• 49.9 million (22.2%) of adults aged 18 years or older have self-reported physician-diagnosed arthritis.

• 21.1 million (9.4% of all adults) have AAAL.

Etiology

Rheumatic diseases are among the oldest diseases recognized, but the cause of rheumatoid arthritis (RA) remains unknown. Genetic factors are important, as are hormonal and psychosomatic factors. Evidence indicates that immunologic factors are involved in the articular and extra-articular manifestations of the disease. RA may represent an unusual host response to one or perhaps many causative agents. An infectious cause is possible, although this has not been established.

Epidemiology

Rheumatoid arthritis occurs worldwide, but no definite geographic or climatic variation in incidence has been established. RA affects all races, but the incidence varies across racial and ethnic groups.

Although no specific genetic relationship has been established, a small increase in incidence has been noted in first-degree relatives of patients with RA. Persons with the human leukocyte antigen (HLA)–DR4 haplotype have a significantly higher incidence of RA.

Patients with RA have a shortened lifespan. The most frequent cause of death is cardiovascular disease. The increased prevalence of atherosclerosis in RA patients is suspected to be related to atherogenic side effects of some antirheumatic medications, the effects of chronic systemic inflammation on the vascular endothelium, or shared mechanisms of action between RA and atherosclerosis.

Complications resulting from an increased frequency of local or extra-articular infections in RA patients have been demonstrated. Mortality may result from conditions such as septicemia, pneumonia, lung abscess, or pyelonephritis. In the past 15 years, the pharmacotherapy of RA has been improved by the development of more effective medications.

Signs and Symptoms

The term rheumatic disease does not have a clear boundary; more than 100 different conditions are labeled as rheumatic diseases, including RA, osteoarthritis, autoimmune disorders such as systemic lupus erythematosus (SLE) and scleroderma, osteoporosis, back pain, gout, fibromyalgia, and tendinitis.

Rheumatoid arthritis is a chronic, multisystemic, autoimmune disorder and a progressive inflammatory disorder of the joints (Fig. 30-1). It is, however, a highly variable disease that ranges from a mild illness of brief duration to a progressive destructive polyarthritis associated with a systemic vasculitis (Fig 30-2).The pathogenesis of RA has the following three distinct stages:

Rheumatoid arthritis often begins with prodromal symptoms such as fatigue, anorexia, weakness, and generalized aching and stiffness not localized to articular structures. Joint symptoms usually appear gradually over weeks to months. The patient may display a wide variety of extra-articular manifestations (Box 30-1).

The revised American Rheumatism Association’s criteria for diagnosis of RA are presented in Table 30-1. If these conditions are present for at least 6 weeks, the patient is designated as having classic RA. Prognostic markers such as a persistently high number of swollen joints, high serum levels of acute-phase reactants of immunoglobulin M (IgM) rheumatoid factor, early radiographic and functional abnormalities, and the presence of certain HLA class II alleles may help identify patients with more severe RA who are still in the early stages of the disease.

1 2 3 5 B. Serology (at least one test result is needed for classification)¶   0 2 3 C. Acute-phase reactants (at least one test result is needed for classification)#   0 1 D. Duration of symptoms^∗∗   0 1

Anatomy and Physiology of Joints

Diarthrodial joints are lined at their margins by a synovial membrane (synovium), with synovial cells lining this space. The lining cells synthesize protein and are phagocytic. Synovial (joint) fluid is a transparent viscous fluid. Its function is to lubricate the joint space and transport nutrients to the articular cartilage. Mechanical, chemical, immunologic, or bacteriologic damage may alter the permeability of the membrane and capillaries and may produce varying degrees of an inflammatory response. In addition, inflammatory joint fluids contain lytic enzymes that produce depolymerization of hyaluronic acid, which greatly impairs the lubricating ability of the fluid.

