Immune and Inflammatory Disease in Older Adults
David R. Thomas
CLINICAL PEARLS
Musculoskeletal system disorders are among the most frequent complaints of older persons and account for a large portion of the care of older persons by primary care physicians.
Aging is characterized by progressively increased concentrations of glucocorticoids and catecholamines and the decreased production of growth and sex hormones, a pattern reminiscent of that seen in chronic stress.
The manifestations of immune disease are clearly related to the proinflammatory nature of cytokines, although the trigger for the initiation of the cytokine cascade is usually not known.
The classification of immune and inflammatory diseases is undergoing a considerable change. Traditional schemes have focused primarily on musculoskeletal conditions. Rheumatoid arthritis has served as a “prototype” disease in inflammatory arthritis research. However, most of the inflammatory mechanisms occurring in the rheumatoid synovium may also occur in tissues affected by other disorders, such as progressive systemic sclerosis, systemic lupus erythematosus, or the salivary glands of Sjögren syndrome patients. Improved understanding of the inflammatory cascade and immune complex diseases has increased the number of conditions attributed to inflammatory and immune complex disease.
Autoimmune diseases present as clinical syndromes caused by the activation of T cells or B cells, or both, in the absence of an ongoing infection or other discernible cause. While the trigger that initiates the cytokine cascade is not always known, the manifestations of disease are clearly related to the proinflammatory effect of cytokines. Tissue damage from trauma or infection, or some as yet unknown trigger of the immune system, activates the inflammatory cells and the subsequent release of the cell-associated proteins called cytokines.
TABLE 34.1 EXAMPLES OF PRO-AND ANTI-INFLAMMATORY CYTOKINES | |||||||||||||||
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Cytokines act principally in a paracrine fashion. In other words, their activity is local, at the site of release. Their concentrations in tissues are therefore several times higher than those found in the peripheral circulation. These cytokines act through specific cell receptors locally and systemically. Cytokines both initiate and regulate acute-phase reactants. Locally, these are expressed as inflammation, and systemically hepatic acute phase proteins are produced with resulting fever and granulocytosis.1
This cascade is designed to isolate and destroy microbial pathogens and to activate tissue repair processes to facilitate a return to the physiologic homeostasis. The cascade is regulated by a complex interactive balance of soluble serum factors (s), receptors for cytokine (r), and receptor antagonists (Ra).
Interleukin (IL)-1s and tumor necrosis factor (TNF-α) are the cytokines responsible for the earliest acute phase reaction. Both cytokines induce a second wave of cytokines, including IL-6 and chemokines. IL-6 is an antiinflammatory and immunoregulatory cytokine required for moderating the local and systemic inflammatory responses. Chemokines regulate the influx of leukocytes to the site of inflammation. The bioactivity of TNF-α and IL-1β is inhibited by naturally occurring antagonists such as IL-1 receptor antagonist (Ra) and soluble TNF receptors (sTNFR), as well as the anti-inflammatory cytokine IL-10. Examples of pro- and anti-inflammatory cytokines are given in Table 34.1.
TABLE 34.2 COMMON INFLAMMATORY CONDITIONS OF AGING (ICD-9 CODE) | |||||||||||||||||||||||||||
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A large number of conditions associated with the activated cytokine cascade produce musculoskeletal symptoms and illness.2 Rheumatoid disorders are classical diseases of the cytokine cascade. Other cytokine cascade disorders, such as osteoporosis and Paget disease, primarily affect the musculoskeletal system. Others, such as metastatic carcinoma and multiple myeloma, cause secondary effects in the musculoskeletal system. Still others reflect immune disorders of the endocrine system, such as type 1 diabetes mellitus or thyroid disorders. Therefore, an increasing number of conditions are being recognized as primary immune complex disease.
Many autoimmune mechanisms can be confused with primary musculoskeletal disorders. For example, hyperthyroidism can be associated with manifestations resembling rheumatoid arthritis, in addition to producing radiologic findings due to the loss of skeletal calcium. Similarly, hypothyroidism in a person with long-standing rheumatoid arthritis may produce symptoms which may be attributed to the rheumatoid process. These crossover symptoms create diagnostic challenges.
