Fig. 1.1
Ulnar drift of hands in an EORA female patient, with associated tendovaginitis of extensors, interosseous muscle atrophy and rheumatoid nodules (Courtesy of Professor J. Vencovský, MD, DSc)
Fig. 1.2
Severe flexion contractures in an EORA female patient, with buttonhole deformities of fingers (Courtesy of Professor J. Vencovský, MD, DSc)
Fig. 1.3
Flexion contractures in knee joints in a patient with a long-term RA, including active gonitis and a marked muscle atrophy (Courtesy of Professor J. Vencovský, MD, DSc)
Fig. 1.4
Involvement of the shoulder joint in an EORA female patient. The joint capsule bulges with a massive effusion (Courtesy of Professor J. Vencovský, MD, DSc)
Fig. 1.5
Involvement of shoulder joints in an EORA female patient. Massive effusion is present in both shoulders, with a bulging joint capsule (Courtesy of Professor J. Vencovský, MD, DSc)
Fig. 1.6
Knee joints: right – stage III OA of the knee with varus deformity, joint space narrowing, subchondral sclerosis and osteophytes in the medial compartment. Left – slight joint space narrowing of the medial tibiofemoral joint and tibial erosion, in EORA
Fig. 1.7
Hip joints: stage II OA of the hip bilaterally and enthesophytes in typical locations. Left – coxitis in EORA, central joint space narrowing to minimum, thinning of the acetabular floor, even slight protrusion and mild subchondral cysts in the femoral head
Fig. 1.8
Left wrist: stage II arthritis in the region of the DIP and PIP joints, stage II rhizarthrosis on the left, periarticular osteoporosis, slight joint space narrowing and widening of the shadow left wrist soft tissue – stage I arthritis within EORA
Fig. 1.9
Left wrist 2: stage II arthritis of DIP and PIP joints, joint space narrowing in the left wrist, mild periarticular osteoporosis, widened shadow of the soft tissue – degree I arthritis
Fig. 1.10
Feet – hallux valgus with bunion and stage I arthritis of MTP joint bilaterally, condition after Köhler disease II. Erosion of MTP III on the right and erosion of MTP III on the left. Cysts and minor marginal erosion of the MTP V joint on the right in EORA
Fig. 1.11
Shoulder: joint space narrowing in the humeroscapular joint, erosion of the lateral edge of the articular surface of the humeral head, subchondral cysts of the humeral head in arthritis, simultaneous sclerosis and osteophytic spurs on articular surfaces – omarthritis, cranial migration of the humeral head towards the acromion – rotator cuff arthropathy in EORA
Fig. 1.12
Hands: diffuse osteoporosis mainly in the periarticular region of the left wrist; widened shadow of the soft tissue around PIP, MCP joints and in wrists; carpal and radiocarpal joint space narrowing bilaterally; cysts in the radiocarpal joint on the left; erosion of MCP I joint on the right, EORA; stages I and II arthritis of DIP, PIP joints, IP joints of thumbs and MCP III on the left side
Posterior subluxation of proximal phalanges causes a hammertoe deformity that may considerably limit walking and standing. Patients often develop also hallux valgus. The disease may severely affect the cervical spine, primarily in the atlantoaxial joint. The transverse ligament, which fixes the dens in a stable relationship to the anterior arch of the atlas, may become lax as a result of inflammation and conduce to anterior subluxation of the atlas. Intervertebral discs and intervertebral joints may be also involved.
A relatively frequent arthritis of temporomandibular joints causes pain in chewing, and these symptoms are often attributed to a tooth disorder. Involvement of cricoarytenoid joints may lead to voice changes, hoarseness or even inspiratory stridor. Sternoclavicular and manubriosternal involvement is quite frequent but mostly clinically irrelevant.
A study published by Yazici et al. [21] states that EORA starts after the age of 60 years and is a distinctly different disorder from YORA. In younger patients the disease is characterised by acute onset, affecting about three times more women than men. In contrast, RA in middle age has typically an insidious and often vague onset. In elderly patients, there is a tendency for the onset of the disease to be acute and infectious-like, involving also large proximal joints, shoulders in particular, while RA in middle age affects mainly small (PIP and MCP) joints of the hands [1, 4] – see Table 1.1.