A variety of disorders produce changes in the number and types of cells and chemical composition of the fluid. Analysis of synovial fluid plays a major role in the diagnosis of joint diseases. Arthrocentesis constitutes a liquid biopsy of the joint. It is a fundamental part of the clinical database, together with the medical history, physical examination, and plain radiographic films. Analysis of aspirated synovial fluid is essential in the evaluation of any patient with joint disease because it is a better reflection of the events in the articular cavity than abnormal blood test results. For example, abnormal test results—for example, antinuclear antibody (ANA), increased erythrocyte sedimentation rate (ESR), elevated uric acid level, increased C-reactive protein concentration, and rheumatoid factor (RF)—can be seen in normal individuals or in unrelated joint diseases.

Disorders such as gout, calcium pyrophosphate dihydrate deposition disease, and septic arthritis can be definitively diagnosed by synovial fluid analysis and may allow for consideration or exclusion of RA and SLE. Synovial fluid analysis can also support a diagnosis of diseases as disparate as amyloidosis, hypothyroidism, ochronosis, hemochromatosis, or even simple edema. In addition, arthrocentesis may alleviate elevated intra-articular pressure. Removal of fluid will relieve symptoms and potentially decrease joint damage. Removal of the products of inflammation is an important component in the treatment of infectious arthritis and may be beneficial for other forms of arthritis.

Routine analysis of synovial fluid should include wet preparation examination for cell count and differential, crystals, Gram stain, and microbiologic culture. Very turbid fluids, or if septic arthritis is considered for other reasons, synovial fluid should be sent for Gram staining and culture. Gram staining is needed if a high likelihood of infection exists. Other observations and procedures can include volume and appearance, viscosity, mucin test, chemical analysis for protein, and glucose.

When examined by the immunofluorescent technique, the rheumatoid synovium can be seen to contain large amounts of immunoglobulin G (IgG) and IgM, alone or together. Immunoglobulins can also be seen in synovial lining cells, blood vessels, and interstitial connective tissues. B cells make immunoglobulin in the synovium of patients with RA. As many as 50% of the plasma cells that can be located in the synovium secrete an IgG RF that combines with similar IgG molecules (self-associating IgG) in the cytoplasm.

Immunologic Manifestations

The current model of the pathogenesis of RA proposes that an infective agent or other stimulus binds to receptors on dendritic cells (DCs), which activates the innate immune system (Fig. 30-3). DCs migrate into lymph nodes and present antigen to T lymphocytes, which are activated by two signals—the presentation of antigen and costimulation through CD28. Activated T lymphocytes proliferate and migrate into the joint. Subsequently, T lymphocytes produce interferon-γ (IFN-γ) and other proinflammatory cytokines. This in turn stimulates macrophages and other cells, including B lymphocytes. B cells appear to be pivotal in the pathogenesis of RA because they can be 10,000 times as potent as DCs in presenting antigen.

Stimulated macrophages and fibroblasts release cytokines, including tumor necrosis factor-α (TNF-α), a central component in the cascade of cytokines. This results in the production of additional inflammatory mediators and further recruitment of immune and inflammatory cells into a joint. Anti–TNF-α treatment strategies (e.g., monoclonal) prevent interaction with receptors on cell surfaces.

The leukotrienes play a major role in the inflammatory response to injury. This class of biologically active molecules has been implicated in the pathogenesis of RA and in other inflammatory diseases (e.g., asthma, psoriasis, inflammatory bowel disease). Leukotrienes are major constituents of a group of oxygenated fatty acids that are synthesized de novo from membrane phospholipid through a cascade of enzymes. Research studies have focused on these molecules because leukotriene inhibitors and antagonists will probably become important agents in the group of antiinflammatory drugs (see later, “Treatment”).

Diagnostic Evaluation

Low serum iron levels and a normal or low iron-binding capacity are common features in RA. The ESR is elevated to a variable degree in most RA patients and roughly parallels the level of disease activity. Serum protein electrophoresis may demonstrate elevations in the alpha-2 and gamma globulin fractions, with a mild to moderate decrease in serum albumin. The gamma globulin increase is polyclonal.

