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Medicine

Brake on corrosion

Rheumatoid arthritis does not have a cure, but the discovery of biological markers is helping to boost the treatment result

It is not known for sure how many of the 900 thousand presumable Brazilian victims of the disease have access to adequate treatment, but a calculation made by Unifesp analyzed two scenarios. In one of them, 20% of the patients would be receiving treatment in the Public Health System. In this case, the cost would be R$ 92 million a year, or 0.2% of the budget, for a single ailment. In the other scenario, the number of those properly treated would reach 70%. The cost would be R$ 322 million, or 0.63% of the health budget. “Is it essential to rationalize expenditure”, says Marcos Bosi Ferraz, the director of Unifesp’s São Paulo Health Economics Center (CPES), who supervised the research, defended as a dissertation for a master’s degree by physician Gustavo Chermont.

Rheumatoid arthritis is usually improperly merely called arthritis and, sometimes, is mistaken for another disease, arthrosis. But arthritis is a generic name for any inflammation that affects the joints. There are, for example, kinds of arthritis caused by traumatic lesions, by gout or by bacteria. These are not very common and affect men more frequently; whereas rheumatoid arthritis is an autoimmune ailment that does not distinguish sex, but has peaks of incidence in women between 50 and 70 years old. Arthrosis, in turn, is wear and tear of the joints related above all to an advanced age.

The role of another kind of marker for the disease was the object of a doctoral thesis defended last July at the Federal University of Rio Grande do Sul (UFRGS) by rheumatologist Charles Lubianca Kohem. The marker is CCR5, a receptor of proteins that leads the leukocytes to leave the blood and make for the joints. Some people have a genetic mutation that leads them not to express this receptor. Kohem’s research compared 92 victims of rheumatoid arthritis with 160 healthy persons to find out whether the carriers of this mutation are immune to the disease or develop it in a blander form. Differences between the two groups were not observed, however. In the research, samples were also analyzed of the synovial liquid, which lubricates the cartilage of the joints, from eight patients with rheumatoid arthritis. This liquid is produced by the synovial membrane, the lining of the wall of the capsule that covers the joint. When the ailment breaks out, the membrane starts to make an aggressive inflammatory substance. It was found that there were more CCR5 receptors in the synovial liquid than in the patients’ blood itself, a sign that they play a role in the evolution of the disease. This is the first study of this kind in the Brazilian population.

Another field for research is the search for serological markers for diagnosis, capable of detecting the existence of antibodies that attack the organism and lead to rheumatoid arthritis. In 1948, the first auto-antibody (antibodies that attack the organism itself) connected with the disease was described. Baptized as rheumatoid factor, it was not very specific, though – it appeared in a vast spectrum of pathologies. In the following decades, two auto-antibodies were identified, against epithelial proteins, related to the attacks of the joints. In the 1990’s, it was discovered that the two antibodies had something in common: they reacted against a protein called filaggrin. Afterwards, it was found that the region of the cell recognized by the auto-antibody was rich in an amino acid, citrulline. The link was found: filaggrin is rich in citrulline.

Having identified this target, citrullinated peptide, the industry was able to develop kits with a quality control for researching the antibodies. The test is known as Anti-CCP (which stands for cyclic citrullinated peptide) and successfully identifies the disease in the initial stages, allowing the damage to be controlled. This evolution has taken place in the last five years. These antibodies have a 70% sensitivity and up to 95% specificity for rheumatoid arthritis.

The doctoral thesis of physician Alberto Max Colonia Nieto, defended in 2004 at Unifesp, looked for a link between the presence of the anti-citrullinated peptide antibodies and the more serious victims. It was found that the presence of the anti-citrullinated peptide antibodies, in isolation, is not capable of differentiating the serious evolution from the benign form.  “But the theme is polemical”, says Coelho Andrade, from Unifesp, the supervisor of the thesis. “Studies outside Brazil suggest that patients with antibodies have a more serious evolution.” In a dissertation for a master’s degree defended this year, physician Renata Trigueirinho Alarcón investigated whether the sick showed more filaggrin protein than healthy persons. It was seen that, on the contrary, they have less filaggrin. It seems paradoxical that the protein that is the target for the aggression appears in a diminished quantity in the victims, but there are other ways of interpreting this data. “The immune system, when it has an antigen that expresses itself a lot, becomes tolerant to it. But, when expression is diminished or inadequate, a favoring of the autoimmune response may occur. It may also be that the real target is another citrullinated protein, and that the filaggrin is just a fortuitous clue”, says Coelho Andrade. There are still many pieces missing in the jigsaw puzzle of the causes of rheumatoid arthritis.