Table 1.1
Comparison of classic versus elderly-onset RA
Classic RA | Elderly-onset RA | |
|---|---|---|
Men/women ratio | 1:3 | 1:1 |
Age at onset | 30–50 years | More than 60 years |
Onset | Gradual | Often acute, systemic manifestations |
Number of joints | Polyarticular | Often oligoarticular |
Involvement location | Small joints | Often large joints |
Course of the disease | Variable severity | Often severe |
Prognosis | Variable | Often severe |
Rheumatoid factor | Predominantly positive | Predominantly negative |
In elderly patients, the clinical features are sometimes similar to those of polymyalgia rheumatica or symmetrical synovitis with pitting oedema (RS3PE) syndrome. In older patients the onset of the disease is more often associated with systemic manifestations and a high sedimentation rate. Comparison of the specific features of the classical and of elderly-onset rheumatoid arthritis is shown in Table 1.1.
1.5 Extra-articular Symptoms
The number and severity of extra-articular symptoms vary with the duration and severity of the disease. A number of these symptoms may be combined with a disorder of the respective organ or with a process associated with another concomitant disease of a different type. As a result, more severe conditions can be often seen in elderly than in middle-aged patients.
Rheumatoid nodules are more often an extra-articular sign in RA and occur in about 20–30 % of patients, almost always together with the rheumatoid factor (RF). They usually develop under the skin over the proximal subcutaneous border of the ulna or over the olecranon. Multiple nodules over small joints of hands are termed rheumatoid nodulosis. Less often the nodules can be seen in the sacral or occipital region and quite rarely in the larynx, heart or lungs. Elderly patients are less likely to have subcutaneous nodules [9].
Tenosynovitis can be observed, mainly in the region of hands and wrists. Rupture of tendons, most frequently flexors or extensors of fingers, leads to development of deformities, with bursitis developing near joints. Muscles are involved quite often, and impaired mobility leads to atrophy and muscle weakness. In the elderly it is associated with the age-related loss of muscle mass. Also osteoporosis associated with RA may be more serious in elderly patients because of combination of several etiological causes.
A serious complication is vasculitis. Clinical manifestations include rash, cutaneous ulcers and both sensory and motor peripheral neuropathy. Pulmonary involvement may manifest itself by pleuritis, interstitial lung fibrosis or rheumatoid nodules. RA is often associated with a number of cardiac disorders, e.g. pericarditis, myocarditis, endocarditis, conductive defects and arteritis which as a rule do not cause symptomatic problems. Secondary amyloidosis occurs in 7 % of progressive RA, i.e. primarily in older patients with a long history of the disease. It is characterised mainly by impaired renal function that may be indirectly caused also by therapy. The most frequent ophthalmological disorder is dry eye syndrome, keratoconjunctivitis sicca (KCS), affecting about 10–35 % of patients.
EORA is sometimes divided into three groups: classic RA, seronegative RA similar to PMR (polymyalgia rheumatica) and a group with predominating Sjögren’s syndrome symptoms. This division of EORA reflects a higher incidence of KCS and xerostomia. The most frequent haematological abnormalities include anaemia and thrombocytosis which develops mainly in the active stage of the disease [1, 4].
1.6 Immunological Changes During Physiological Ageing in Relation to Development of EORA and Immunopathological Condition
It is estimated that 25 % of human longevity is influenced by genetics, while the remaining 75 % is determined by lifestyle and environmental influences. In people aged 90 and more years, genetic factors are responsible for more than 25 % of their lifespan. The share of genetic factors in the general activity of the immune system differs in terms of natural and specific immunity. Natural immunity, including inflammation, is determined genetically, with almost no impact of environmental factors. Therefore, it is also called innate immunity. In contrast, specific immunity is genetically determined only roughly.
This concerns mainly the T-lymphatic component. Its activities are modified by specific environmental factors in the course of the human life.
The capacity of the human immune system is supposed to be the highest immediately after birth. Subsequently it gradually decreases due to various stress factors or a past history of inflammatory responses and diseases (mainly chronic). One of the factors is also the fact that during evolution the human organism was set to live 40 or 50 years, but today the immune system must remain active for a much longer time. However, evolution changes take place in much longer period than in human lifespan. Accordingly, the annual age-dependent decline of immunity functions is higher than in other examined physiological functions.