Immunologic features of RA include RF, anti–cyclic citrullinated peptide (anti-CCP), immune complexes, characteristic complement levels, and ANAs. For example, patients with Felty’s syndrome, the association of RA with splenomegaly and leukopenia, almost always develop a high-titer rheumatoid factor assay, a positive ANA assay, and rheumatoid nodules. In addition, these patients have a high titer of immune complex and low total serum complement levels.

Rheumatoid Factor

RFs are immunoglobulins of any isotype with antibody activity directed against antigenic sites on the Fc region of human or animal IgG. RFs have been associated with three major immunoglobulin classes, IgM, IgG, and IgA. IgM and IgG RFs are the most common.

Immunoglobulin M rheumatoid factor is manifested in approximately 70% of adults but is not specific for RA. Being RF-positive correlates with the following:

• Severity of the disease (in general)

• Nodules

• Other organ system involvement (e.g., vasculitis, Felty’s syndrome, Sjögren’s syndrome)

Agglutination tests for RF, such as the sensitized sheep cell test and latex agglutination, generally detect IgM RFs. Latex agglutination is sensitive but can produce a fairly high number of false-positive results. Because conventional procedures are semiquantitative, they may be insensitive to changes in titer and may detect only those RFs that agglutinate. Immunoturbidimetric assays and enzyme-linked immunosorbent assays (ELISAs) are automated methods of analysis. The presence of abnormal levels of all three RF isotypes—IgM, IgG, and IgA—has a specificity of 99% for RA.

Rheumatoid factor has been associated with some bacterial and viral infections, including hepatitis and infectious mononucleosis, and some chronic infections, such as tuberculosis, parasitic disease, subacute bacterial endocarditis, and cancer. Elevated values may also be observed in the normal older population. The concentration of RF tends to be highest when the disease peaks and tends to decrease during prolonged remission.

Cyclic Citrullinated Peptide Antibodies

CCP antibodies are a highly specific indicator for RA. Antibodies to CCPs (anti-CCP1) were first described in 1998 and, following the introduction of commercial ELISA products using the so-called second-generation peptides (CCP2), there has been increased interest in using this marker in the diagnosis of RA. Anti—CCP IgG antibodies are present in about 69% to 83% of patients with RA and have specificities ranging from 93% to 95%. These autoantibodies may be present in the preclinical phase of disease, are associated with future RA development, and may predict radiographic joint destruction. Antibodies can be detected in sera from individuals up to 14 years before the first clinical symptoms of RA appear.

Compared with other assays for RF, CCP is considered to be more sensitive. This antibody is reported to have high specificity (>95%) and sensitivity (80%) for RA. Early diagnosis and effective treatment provide a window of opportunity for controlling this autoimmune disease. Anti-CCP and rheumatoid factor assays constitute a rheumatoid arthritis panel.

Autoantibodies against mutated and citrullinated vimentin (MCV), a member of the citrullinated protein family, are highly specific markers for RA. A lateral flow immunoassay (LFIA) for the qualitative detection of anti-MCV antibodies, anti-MCV ELISA (ORGENTEC Diagnostics, Mainz, Germany) has been developed as a point of care test.

Other Markers

Antibodies to anti–perinuclear factor (APF) and keratin (anti–keratin antibody [AKA]) are highly specific for RA. Antibodies to APF are reported to be present in the sera of 49% to 91% of RA patients, with specificity greater than 70%.

Immune Complexes

Soluble circulating immune complexes and cryoprecipitable proteins consisting of immunoglobulins, complement components, and RFs are demonstrable in the sera of some patients with RA. Anti–gamma globulin isotypes, IgM, IgG, and IgA classes, are important complexes.