Early destruction
Three thousand years ago, one third of the adult populations of fishermen, pickers and hunters who lived on the coast of Rio de Janeiro could have been suffering from arthrosis, the progressive destruction of the tissues of the joints that can impair their movements. These days, the wear and tear of the cartilage of the hands, arm, backbone, hips, knees or feet usually manifests itself with greater frequency after the age of 50, but in those days the first signs of it could appear far earlier, before the age of 30. Early arthrosis was the result of the wear and tear of the joints brought about by the day-to-day activities of these prehistoric groups, according to the studies carried out by Claudia Rodrigues Carvalho, a bioanthropologist from the National Museum of the Federal University of Rio de Janeiro (UFRJ), in her work for a doctorate carried out at the National Public Health School, of the Oswaldo Cruz Foundation (Fiocruz), in Rio de Janeiro.

“This research shows that arthrosis is not a problem exclusive to contemporary man”, says Claudia. Her work, which is based on the analysis of 78 skeletons held in UFRJ’s museum, indicates that problems in the joints were more common in men than in women. “It doesn’t mean that women used to work less”, she stresses. But the standards of arthrosis and the indicators of muscle development observed in the skeletons suggest that the men used to take care of the tasks that would require more physical effort, like rowing, milling, crushing, scraping, dragging nets, carrying heavy objects, or going for long walks. Today, it is the other way round: what is also called osteoarthrosis, osteoarthritis or articular degenerative disease, is more common with women. Luckily, different from those days, nowadays one can count on analgesics, anti-inflammatories, cortisone derivatives or even surgeries for relieving the pain that intensifies as the cartilage – a sort of cushion between the bones – disappears, causing attrition between the bones, which come into direct contact.

There were also differences between the various populations studied. The joints of the arms and legs – particularly the knees – would begin to degenerate relatively early, between the ages of 20 and 29, in the prehistoric populations of Ilha Grande and Guaratiba, on the south coast, and a bit later, between 30 and 39, in the communities from Saquarema, in the Lakes Region, today the surfers’ paradise, with its strong waves and crystalline waters. These conclusions suggest that the ancient inhabitants of Ilha Grande had a harder life, with more physical demands – indeed, even today it is an island that is difficult to access and to navigate around, off the coast of Rio. “The group that inhabited Ilha Grande must have navigated much more frequently in agitated waters than those from Saquarema”, the researcher says.

Today, repetitive physical effort – driving a lot or spending many hours at the keyboard of a computer, for example – can also injure tendons and joints. Rather uncommon before the age of 40, but frequent from the 60’s and predominant in octogenarians, this disease can be aggravated by a peculiarity of the modern world, obesity, since the excess weight forces the wear and tear of the joints, especially the knees. “These results confirm that social and behavioral options are reflected in our quality of life”, she says. “Everything that man does has a biological cost.”

Penha Rocha, of Rio de Janeiro
To start with, the symptoms are vague. Pains, tiredness and loss of weight appear. Next, the joints of the hands become swollen. Progressively, the discomfort impairs joints all over the body. There may be deformations and, in the portion of more serious cases, physical incapacity. For one in ten victims of rheumatoid arthritis, simple tasks like getting out of bed or getting dressed are stations of a private Calvary. The disease, which affects an army of 1.8 million Brazilians, results from an inflammatory corrosive process in the joints set off by the patient’s own immune system. As they advance in the comprehension of the ailment, researchers find that the jigsaw puzzle has more pieces than used to be reckoned. It is known that there is an important genetic contribution, and that environmental factors are also necessary for unleashing it, but the sequence of events that sparks off the aggression is not known for sure. In the absence of answers about the causes, a prolific line of investigation has been the early identification of the victims that are going to show a more serious evolution – and that deserve to be treated with medicines that can cost up to R$ 5 thousand a month – and those whose symptoms are controllable by simpler drugs.