Disorders in the musculoskeletal system are among the most frequent complaints of older persons, and account for a large portion of their care by primary care physicians (see Table 34.2). These disorders fall into three categories: (i) The classic rheumatoid diseases, (ii) conditions not generally regarded as rheumatoid in nature whose clinical manifestations are expressed in the musculoskeletal system, and (iii) a wide range of localized musculoskeletal disorders that fall under the general category of “soft tissue rheumatism.”
AGING OF THE IMMUNE SYSTEM
Aging is characterized by progressively increased concentrations of glucocorticoids and catecholamines and decreased production of growth and sex hormones, a pattern suggestive of that seen in chronic stress. Aging has also been associated with increased levels of circulating inflammatory components including elevated concentrations of TNF-α, IL-6, IL-1Ra, and sTNFR, acute phase proteins such as C-reactive protein (CRP) and serum amyloid A, and high neutrophil counts. Plasma levels of TNF-α have been positively correlated with IL-6, sTNFR-II, and CRP in centenarians, suggesting an activation of the entire inflammatory cascade. However, the increase in circulating inflammatory factors in healthy elderly humans is limited, and far less than levels seen during acute infections at any age.3,4
There remains uncertainty as to whether changes in cytokine levels are due to age itself or to underlying disease.5 The increase in plasma levels of IL-6 with age may occur because of catecholamine hypersecretion and sex-steroid hyposecretion6—or acquired physiologic insults (visceral obesity, smoking, stress, etc.),7 subclinical infections such as Chlamydia pneumoniae or Helicobacter pylori, or, finally, dental infections and asymptomatic bacteriuria.8
Proinflammatory cytokines are thought to play a pathogenetic role in age-associated diseases such as Alzheimer disease, Parkinson disease, atherosclerosis, type 2 diabetes, sarcopenia, and osteoporosis.9 Low-grade inflammatory activity in older populations is related to dysregulated cytokine production, which is further exacerbated by ageassociated pathology. Cause-effect or effect-cause awaits further study for many conditions attributed to aging that may have a basis in immune function.
TABLE 34.3 REVISED DIAGNOSTIC CRITERIA FOR RHEUMATOID ARTHRITIS CLASSIFICATION | ||||||||||||||||||||||
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RHEUMATOID ARTHRITIS
Rheumatoid arthritis occurs worldwide and is estimated to occur in 1% to 2% of the population, with a female to male ratio of 3:1. High levels of TNF-α and IL-1β have been demonstrated in synovial fluid and in the circulation of patients with rheumatoid arthritis.10,11 The role of these proinflammatory cytokines has been bolstered by recent interventions involving TNF-α and IL-1 inhibitors.12 An antigen, yet unknown, appears to initiate the autoimmune response. Suspect triggers such as the Epstein-Barr virus, the influenza virus, or the hepatitis C virus, are associated with joint symptoms that are exactly like rheumatoid arthritis; however, unlike true rheumatoid arthritis symptoms, these last only a few weeks.
Rheumatoid arthritis is diagnosed by the presence of five of seven diagnostic criteria, as shown in Table 34.3. The rheumatoid factor is present in 80% of patients. However, 5% of the elderly may have a false-positive rheumatoid factor. Citrullinated peptides are present in 90% of patients with rheumatoid arthritis, but due to their cyclic pattern may not be detected in half the patients tested. Radiologic changes on magnetic resonance imaging (MRI) are useful in diagnosing classic joint erosions.
The treatment of rheumatoid arthritis has been markedly improved by the recognition that bone erosions occur early in the disease; therefore therapy should be instituted promptly. Because rheumatoid arthritis is both most
aggressive and most responsive to treatment in the first 2 years, it is now recommended that drug therapy begins within months of diagnosis.
aggressive and most responsive to treatment in the first 2 years, it is now recommended that drug therapy begins within months of diagnosis.
Treatment options for rheumatoid arthritis can be divided into disease-modifying treatments and non-disease-modifying treatments. Non-disease-modifying treatments such as anti-inflammatory agents can be used to control symptoms and pain, but do not affect the progression of the disease.
