rheumatoid arthritis What are the causes of rheumatoid arthritis?

1.3 What are the causes of rheumatoid arthritis?

1.1 General

Rheumatoid arthritis (RA) is a chronic inflammatory disease, autoimmune in nature, characterized by the symmetrical involvement of multiple joints and the presentation of various non-specific general symptoms and extra-articular manifestations. Freed to its natural evolution and in the absence of adequate treatment, the disease can cause, in advanced stages, important physical limitations, as well as a marked deterioration of the quality of life.

RA is typically manifested by pain, swelling, and stiffness or difficulty of movement in various small and large joints. The general symptoms, which sometimes precede the joint manifestations and tend to persist throughout the evolution of the disorder, basically include tiredness, discomfort, slight fever, lack of appetite and loss of body weight. The possible extraarticular manifestations, which usually occur when the disease is already established, mainly affect the skin, blood vessels, heart, lungs, eyes and blood.

RA is much more frequent in females than in males and usually appears in older adults, but it can start at any stage of life and affect any person, regardless of race, sex and occupation.

The most frequent initial symptom is morning joint stiffness (especially in the joints of hands and feet), which occurs after nighttime rest and involves a considerable difficulty in movement. The morning stiffness can be accompanied by fatigue, fever, loss of appetite and muscle weakness, a picture that sometimes appears weeks or months before the pain and signs that indicate joint inflammation, ie swelling, heat and redness in the joints committed.

The evolution of the disorder is very variable, since in some people the progress of the lesions stops spontaneously, while in others it progresses throughout life. The most common, however, is that the disorder develops over many years or throughout life, with alternating periods of symptomatic exacerbation - or "symptomatic outbreaks" - that usually last a few weeks or a few months and periods of relative or absolute calm.

During symptomatic outbreaks, the affected joints are swollen, swollen and hot, painful and difficult to move, especially after nighttime rest. In the absence of timely treatment, these exacerbations tend to be more frequent and lasting, so that the affected joints progressively lose mobility, while characteristic skeletal deformities occur. Without treatment, the most common is that RA leads to a significant deterioration of functionality and quality of life.

The treatment of RA consists of a series of general measures related to lifestyle, rest and exercise, together with a pharmacological therapy in which a wide range of medications can be used; In addition, in some cases, the application of certain surgical interventions is indicated. Unfortunately, there is still no treatment available to cure the disease. However, taken as a whole, all the therapeutic measures currently available can alleviate symptoms and improve prognosis, which has a very positive impact on the quality of life of those affected.

The best therapeutic results are achieved when an early diagnosis is made and treatment is established in the initial phases of the disease. It is also very important that the affected person follows in a rigorous way the indications given by the physicians in the periodic follow-up visits that are scheduled, precisely, in order to control the evolution of the disease.


1.1.1 Autoimmune diseases and inflammation

Autoimmune diseases are a large group of disorders in which, for reasons not yet well understood, the immune system, responsible for the defense of the body, reacts against tissues of the body that it erroneously identifies as strangers, as if they represent a threat .

Among the various autoimmune diseases, some affect a certain body structure, while others are systemic, as the injuries they cause involve the body as a whole. The AR corresponds to this last group, since the target of autoimmune attacks is the connective tissue, which basically fulfills a function of union and support and that, therefore, is present in virtually all organic structures. For this reason, RA is also part of the so-called conectivopathies.

Despite this, in RA, injuries especially affect the joints, although injuries to the skin, blood vessels, bones, eyes, and organs such as the lungs and the heart are also common.

Defensive cells and antibodies. The immune system aims to protect the body from elements that pose a threat, such as, for example, microorganisms or tumor cells. Among the various components that are part of the immune system include white blood cells or leukocytes, which circulate in the blood and are distributed through different tissues with the mission of exercising a constant "vigilance": if they detect the presence of a potentially dangerous element, They will try to eliminate it by various mechanisms.

There are different types of leukocytes, which act in different ways. Some specialize in the detection of suspected foreign elements, others are capable of attacking them directly and others, however, manufacture specific proteins to neutralize or inactivate them. These proteins are called antibodies.