Researches carried out at several universities in the country are dedicating themselves to looking for genetic or biological signs that make it possible to foresee the outbreak of the disease or to show who will suffer from the more aggressive form. Manoel Bértolo, the professor of Rheumatology of the School of Medical Sciences of the State University of Campinas (Unicamp), is concluding a study that will trace genetic markers for rheumatoid arthritis in Brazilian of African origin. The study should be concluded by the end of the year, but Bértolo’s team has already observed that the markers are different from those found in a sample of 60 patients of European descent, analyzed in 1996. Both the studies research the class of genes connected with immunological histocompatibility that, as has been known for decades, play a role in the emergence of various rheumatic ailments.

Polymorphism
These genes, located in the short arm of chromosome 6, encode the HLA (human leukocyte antigen). These molecules are highly polymorphic, that is to say, they can show themselves in several different configurations (sequences of amino acids). The international literature indicates that the HLA-DR4 allele, one of these configurations, is linked to the disease in different populations and ethnic groups, but in other groups an increase in the HLA-DR1 allele was also observed in the patients. In 1993, a sequence of amino acids was found in the 70 – 74 region of the molecule of the HLA-DR that could be common to all the alleles connected with rheumatoid arthritis – amongst them, the most common are DRB1*0101, *0404 and *0401. This small stretch was given the name of shared epitope and is the target of intense research to understand its association with the disease. But, in African populations, this sequence is not linked to the ailment, which raises the suspicion that there are other genes involved. The incidence of rheumatoid arthritis varies amongst different population groups. Certain indigenous American tribes have a prevalence of 10%. In Brazil, the studies have found an occurrence from 0.2% to 1.0%.

Bértolo’s researches, in a pioneering manner, are looking for the genetic roots of the problem in Brazilians. “There’s no point in targeting studies of polymorphism done in other countries, since the genetic markers vary according to the population group”, Bértolo says. In the study done with Brazilians descended from Europeans, Bértolo’s team concluded that the HLA-DRB1*0101 and *0102 alleles were associated with susceptibility to rheumatic arthritis, while the HLA-DRB1*0401 and *0404 alleles were connected with the more serious forms of the disease; whereas in the research done with Afro-Brazilians, preliminary data suggests that HLA-DRB1*09 is the one connected with susceptibility to the ailment.

The investigation of the genetic origins of rheumatic arthritis will be the target of a nationwide survey, forecast to begin in 2006. Teams from the University of Brasilia, the Federal Universities of Rio Grande do Sul, Ceará and São Paulo (Unifesp) and the University of São Paulo, in Ribeirão Preto, are going to follow up 300 patients. Each center will study at least five polymorphic genes relevant to an understanding of the mechanisms of the disease. “The objective is to group together genes with a partial influence, to get a picture that gives replies of greater clinical usefulness”, says Luis Eduardo Coelho Andrade, Unifesp’s professor of rheumatology, who is going to coordinate the study.

Consortiums of researchers from various parts of the world are trying to unveil the intricate process that leads to the disease. In the case of developing countries, the search for markers has extra importance. As the cost of the therapies has growing weight in the health budget, getting to know the proper treatment for each kind of patient is a way of rationalizing costs and offering assistance to more victims. There is a class of medicines that blocks a protein called tumor necrosis factor, which causes a major part of the inflammation and pain in the joints. Research at the University of Nebraska revealed an improvement in 20% of the serious patients that were not responding to cortisone. The treatment costs R$ 5 thousand a month.

Only a portion of the victims needs drugs like this one. Applied early, they prevent a more dramatic evolution of the disease. The researchers are looking for tools that distinguish these patients from the immense majority that manages to control the symptoms by resorting to anti-inflammatories and corticoids. A study made by Unifesp calculated at R$ 1,100.00 the annual cost per rheumatoid arthritis patient treated by the SUS. The survey took into account, among others, outpatient and inpatient costs, besides the cost of the medicines, which corresponds to 70% of the total. The R$ 1,100.00 does not seem a lot when compared with the costs of the patients in other countries. In the United Kingdom in France, this expenditure amounts to US$ 9.3 thousand (about R$ 22.3 thousand). But it is a considerable cost as far as the limited Brazilian health budget is concerned.

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