The result of progressive changes in functioning of the immune system is immunosenescence. It is defined as abnormal regulation of immune responses, resulting in an increased susceptibility of the elderly population to infections and autoimmune, degenerative and tumorous diseases caused by cellular and molecular changes in mechanisms of the innate and acquired immunity. Innate immunity mechanisms are impaired by decline in dendritic cells that are the basic antigen-presenting cells inducing immune response. Macrophages have a decreased expression of toll-like receptors (TLRs) and, consequently, also reduced antimicrobial activity. On the other hand, their inflammatory activity grows as a result of increased production of pro-inflammatory cytokine IL-6. With the increasing age, expression of low-affinity Fc receptor for IgG (CD16) decreases on neutrophils, which results in a significant reduction of their phagocytic function. Activity of NK cells does not change or slightly grows. Elderly people have slightly lower levels of several complement components. The degree of its activation considerably decreases during infection which is another cause of their increased susceptibility to infectious diseases [22].
Another contributing factor is decreased capacity of antibody- and cell-mediated specific immunity. It is manifested mainly in responses to new infectious agents or vaccines. For instance, old people are substantially more susceptible to infectious complications after flu infection. In addition, the effect of flu vaccines on them is much less effective than in young and middle-aged adults [23]. The reason is primarily substantial changes in the T-lymphocyte repertoire. Adequately efficient immune response to a new infectious antigen depends on the function and repertoire diversity of naïve T-lymphocytes (which have not come into contact with the respective antigens, yet). These T-lymphocytes must be able to recognise a pathogenic antigen and, in response to it, to proliferate and differentiate into T-lymphocyte subpopulations with the necessary effector and regulatory functions. In addition, they must be able to migrate to the place of action. The key factor of this process is sufficient diversity of antigen receptors on the surface of naïve T-lymphocytes, providing a sufficient number of those of them that recognise antigenic determinants on a newly infecting pathogen. T-lymphocytes that have recognised it subsequently become activated and differentiate into helper Th-lymphocytes (CD4+), conditioning proper activity of B lymphocytes with a subsequent production of antibodies, or into cytotoxic Tc-lymphocytes (CD8+) with the respective effector functions.
In young people, the group of naïve T-lymphocytes is adequate to fulfil these functions, while in old people, it is significantly limited not only in terms of their numbers but also diversity of their antigen receptors that are able to recognise a new antigen. As a result, the function of effector and regulatory CD4+ and CD8+ T-lymphocytes, differentiating from them, is also reduced. On the other hand, the number of memory T-lymphocytes dramatically grows. They have already been in contact with their specific antigens and remember them, and therefore in repeated contact, they quickly become activated and may proliferate and form clones of effector cells. However, most of them are not able to become activated by new antigens. Reduction of the number and diversity repertoire of naïve T-lymphocytes and overfilling of the immunological space with memory T-lymphocytes is the main cause of impairment of anti-infection and antitumour immune defence of old people. In people older than 100 years, the naïve cytotoxic T-lymphocytes are already absent. Lymphocytes in their blood are almost solely of the memory phenotype. This change in the ratio of naïve and memory T-lymphocytes does not progress in a linear way during the life and changes dramatically in favour of memory T-lymphocytes mainly after the age of 60–65 years.
1.6.1 Paradox of Immunodeficiency and Stimulation of Chronic Inflammation During Ageing
This paradox consists on the one hand in deterioration of the function of the immune system caused particularly by progressive decreasing of the function of T-lymphocytes and, on the other hand, in development of chronic inflammation documented by the age-related increased levels of pro-inflammatory cytokines (IL-6, TNF, IL-1, IL-8), acute-phase proteins (C-reactive protein, serum amyloid A) and a higher frequency of chronic inflammatory diseases, such as Alzheimer’s disease and Parkinson’s disease, amyotrophic lateral sclerosis, elderly-onset rheumatoid arthritis (EORA), autoimmune diseases – elderly-onset systemic lupus erythematosus – atherosclerosis and other diseases [24].
