavailability of several oral drugs transported by OATP 1 A2 (eg, fexofenadine, acebutolol, celiprolol, L-thyroxine), while orange juice has the same effect on others (atenolol, celiprolol, ciprofloxacin) as well as fexofenadine. Naringin, a flavonoid in grapefruit juice, seems to be a major causal component. This suggests that other vegetable and fruit juices might have the same effect. The inhibitory effect appears to last between two and four hours, so that the interaction might be avoided with appropriate intervals between drug administration and juice consumption.
In an era when bacterial resistance represents one of the greatest challenges to global health, it seems remarkable that the 30-year old antibiotic co-amoxiclav can still cure thousands of chest infections each winter, Jenny Bryan reports.
In the 1970s, combining the broad-spectrum antibiotic amoxicillin with the beta-lactamase inhibitor clavulanic acid proved a highly effective answer to the dual problems of emerging penicillin resistance and increased mixed infection,' and Beecham Pharmaceuticals (now part of GlaxoSmithK]ine) launched Augmentin to eager physicians in 1981.
"The amoxicillin and clavulanate combination kept the activity of amoxicillin against streptococci, including pneumococci, but restored the activity of amoxicillin against beta-lactamase producing organisms, such as staphylococci, Escherichia coli and Haemophilus influenzae, and extended its activity against klebsiella and Bacteroides fragilis infections," explains Alasdair Geddes, emeritus professor of infectious diseases at the University of Birmingham, who took part in one of the early clinical trials of the drug.Discovery of amoxicillin
Expansion of the penicillin group of antibiotics began in the 1950s when microbiologist George Rolinson joined Beecham Research Laboratories to establish a microbiological research division. On the advice of Sir Ernst Chain, who shared the Nobel Prize for Physiology or Medicine for his work on penicillin, Rolinson and his team set about the chemical modification of the acyl side chain of penicillin to make semi-synihetic penicillins with new propertics.2 They used the penicillin nucleus, 6-aminopenicillanic acid (6-APA), with the three carbon, one nitrogen 6-lactam ring at its centre, to develop meticillin (launched in 1960), ampicillin (launched in 1961) and cloxacillin (launched in 1962).2
Ampicillin had a broader spectrum of activity than penicillin G or V and increased activity against Gram-negative organisms but, early on, there were resistant isolates that were attributed to the breakdown of the 6-lactam ring by bacterial β-lactamase enzymes and to intrinsic mechanisms.'
Continued research at Beecham yielded a further broad spectrum penicillin with a similar range of activity to ampicillin but with much better oral absorption, resulting in blood levels twice those achieved with similar doses of ampicillin .4 This was amoxicillin.
Rolinson subsequently described in vivid terms the inhibitory effects of amoxicillin and other β-lactam antibiotics on division of bacterial cells, and the subsequent cell lysis, which he recorded as time lapse sequences on cine film:' "The cell wall could be seen to rupture abruptly, usually at a division site, allowing the cytoplasmic membrane to bulge out, forming a spheroplast. Rupture of the spheroplast then followed, due to osmotic pressure, resulting in loss of the cytoplasmic contents and lysis of the cell.... With certain β-lactams, for example amoxycillin, the onset of lysis was seen very early, cell growth barely reaching two cell units in length before rupture of the wall occurred."
Combating resistance
Despite its impressive bioavailability and bactericidal activity, amoxicillin'' β-lactam ring proved just as easy a target for bacterial β-lactamases as its predecessors.
"By 1965, the frequency of clinical isolates producing 6-lactamases had risen dramatically, and it was shown that the ability to make the enzymes was transferred between bacteria via plasmids. This meant that resistance could be spread very rapidly and even passed between different species of bacteria," explains Professor Geddes.
Beecham researchers went to work to find a solution. Large scale screening of microorganisms that could produce β-lactamase inhibitors got under way in 1967 but it took five years for the scientists to find what they were looking for. This was Clavulanic. acid. Produced by Streptococcus clavuligerus, clavulanic acid was a β-lactam molecule with low antibacterial activity but whose β-lactam ring was shown to bind irreversibly to bacterial β-lactamase, preventing it from inactivating β-lactam antibiotics.