Inflammation and autoantibodies. Inflammation is the fundamental defensive reaction that sets the immune system under threat. Although a great diversity of elements and mechanisms are involved in the inflammatory reaction, the inflammatory process can be summarized as follows: when a potentially harmful foreign element is detected, the defensive cells issue an order that the blood vessels in the area in question be treated. they expand, to favor thus the arrival of a greater number of defensive cells and elements; but next to these elements, a greater flow of liquid also arrives, reason why the affected zone swells, pressing and exciting the nerve endings, generating therefore the sensation of pain. That is why the inflammation is usually manifested by swelling, redness, heat and pain in the affected area.

In autoimmune disorders, for reasons not yet clarified, defensive cells not only trigger inopportune and often persistent inflammatory processes, but also make antibodies that react against the body's own tissues, which is why they are known as autoantibodies. These autoantibodies, together with the repeated and persistent inflammatory processes, are the cause of the lesions characteristic of autoimmune disorders.

There are several autoantibodies more or less specific to RA. The most important are rheumatoid factor (FR) and citrullinated cyclic anti-peptide antibodies (anti-CCP). The identification and assessment of these autoantibodies, which is carried out through specific tests in blood analysis, is one of the most important aspects that doctors take into account when establishing the diagnosis, controlling the evolution and even outlining the prognosis. of the AR.

In recent years there has been a great advance in the knowledge of the mechanisms and elements involved in the inflammatory processes of autoimmune disorders. In relation to RA, it has been seen that a protein known as TNF plays an essential role in the initiation and perpetuation of joint inflammation. Therefore, modern biological drugs, which act against this protein, have begun to be used in the treatment of RA, which has significantly improved the prognosis of the disease.



1.1.2 Anatomy of the joints

The joints are the structures in which the bones are connected and which provide both mobility and stability to the different skeletal segments. There are several types of joints, some fixed and others, most, more or less mobile. Movable joints, which are those that are affected in RA, are formed by the ends of two or more bones and other components no less important, such as the articular cartilage, the joint capsule and the synovial membrane.

The basic elements of the joint are the bones. The shape of the bone ends varies in each articulation, and precisely its correspondence, that is, its fit, conditions the mobility of the involved skeletal segments. But the bony surfaces are not in direct contact, but upholstered by a band of elastic tissue, the articular cartilage, which prevents friction and wear. In large joints, such as the knees and hips, the articular cartilage is about 3-4 mm thick, while in the joints of the fingers it only has a fraction of a millimeter.

The joint capsule is an envelope that, like a bag, includes the entire joint. It is formed by two membranes, one external, which is fibrous and resistant, and one internal, which is softer and is called synovial membrane. The fibrous membrane is firmly attached to the bones that are linked in the joint and provides stability to the structure; even in some sectors their fibers form bands that attach to the bones, the ligaments, which guarantee this stability.

The synovial membrane covers the inner surface of the joint capsule and has the mission of producing a viscous fluid, the synovial or joint fluid, which fills the joint cavity and acts as a lubricant that reduces friction between the structures of the joint. In addition, the synovial membrane contains immune cells and, therefore, has a prominent role in the defense of the joint, which is the place where inflammatory reactions occur.

Figure 1. Main components of a mobile joint

1.1.3 Rheumatic diseases and «rheumatism»

Rheumatic diseases are a large group of disorders that generally affect the locomotor system or musculoskeletal system -comprised basically by bones, muscles, tendons and joints- and that are not directly or immediately related to trauma. including autoimmune pathologies that affect the connective tissue.

Some rheumatic diseases can cause arthritis, that is, the inflammation of one or more joints, as is the case of RA. But others, on the other hand, can affect exclusively the bones, as in the case of osteoporosis, or they are due to a degenerative process, as in the case of osteoarthritis, the most frequent rheumatic disease.

The specialty that deals with these diseases is known as rheumatology, but the term "rheumatism" has no definite meaning in current medicine. This term, which comes from the Greek and means "flow", was formerly used in the context of the so-called "theory of humors", when it was thought that rheumatic diseases were produced by the flow of a humor to the joints, causing their inflammation. Nowadays, specialists prefer not to use this term.

Table 1. Main rheumatic diseases

1.1.4 The joint lesion in rheumatoid arthritis

The joint lesions of RA occur as a result of arthritis, that is, joint inflammation.

The onset of the disorder corresponds to the inflammation of the synovial membrane that lines the inside of the joint capsule: a synovitis is thus produced, characterized by the proliferation of various types of immune cells and by the excessive production of synovial fluid, all of which causes manifestations of joint inflammation.