Disease-modifying drugs modify the progression of the disease. A meta-analysis of clinical trials has suggested that the efficacy of methotrexate, sulfasalazine, intramuscular gold, and penicillamine is similar. Antimalarial drugs (e.g., chloroquine and hydroxychloroquine) are less effective. Penicillamine, because of concern about its toxicity, and oral gold, because of its marginal efficacy, are rarely used today.
Corticosteroids are potent suppressors of the inflammatory response in rheumatoid arthritis but have significant dose-dependent side effects. Controversy exists for when, if, and how corticosteroids should be used to treat rheumatoid arthritis. Corticosteroids clearly decrease the radiographic evidence of disease progression of rheumatoid arthritis. As a result, 30% to 60% of patients receive corticosteroids in low doses (e.g., ≤10 mg of prednisone per day) (Evidence Level B).
Methotrexate is considered the first-line disease-modifying agent and is generally used to compare other therapies. Side effects often limit the use of methotrexate but concomitant administration of folic acid (1 to 3 mg per day) significantly decreases many toxic effects without a measurable decrease in efficacy.
Newer treatment options are based on the observation that synovial inflammation in rheumatoid arthritis is produced by macrophage-derived cytokines. Several products that inhibit the actions of TNF-α (infliximab, etanercept, and adalimumab) and one that inhibits the action of IL-1 (anakinra) are available to treat rheumatoid arthritis. Blockade of TNF-α by etanercept or a monoclonal antibody (infliximab) is highly effective in preventing erosions when used in combination with methotrexate. Leflunomide, a pyrimidine antagonist that blocks deoxyribonucleic acid synthesis by the enzyme dihydroorotate dehydrogenase, has an efficacy similar to that of methotrexate and can be used either alone or in combination with methotrexate.
Blockade of IL-1r with a recombinant IL-1Ra antagonist is less effective than blockade of TNF-α in patients with rheumatoid arthritis, but it may retard the development of bone erosions.13 The long-term safety of these new agents, particularly with respect to the risk of infections, cancer, and other autoimmune diseases, is still of some concern.14
Improvement in rheumatoid symptoms can be documented by the American College of Rheumatology (ACR) scale.15 An ACR 20 is defined as a reduction by 20% or more in the number of tender and swollen joints, plus similar improvement in at least three of the following five measures: Pain, global assessments by the patient and the physician, self-assessed physical disability, and levels of acute phase reactant. Improvements of ACR 50 to 70 should be the aim of treatment. Failure to achieve this much improvement should trigger a referral or a change in therapy.
Blockade of TNF-α by anticytokine drugs is also effective in Crohn disease, refractory psoriatic arthritis, and ankylosing spondylitis.
Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE or lupus) is a multisystem, chronic autoimmune disorder involving a number of self-antigens. The annual incidence of lupus is about 5 per 100,000 persons. The incidence peaks for women in late middle age, and somewhat later for men. Lupus occurs within families, but there is no identified gene or genes that have been linked to the disorder. Environmental factors have also been implicated in the development of lupus, including infections, antibiotics in the sulfonamide and penicillin groups, exposure to excessive stress, and ultraviolet light.
Lupus can occur at any age and in either sex, but it occurs more frequently in women than men, with a ratio of 9:1. In persons older than 60, the sex ratio declines to 4:1. Estrogen may play a role in lupus. The symptoms often increase before menstruation and during pregnancy, but the link remains speculative.
Lupus occurs when antibodies are produced against the components within the nucleus of cells. These autoantibodies then react with body tissues as if the tissue were an antigen, and immune complexes are formed. These immune complexes accumulate in the joints, kidneys, skin, blood, and other tissues, activating the complement cascade, inflammation, pain, and organ damage.
Although the tissue inflammation is widespread, most patients present with isolated manifestations, leading to confusion with other diseases such as immune thrombocytic purpura, primary Raynaud, or rheumatoid arthritis. Polyarthritis and skin manifestations are the presenting features in about 75% of patients. Glomerulonephritis, lymphadenopathy, anemia, leucopenia, pleurisy, mouth ulcers, and central nervous system symptoms are other clinical features. Most patients have constitutional symptoms. The diagnosis of lupus can be made by finding four or more symptoms over time of a list of 11 clinical criteria developed by the American Rheumatism Association, shown in Table 34.4.
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