What is the cause of these negative changes? Presumably the main causes of deteriorating function of lymphocytes are alterations in their response to the regulatory effect of certain cytokines (IL-2, in particular) and increased sensitivity to induction of the programmed cell death – apoptosis – through receptor for tumour necrosis factor (TNF). Throughout the whole life, the human body continuously responses by defensive inflammation to a wide range of infectious and other insults causing tissue damage. The triggering (alarm) cytokine, which is commonly released into circulation in the case of acute inflammation, is the tumour necrosis factor (TNF). Therefore, also its systemic concentration grows with age. This results in progressive increase of apoptosis and reduction of T-lymphocytes that have receptors for TNF on their surface. The cells that underwent apoptosis are phagocytosed by phagocytes, such as macrophages and dendritic cells, whose phagocytic function, however, decreases with age.
Therefore, they are not able to liquidate rapidly and efficiently apoptotic lymphocytes. As a result, the apoptosis process turns into secondary necrosis, with a developing chronic inflammation which damages the surrounding tissue.
During the process of ageing, development of chronic inflammation stimulates elevated levels of pro-inflammatory cytokines. Causes of such increase are not exactly known. However, they certainly include repeated defensive inflammatory responses with production of free radicals and other inflammatory mediators that are toxic not only for the damaging infection agent but also for cells of the surrounding tissue. Another factor is apoptosis of lymphocytes increasing with age and their inadequate removal by dendritic cells and macrophages. Apoptosis is associated with activation of caspases, some of which directly produce active pro-inflammatory cytokines IL-1β and IL-18.
This chronic systemic inflammatory condition, characteristic of ageing, is termed inflammaging. It is a low-grade chronic systemic stimulation of pro-inflammatory responses [24, 25]. It may be considered as a certain evolutionary relict that contributed in the past to survival of human population, particularly in the conditions of devastating epidemics and pandemics of infectious diseases. At that time, mainly individuals with a more efficient pro-inflammatory genotype survived. Inflammatory genotype predominates also in the current human population. As a defence against infectious diseases, it is more efficient in children, although this advantage has been recently debated in connection with epidemic spread of allergic diseases. In advanced age, this advantage of inflammatory genotype is erased, as it causes increased susceptibility to chronic inflammatory diseases, for instance, elderly-onset rheumatoid arthritis, polymyalgia rheumatica, giant cell arteritis and other autoimmune diseases (elderly-onset SLE, Werner’s syndrome as a variant of systemic sclerosis and others).
A particular inflammatory genotype of each individual is determined by about 400 different genes with multiple polymorphisms that determine quantitative differences between their carriers. Based on them, two extreme genotypes may be distinguished. “More pro-inflammatory” genotype is characterised by low production of anti-inflammatory cytokine IL-10 and high production of pro-inflammatory cytokine IL-6, while “less pro-inflammatory” genotype by high production of IL-10 and low production of IL-6. Individuals with a genetic predisposition to produce high levels of IL-6 and low levels of IL-10 have a lower ability of normal regulation of the inflammatory process and a decreased resistance to inflammatory and tumorous diseases. At the same time, they exhibit an increased incidence of syndromes of innate (natural) autoimmunity, and their chance to live long declines. This may be indicated also by the fact that a great majority of individuals in the age category of 90–100 years are only “producers” of high levels of IL-10 [27]. Syndromes of innate autoimmunity, including, for instance, atherosclerosis and the related pathological entities [28], should be distinguished from conventional autoimmune diseases, the pathogenesis of which is predominated by specific immunity mechanisms (autoantibodies, autoagressive T-lymphocytes).
On the other hand, disorder of immune homeostasis during physiological ageing may be involved also in the pathogenesis of conventional autoimmune diseases.
On the basis of the existing findings, it may be concluded that metabolic, functional and clinical manifestations associated with age quite well correlate with the functional activity of the immune system. The immune system is part of the neuroendocrine-immune system that plays a decisive role in regulation of homeostasis in humans. Therefore, its inadequate or otherwise abnormal function will be reflected also in homeostasis changes influenced by genetic, internal and external factors. Genetic factors determine the genotype of an individual that cannot be practically influenced. It has been shown that in terms of the quality of life and longevity, the genotype of producers of high levels of anti-inflammatory IL-10 and low levels of pro-inflammatory IL-6 is more advantageous than a genotype with the opposite characteristics of these two cytokines.