The IgA, IgM, and IgG isotypes of RF are detected years before any symptoms of RA become apparent. The various vascular and parenchymal lesions of RA suggest that the lesions result from injury induced by immune complexes, especially those containing antibodies to IgG. Vasculitis is associated with complexes made up of IgG and 7S IgM RFs. A positive laboratory assay for mixed cryoglobulins indicates the presence of a large number of immune complexes and is associated with an increased incidence of extra-articular manifestations, particularly vasculitis.

Complement Levels

Serum complement levels are usually normal in patients with RA, except in those with vasculitis. Hemolytic complement levels are reduced in the serum of less than one third of patients, especially in patients with very high levels of RF and immune complexes. Levels of C4 and C2 are most profoundly depressed in these patients.

Antinuclear Antibodies

Antinuclear antibodies have been found in 14% to 28% of RA patients, who usually have advanced disease. However, disease manifestation is the same in ANA-positive and ANA-negative patients.

Juvenile Idiopathic Arthritis

Etiology

The term juvenile rheumatoid arthritis (JRA) has fallen out of favor worldwide for a number of reasons. JRA is not, as the language implies, simply a pediatric replica of the condition that affects adults. Only about 10% of children have an arthritic disease that closely mirrors rheumatoid arthritis in adults. Researchers have concluded that the JRA category is drawn too narrowly and should include some related diagnoses, such as ankylosing spondylitis. Juvenile idiopathic arthritis (JIA) and juvenile rheumatoid arthritis (JRA) can’t be used interchangeably because there are differences between the diagnoses they include (Table 30-2).

Juvenile idiopathic arthritis (JIA) is a condition of chronic synovitis beginning during childhood. It is believed that there are a number of causes, including factors such as infection, autoimmunity, and trauma. Research at Tulane University Medical Center have suggested that JIA may be associated with a retroviral particle called human intracisternal A-type particle (HIAP). Antibodies to this particle have been found in a very high percentage of patients with JIA. These antibodies have also been found in many patients with three other autoimmune disorders—SLE, Sjögren’s syndrome, and Graves’ disease. Researchers believe that these four disorders may result from the presence of HIAP, together with genetic factors and some internal or external stimulus, which all combine to dictate the specific symptomatology.

Epidemiology

The incidence of JIA in the U.S. pediatric population is from 0.1 to 1.1/1000.

Signs and Symptoms

Diagnostic criteria include onset before age 16 years, presence of arthritis (i.e., joint swelling for 6 consecutive weeks or longer), and exclusion of other conditions known to cause or mimic childhood arthritis. Several distinct subgroups of JIA have been recognized.

Immunologic Manifestations

Immunologic features of JIA can include the presence of RF, immune complexes, and ANAs.

Rheumatoid Factors

Approximately 20% of children are positive for RF. Most patients who are positive for RF probably represent adult RA occurring in childhood. So-called hidden RF can be detected in 65% of children with negative latex fixation test results. Children in this category do not develop the clinical manifestations of adults with RA.

Immune Complexes

Soluble immune complexes may be detected in patients with active synovitis. Analysis of these complexes is not useful for the diagnosis, prognosis, or monitoring of patients.

Antinuclear Antibodies

ANAs are detectable in few patients with JIA, except that most girls with pauciarthritis and chronic iritis demonstrate a positive ANA test result.

Treatment

The major goals of treatment of arthritis are as follows: (1) reduce pain and discomfort; (2) prevent deformities and loss of joint function; and (3) help the patient maintain a productive and active life. Inflammation must be suppressed and mechanical and structural abnormalities corrected or compensated for with assistive devices. Treatment options include reduction of joint stress, physical and occupational therapy, drug therapy, and surgical intervention.

There are several general classes of drugs (Table 30-3) traditionally used in the treatment of RA. A newer class of agents for treatment of RA, recombinant fusion proteins, selectively modulates the CD80 or CD86-CD28 costimulatory signal required for full T cell activation. Other drugs may also be used for treatment.