With the passage of time, the synovitis becomes chronic: the synovial membrane thickens and in its thickness an invasive scar tissue type is formed, known as pannus, which grows into the joint and affects the articular cartilage.

If the disease does not stop, after a while the pannus infiltrates the articular cartilage and even affects the bony ends of the joint, which, added to the action of the chemical mediators produced by the immune cells, ends up causing erosions bone and osteoporosis (loss of density of bone tissue). In these advanced stages of the disease, joint injuries cause joint stiffness and deformation.

Figure 2. Articulation with rheumatoid arthritis

1.1.5 Differences between rheumatoid arthritis and osteoarthritis

Arthrosis and RA are frequent rheumatic diseases, especially the first one, and some of its manifestations are similar, which can generate confusion and misunderstandings. However, both their origin and their evolution and treatment are very different. It is convenient that people with RA know these differences, since this will help them to avoid assumptions, to better understand with their healthcare team and, ultimately, to control their disease more effectively, given that the therapeutic strategies that are applied are different in one and another disorder.

Causes. RA is an inflammatory disease that primarily affects the synovial membrane, while arthrosis is a noninflammatory pathology, as it corresponds to a degenerative disorder of the articular cartilage.

Risk factor's. Both disorders share some risk factors, that is, circumstances that favor the appearance and evolution of the disease: the female sex (both disorders are much more frequent in women than in men), the genetic predisposition (which is particular and different in each disorder), menopause and obesity. However, other risk factors are very different. Thus, it is currently considered that smoking, stress and infections could contribute to the appearance and progression of RA, while in occupational osteoarthritis occupation and professional activity are important, as well as intense physical activity, since the movements repetitive and overloading of the joints favor the wear of the articular cartilage.

Frequency. According to epidemiological data from Spain, RA affects only 0.5% of the adult population, while osteoarthritis is much more frequent: it is estimated that about 24% of the population suffers from it.

Injuries In RA, lesions are caused by inflammation, and not only develop in the joints, but often affect other organs and tissues, such as the lungs, heart, skin and eyes. In osteoarthritis, on the other hand, lesions only occur in the joints and are not inflammatory in nature.

Affected joints In RA, the most commonly injured joints are those of the extremities (particularly those of the fingers and toes, ankles, knees, shoulders and elbows), which are usually affected symmetrically on both sides of the body. body. In osteoarthritis, on the other hand, the joints most commonly affected are the knees and the hips, although practically all large and small joints can suffer this alteration, and it is not usual for the lesions to be symmetrical on both sides of the body.

Figure 3. Affected joints in osteoarthritis and rheumatoid arthritis

Symptoms and evolution. RA usually develops in the form of symptomatic outbreaks, during which the affected joints are inflamed, painful and have difficulty in movement, as well as a certain degree of stiffness. The pain usually lasts all day, although it tends to intensify during the night and with rest. As for the rigidity, it is usually generalized, it is more intense when getting up and usually lasts more than half an hour. In addition, general symptoms are frequent, such as slight fever, malaise, fatigue, loss of appetite and loss of body weight.


In osteoarthritis, on the other hand, the main symptom is joint pain, which usually intensifies with overload and movement, while it improves with rest. Joint stiffness is also common, limited to the affected joint, appears after a period of inactivity, usually lasts less than half an hour and disappears quickly with exercise. In addition, osteoarthritis does not cause general symptoms.

Table 2. Differences in joint pain and stiffness in rheumatoid arthritis and osteoarthritis

Diagnostic forms In both disorders, a complete physical examination is performed and radiological tests are requested. However, to define the diagnosis of RA, it is necessary to request blood tests and evaluate certain parameters, such as the erythrocyte sedimentation rate (ESR), the rheumatoid factor and perform certain immunological tests.

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1.2 Who is affected by rheumatoid arthritis?

Rheumatoid arthritis (RA) is a relatively common disease. According to global statistical data, it affects between 0.3 and 1% of the population, which means that currently there will be between 100 and 200 million people in the whole world suffering from this disorder.

In Spain, according to the most current epidemiological surveys, RA affects approximately 0.5% of the adult population, with which there would be, in total, more than 200,000 affected. Each year about 10,000-20,000 new cases are diagnosed.