Combination
Amoxicillin was chosen to be co-administered with clavulanic acid because of its good oral absorption and broad spectrum antimicrobial activity and in early trials in patients with urinary tract infection caused by amoxicillin-resistant bacteria, cure rates of up to 70 per cent were achieved.
"Getting the right dose of amoxicillin proved important for efficacy and getting the right dose of clavulanic acid was key to tolerability," recalls Professor Geddes who was an investigator in the trials.
"Increasing the amoxicillin dose from 250mg every eight hours to 500mg doubled the efficacy in amoxicillin resistant organisms from a disappointing 30 per cent to 70 per cent. But doubling the dose of clavulanic acid from 125 mg every eight hours to 250mg was associated with a 40 per cent prevalence of nausea with no further improvement in cure rate," he adds.
Other studies demonstrated the benefits of the novel combination in respiratory, soft tissue and venereal infections.
Optimising efficacy
Today, co-amoxiclav is most commonly used in the treatment of community-acquired infections, notably respiratory tract infections. Though introduced in a three times daily dose of amoxicillin 250mg/clavulanic acid 125mg, an amoxicillin 500mg/clavulanic acid 125mg dosage soon followed.
In some countries, even higher doses of amoxicillin (875mg and 1,000mg) were introduced for severe infection, but the clavulanic acid dose remained the same . More convenient twice daily formulations of 500/125mg and 875/125mg co-amoxiclav are marketed in some countries, and twice daily dosages of paediatric formulations are also available.
In the 1990s, research showed that the bacteriological efficacy of β-lactams is associated with the time that free serum levels remain above the minimum inhibitory concentration (MIC). In animal models of S pneumoniae infection, it was shown that the level of amoxicillin needed to remain above the MIC for 30 to 40 per cent of the dosing interval for maximal bacteriological activity.
Based on pharmacokinetic and pharmacodynamic predictions, it was calculated that amoxicillin/Clavulanic acid 875/125mg twice daily would achieve maximal bacteriological efficacy against strains with amoxicillin or amoxicillin/ clavulanic acid MICs equal to or greater than 2mg/L but not equal to or greater than 4mg/L, although the 875/125mg three times daily and 1,000/125mg three times daily regimens were likely to have some efficacy against strains with MICs of 4mg/L.
To address the need for more long-lasting blood levels against isolates with high MICs, GlaxoSmithKline developed a pharmacokinetically enhanced formulation of amoxicillin/Clavulanic acid 2,000mg/125mg, taken as two 1,000mg/62.5mg tablets twice daily. This used a bilayer system to deliver an immediate and an extended release component, the latter flattening the concentration curve and increasing the time that amoxicillin levels remained above the MIC to 49 per cent in isolates with an MIC greater than 4mg/L, and 35 per cent in those with an MIC over 8mg/L. This formulation was subsequently approved in the US and some European countries for the treatment of adult respiratory tract infection due to resistant pathogens, but not in the UK, where the prevalence of S pneumoniae strains resistant to amoxicillin/Clavulanic acid tends to be lower than in many countries.
Still effective
Although guidelines discourage antibiotic use for self-limiting respiratory infections, they do advise prompt use in high risk patients and in those who are systemically very unwell or show signs of pneumonia or other complications.' It is, therefore, reassuring that a recent analysis of susceptibility data of lower respiratory tract isolates of S pneumoniae, S aureus and H influenzae from sentinel microbiology laboratories in England,
Wales and Northern Ireland showed that 92 per cent of isolates were susceptible to coamoxiclay.
As Professor Geddes concludes: "The rationale for using the combination of amoxicillin and clavulanic acid remains the same today as it was 30 years ago when it was launched. Clearly, it shouldn't be prescribed for everyone with a chesty cough but it still has an important and unique role to play in the treatment of a range of community-acquired respiratory and other infections."