Nonsteroidal Antiinflammatory Drugs

Traditional treatment of RA consists of nonsteroidal antiinflammatory drugs (NSAIDs; e.g., salicylates, ibuprofen). The major effect of these agents is to reduce acute inflammation. Aspirin is the oldest drug of the nonsteroidal class, but the use of aspirin as the initial choice of drug therapy has largely been replaced by the newer NSAIDs.

Prostaglandins are a group of related compounds that are important mediators of a wide variety of physiologic processes, including immunomodulation. Prostaglandins are derived primarily from arachidonic acid via the cyclooxygenase enzymes (COX) pathway. NSAIDs inhibit prostaglandin synthesis by blocking two isoforms of COX, COX-1, and COX-2. Newer NSAID agents (e.g., Vioxx, Celebrex) selectively block the COX-2 enzyme that is primarily upregulated in response to tissue damage during inflammation but preserves COX-1 activity and enhances the safety profile.

Corticosteroids and Glucocorticoids

Corticosteroids (e.g., cortisone and prednisolone [prednisone]) have antiinflammatory and immunoregulatory activity. Glucocorticosteroids pass through the cell membrane into the cytoplasm and activate the cytoplasmic glucocorticosteroid receptor, which represses gene expression through the transcriptional interference of activator protein 1 (AP-1) and nuclear factor kappa B (NF-κB). The proteins inhibited by glucocorticosteroids include interleukin-1 (IL-1), IL-2, IL-6, IL-8, TNF-α, and IFN-γ. Glucocorticosteroids were the original selective COX-2 inhibitors. Oral corticosteroids can produce a variety of complications, including high blood pressure, increased susceptibility to infection, and osteoporosis.

Disease-Modifying Antirheumatic Drugs

The disease-modifying antirheumatic drugs (DMARDs) include methotrexate, intramuscular gold salts, hydroxychloroquine, sulfasalazine, d-penicillamine, and immunosuppressive and other cytotoxic drugs (e.g., cyclosporin A, cyclophosphamide, azathioprine). Newer drugs for the treatment of RA include leflunomide, etanercept, adalimumab, infliximab (Remicade), and anakinra Antimalarials may be used as well.

Methotrexate has become the most popular DMARD because of its early onset of action (4 to 6 weeks), good efficacy, ease of administration, and high patient tolerability. Methotrexate is a folic acid antagonist. The immunosuppressive and cytotoxic effects of methotrexate are caused by the inhibition of dihydrofolate reductase.

Immunosuppressive and cytotoxic drugs other than methotrexate are used only for patients who have aggressive disease or extra-articular manifestations such as systemic vasculitis. The most common drugs are azathioprine (Imuran), cyclophosphamide (Cytoxan), and cyclosporin A. Because of the potential for high toxicity, these agents are used for life-threatening extra-articular manifestations or severe articular disease refractory to other therapy.

• Azathioprine is a purine analogue that can cause severe bone marrow suppression, particularly in patients with renal insufficiency or when used concomitantly with allopurinol or angiotensin-converting enzyme (ACE) inhibitors.

• Cyclophosphamide is an alkylating agent associated with serious toxicities, including bone marrow suppression, hemorrhagic cystitis, premature ovarian failure, infection, and secondary malignancy, particularly an increased risk of bladder cancer. Thus, cyclophosphamide is not used in the treatment of uncomplicated RA.

• Cyclosporine (cyclosporin A) is an immunosuppressive agent approved for use for preventing renal and liver allograft rejection. Cyclosporine inhibits T cell function by inhibiting the transcription of IL-2.

Other Drugs

Antimalarial drugs are rapidly absorbed, relatively safe, well tolerated, and often effective remittive agents in the treatment of RA, particularly mild to moderate disease. The mechanism of action of antimalarial drugs in the treatment of patients with RA is unknown.