The frequency of RA does not only vary between different countries and regions, but also according to sex and age. Thus, the disorder is three times more frequent in women than in men and is much more common in older people than in young adults, with a more frequent onset age between 40 and 60 years of age. Consistent with these data, it is estimated that RA affects around 5% of women over 55 years of age, among whom the disease would be 5-10 times more frequent than in the general population. Despite the precisions pointed out, it must be borne in mind that RA can really appear in any period of life, without excluding childhood or adolescence.

It should be noted that RA is more frequent in those who have a certain genetic predisposition to suffer from it, although this does not mean that the children and relatives of a patient necessarily have, and for this reason, a high risk of developing the disease.

It is also more common among people who have a plasma protein known as rheumatoid factor, about 5% of the general population. Therefore, the detection of rheumatoid factor is part of the analysis that is requested to make the diagnosis and control the evolution of the disease.

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1.3 What are the causes of rheumatoid arthritis?

The causes of RA are still not known in depth. What is known is that it is an autoimmune disorder and that causes or genetic factors, as well as non-genetic causes or factors, are involved in its origin.

Genetic factors. Genetic factors increase the risk of the disease developing. The investigations carried out in recent years suggest that RA is a polygenic disease, which means that there are several genes that would be involved in its origin. Specifically, we have identified the existence of certain alleles (ie, structural variations in the genes) that, by very diverse and complex mechanisms, could predispose to the development of RA.

The list of alleles studied is extensive, but it has been found that some of them play an important role as markers of the disease, which means that they can be used to establish the risk of developing RA, to perform the diagnosis of RA itself and even to outline the forecast. This is the case of the so-called "shared epitope" (CD), whose carriers have a 2.5-4.5 times higher risk of developing the disease and which is present in 80% of people already affected by RA.


These genetic findings may explain why RA is more common in some countries and regions, as well as in some families. Thus, it has been seen that the possibility that two identical twin brothers (with the same genes), carriers of the alleles that predispose to the appearance of RA, end up effectively developing the disease is at 30%. In addition, it is estimated that, on the whole, all genetic factors would be responsible for 60% of the causality of the RA.

History of RA in the family. In accordance with the above, it is considered that the family history of RA - the fact that parents, grandparents, siblings or close relatives of a person have suffered or suffer RA - constitute a risk factor to be taken into account. However, it should be emphasized that genetic factors are only predisposing, and not determinant, which means that a person who carries a genetic trait that potentially promotes the development of RA will not necessarily end up developing the disease.

Non-genetic factors Non-genetic factors are not well known either. The most relevant are infections, female hormones, smoking, stress, obesity and the type of food.

Infections It has been postulated that infections by various viruses or bacteria could trigger the disease or aggravate its course. This theory is based on the fact that in some occasions the RA has presented in a similar way to epidemic outbreaks, and also in that in past decades, when so many hygienic measures were not adopted to prevent infections, the disease was more frequent, in particular among people who had received blood transfusions. This theory has not been proven, although it is likely that a more consistent explanation will be found in the future. In any case, it should be clear that RA is not a contagious disease that is transmitted directly from person to person.

Female hormones. Apparently, female hormones, particularly estrogens, protect against RA, since it has been found that both contraceptive use and pregnancy reduce the risk of developing the disease and reduce or delay its manifestations, while in the period after childbirth and in menopause, when the activity of these hormones is reduced, the opposite occurs.

Smoking and stress. A clear statistical relationship has been found between smoking and stress, on the one hand, and the risk of developing RA, especially in genetically predisposed people. For example, it has been seen that, in many patients, the first manifestations and symptomatic outbreaks of RA are preceded by times of stress and / or increased consumption of tobacco.

Obesity and type of feeding. It has been shown that RA is more frequent in obese people. It has not been possible to demonstrate that any particular diet has an effect on the risk or prognosis of RA, although it is likely that diets rich in blue fish contribute to reducing the intensity of joint inflammation and that a healthy diet in general results beneficial in the prevention of this disease.

Other possible causal factors. Currently, scientists are investigating other possible causal factors, both genetic and non-genetic, such as the changes or spontaneous mutations in the genes that regulate the manufacture of the numerous molecules that intervene in inflammatory processes. It is likely that the results of these investigations can explain why none of the factors mentioned above have a decisive influence on the appearance and evolution of RA.