To a certain extent, it is possible to influence the phenotype of each individual. It is determined primarily by environmental factors, eating, working and social habits. Onset of immunosenescence may be postponed in individuals who live in a hygienic environment with a minimal exposure to persisting viral and parasitic infections, with available adequate medical care, vaccination, safe food, uncontaminated water and air, i.e. in an environment with minimal incidence of antigens and stress factors that would exhaust the immune system and lead to accumulation of chronic inflammatory responses. All these factors that were established in the advanced countries in the middle of the last century have contributed to lengthening of the average human lifespan but, on the other hand, quite probably also to epidemic development of allergic diseases. This is also the rationale behind the hygienic hypothesis that, namely, insufficient infectious stimuli and “excessive” hygiene, mainly in childhood, result in abnormally developed “maturity” of the immune system, which is manifested by increased susceptibility to development of allergic inflammatory responses. Their clinical forms include allergic eczema, nasal allergy, allergic hives and bronchial asthma.
Thus it seems that from the viewpoint of a normal development and activity of the immune system, its “inactivity” with a low pressure of antigens is equally disadvantageous as excessively repeated responses to the presence of infectious agents or other factors damaging its cells and tissues. Infectious agents may lead to a more rapid onset of immunosenescence and development of a systemic chronic inflammation with subsequent clinical manifestations, such as cardiovascular diseases, a majority of tumorous and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus, osteoporosis, osteoarthritis (OA), Alzheimer’s and other degenerative diseases [26].
A new medical discipline – preventive anti-ageing medicine – focuses on postponing the onset and decreasing intensity of manifestations of immunosenescence, by extensive therapies and preventive procedures aimed at achieving an optimal lifespan and enhancing the quality of life.
Its goal is to influence the ageing process by pharmacological and psychotherapeutic means and reduce morbidity and disability in the old. Its important part is strengthening of immunity by various immunostimulatory means, such as probiotics, sufficient supply of proteins, certain vitamins and trace elements (especially selenium) and reasonable physical and mental activity.
1.7 Hormonal Findings and Cytokine Levels in Polymyalgia Rheumatica, EORA and EORA/Polymyalgia Rheumatica
Polymyalgia rheumatica (PMR) may in terms of differential diagnosis pose certain problems as concerns nosographic distinction between EORA and EORA with PMR-like onset (EORA/PMR). Cutolo et al. [29] and Sully et al. [30] studied levels of TNF-alpha and IL-6 in the above-mentioned nosological entities and found out that concentrations of TNF-alpha and IL-6 in plasma were higher in PMR, EORA and EORA/PMR as compared to the control group. The results also showed that IL-6 concentration was higher in PMR and EORA/PMR than in the group of EORA patients. Concentration of the IL-1Ra receptor antagonist was higher in EORA patients as compared to the controls, and similarly IL-1Ra was also more frequent in PMR and EORA/PMR patients. Concentration of adrenal androgen dehydroepiandrosterone sulphate (DHEAS) was lower in EORA/PMR than in EORA patients. Progesterone (PRG) levels were provably higher in all studied diseases. After administration of glucocorticoids, the levels of serum TNF-alpha and IL-6 provably decreased in all three nosological entities.
IL-1Ra provably increased in PMR patients as well as in the group of EORA/PMR patients. As expected, after glucocorticoid treatment the levels of cortisol, DHEAS and PRG decreased both in PMR and EORA/PMR patients.
The results of both studies have indicated that different cytokine and steroid profiles suggest that in PMR and EORA/PMR, the inflammatory response is more intensive than in EORA alone, and the effect of glucocorticoid treatment is more efficient than in EORA alone. The results of a recent research in this field (Cutolo et al. [29]) have confirmed in PMR a lower production of adrenal cortex hormones, such as cortisol and DHEAS in basal secretion [31]. It seems that the disorder relates to the impaired response of adrenal glands to Adrenocorticotropic hormone (ACTH) stimulation, e.g. elevated PRG levels in untreated patients and subsequently after 1-month glucocorticoid treatment with a decrease of levels of inflammatory mediators, such as IL-6. For this reason PMR may be classified as a disease with a concurrent hypofunction of the hypothalamic-pituitary-adrenal axis [32, 33]. Cutolo et al. [29] point out an important fact that the decrease of the cortisol level after 1-month glucocorticoid treatment was more significant in PMR and EORA/PMR than in EORA patients. This indicates that changes in the function of the adrenal axis in EORA patients might not be as marked as in PMR.
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