Recombinant fusion proteins represent a new class of drugs that selectively modulate specific cell surface receptors, CD80 or CD86, on the surface of an antigen-presenting cell that binds to CD28 on the T cell. A recombinant fusion protein, abatacept, has been modified to prevent complement fixation. It competes with CD28 for CD80 and CD86 binding and can be used to modulate T cell activity selectively. This selective costimulation modulator has been proposed to be useful for patients who have an inadequate response to anti–TNF-α therapy.

Diagnostic Procedures

Diagnostic testing for RA primarily involves RF assays (see rapid agglutination procedure).

Rapid Agglutination

Principle

The principle of serologic testing for rheumatoid arthritis is based on the detection of macroglobulins collectively called RF. RF behaves like antibodies against human gamma globulin (IgG).

In rapid testing, sheep RBCs or latex reagent consists of a stabilized RBC or latex suspension coated with albumin and chemically bonded with denatured human gamma globulin. This reagent serves as an antigen in the procedure. If RFs are present in the serum, macroscopic agglutination will be visible when the reagent is mixed with the serum.

The determination of RFs is important in the prognosis and therapeutic management of rheumatoid arthritis; however, biologically false-positive test results may be observed in a variety of disorders, such as SLE, Sjögren’s syndrome, syphilis, and hepatitis.

Procedure Notes

The strength of a positive reaction may be graded as follows:

• 1+: Very small clumping with opaque fluid background

• 2+: Small clumping with slightly opaque fluid background

• 3+: Moderate clumping with fairly clear fluid background

• 4+: Large clumping with clear fluid background

Results

Qualitative Test Results^∗

• Negative: No agglutination or color change is seen in the reagent. The reagent should have a smooth appearance against a yellow/greenish background.

• Positive: The agglutinated reagent will become visibly blue against a yellow background.

• If a positive result is obtained with the undiluted specimen, the specimen should be diluted 1:10 to determine the relationship between the level of RF present and a particular disease state.

• If the 1:10 diluted specimen demonstrates readily visible agglutination, RF is present in the specimen at a level generally associated with RA. If the undiluted specimen demonstrates agglutination and the 1:10 diluted specimen demonstrates the absence of agglutination or a fine granular background, RF is present in the specimen at a low level, which may exist in disease states other than RA.

Semiquantitative Test Results

When positive samples are examined by serial dilution, the titer is the reciprocal of the last dilution that produced a positive result (agglutination).

Sources of Error

False-positive results may be observed if the following occurs:

• Serum specimens are lipemic, hemolyzed, or heavily contaminated with bacteria.

• The reaction time is longer than 3 minutes. A false-positive result may also be produced as a result of a drying effect.

Biological false-positive results can be manifested by disorders such as SLE, Sjögren’s syndrome, syphilis, and hepatitis. A low rate of positive reactions has been observed in abnormalities such as periarteritis nodosa, rheumatic fever, osteoarthritis, tuberculosis, cancer, some diseases of viral origin, osteoarthrosis, arthritis type undetermined, myositis, and polymyalgia rheumatica. Circulating RF appears to represent a phenomenon of aging, independent of disease.

Clinical Applications

RF is present in the serum of approximately 70% to 80% of patients with clinically diagnosed RA. Almost all patients with variants of RA (e.g., Felty’s or Sjögren’s syndrome) demonstrate positive results. The highest titers are often found in severe cases of RA. Although the latex agglutination procedure has a 95% correlation with a clinical diagnosis of probable or definite RA, RF is not exclusively limited to patients with RA.

In using latex tests for the detection of RF, a positive result can be expected in less than 5% of healthy individuals. In patients 60 years and older, as many as 30% may be seropositive.

Limitations

As with other diagnostic procedures, the results obtained by an assay yield valuable data that must be evaluated as a component of the total clinical information obtained by the physician. Approximately 25% of patients with definite RA may exhibit negative results for serum RF. Specimens from patients with JIA are usually negative for circulating RF. The strength of the agglutination reaction in the qualitative procedure is not indicative of the actual titer. Weak reactions may occur with slightly elevated or greatly elevated concentrations.

Chapter Highlights