Rheumatoid Arthritis Clinical and Lab. Manifestations

Rheumatoid Arthritis Clinical and LaboratoryManifestations

In most cases, rheumatoid arthritis is a chronic progressive disease that, if left untreated, can cause joint damage and disability.
Physical findings are most notable for joint-centered swelling, deformities, and painful or reduced join motion.
Extra-articular disease occurs in seropositive patients and includes rheumatoid nodules, Sjögren’s syndrome, interstitial lung disease, and vasculitis.

Laboratory tests that support a diagnosis of rheumatoid arthritis include elevated erythrocyte sedimentation rate and C-reactive protein, positive rheumatoid factor, positive anti-cyclic citrullinated peptide (CCP) antibody. Further evidence of chronic inflammation includes anemia and hypoalbuminemia.
Radiographs may reveal periarticular osteoporosis, joint space narrowing, erosions, and deformities. Magnetic resonance imaging and ultrasound may be more sensitive in early disease.

The onset of disease can occur at any age but peak incidence occurs within the fourth and fifth decades of life. The average annual incidence of RA in the United States is 0.5 per 1000 persons per year .
The overall prevalence of RA is 1% to 2%, and it steadily increases to 5% in women by the age of 70 (It is important to remember that RA is a systemic disease and individuals may therefore present with symptoms such as fever, weight loss, and fatigue; however, joint symptoms are usually the most prominent.

Most commonly, the onset of symptoms of joint pain and swelling is insidious, occurring over weeks to months. However, a minority of patients may present with an abrupt explosive onset polyarthritis.
Still others may present with transient self-limited episodes of mono- or polyarthritis lasting days to weeks. This presentation is known as palindromic rheumatism. Approximately 50% of patients with palindromic rheumatism will go on to develop (i.e., fulfill criteria for) RA, and only 15% remain symptom-free after 5 years.

Occasionally RA may present as a monoarthritis; however, infectious and crystalline etiologies should always be ruled out first when inflammation affects a single joint. Rheumatoid arthritis is the most common form of inflammatory arthritis that affects diarthrodial joints.
In early disease,the wrists ,metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints of the fingers, interphalangeal joints of the thumbs, and metatarsalphalangeal (MTP) joints are most commonly affected. As the disease progresses, larger joints such as the ankles, knees, elbows, and shoulders frequently become affected.


In contrast, involvement of the temporo-mandibular and sterno-clavicular joints and cervical spine are relatively uncommon, and the distal interphalangeal (DIP) joints and thoracolumbar spine are nearly always spared.
Joint involvement is classically symmetrical in nature, and morning stiffness lasting more than an hour is a hallmark symptom of RA. Frequently patients with newly diagnosed RA arise from bed 1 to 2 hours earlier than usual to allow time in order to loosen up.

Neck pain and stiffness tend to occur later in disease and may signal tenosynovitis of the transverse ligament of C1, which stabilizes the odontoid process of C2.
The symmetry, bilaterality, and predilection for small joints (especially early in disease) are incorporated into the Revised 1987 American Rheumatism Association (now the American College of Rheumatology) Criteria for the classification of RA

A number of prognostic variables that predict a poor outcome have been identified and include female sex, strong family history, human leukocyte antigen-DR4 cluster susceptible genes (the so-called shared epitopes; ), a high number of swollen/tender joints, a high score on a patient-rated instrument for measuring disability (the Health Assessment Questionnaire or HAQ), high titer of rheumatoid factor (RF), high titer of anticyclic citrullinated peptide (anti-CCP) antibodies, low socioeconomic status, low educational status, psychosocial problems, and the presence of erosions on joint radiographs.

THE 1987 REVISED CRITERIA FOR THE CLASSIFICATION OF RHEUMATOID ARTHRITIS

1. Morning stiffness: Morning stiffness in and around the joints, lasting at least 1 hour before maximal improvement.
2. Arthritis of three or more :At least three joint areas simultaneously have had soft tissue swelling or fluid (not bony overgrowth joint areas alone) observed by a physician. The 14 possible areas are right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints.
3. Arthritis of hand joints :At least one area swollen (as defined above) in a wrist, MCP, or PIP joint.
4. Symmetric arthritis: Simultaneous involvement of the same joint areas (as defined in item 2) on both sides of the body (bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry).

5. Rheumatoid nodules :Subcutaneous nodules, over bony prominences, or extensor surfaces, or in juxta-articular regions, observed by a physician.
6. Serum rheumatoid factor :Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in <5% of normal control subjects.
7. Radiographic changes :Radiographic changes typical of rheumatoid arthritis on postero-anterior hand and wrist radiographs, which must include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints (osteoarthritis changes alone do not qualify).
Duration for more than 6 weeks.

2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria

Joint involvement, designating the metacarpophalangeal joints, proximal interphalangeal joints, the interphalangeal joint of the thumb, second through fifth metatarsophalangeal joint and wrist as small joints, and shoulders, elbows, hip joints, knees, and ankles as large joints: 6 point out of 10 concidered RA
Involvement of 1 large joint gives 0 points
Involvement of 2-10 large joints gives 1 point


Involvement of 1-3 small joints (with or without involvement of large joints) gives 2 points
Involvement of 4-10 small joints (with or without involvement of large joints) gives 3 points
Involvement of more than 10 joints (with involvement of at least 1 small joint) gives 5 points

serological parameters – including the rheumatoid factor as well as ACPA – "ACPA" stands for "anti-citrullinated protein antibody": Negative RF and negative ACPA gives 0 points
Low-positive RF or low-positive ACPA gives 2 points
High-positive RF or high-positive ACPA gives 3 points
acute phase reactants: 1 point for elevated erythrocyte sedimentation rate, ESR, or elevated CRP value (c-reactive protein) duration of arthritis: 1 point for symptoms lasting six weeks or longer

Extra-Articular manifastations

Skin :Rheumatoid nodules (25%–50%)
Hematologic :Normocytic normochromic anemia (25%–30%), thrombocytosis, thrombocytopenia,lymphadenopathya ,Felty’s syndrome ,Splenomegaly with neutropenia, large granular lymphocytes .
Hepatic :Nonspecific transaminitis .
Pulmonary :Pleural thickening, pleural effusions,pulmonary nodules, diffuse interstitial lung disease, BOOP, Caplan’s syndrome, cricoarytenoid arthritis ,pulmonary arteritis, PAH, shrinking lung .
Cardiac :Pericarditis, accelerated atherosclerotic disease, valvulitis

Rheumatoid nodules

Ophthalmologic :Keratoconjunctivits sicca (10%–15%),episcleritis, scleritis, uveitis,ulcerative Keratitis
Neurologic :Peripheral entrapment neuropathy, cervical myelopathy due to cervical spine Sublaxation
Muscular :Muscle atrophy, inflammatory myositis.
Renal :Low grade membranous glomerular nephropathy, reactive amyloid.
Vascular: Small vessel vasculitis, systemic vasculitis.


LABORATORY FINDINGS
The most commonly used inflammatory biomarkers in clinical practice are the ESR and CRP. These markers are usually, but not always, elevated in RA patients with active disease and decline with treatment. Thus, the two inflammatory markers can be followed along with the patients’ symptoms and joint examination to monitor disease activity over time. High ESR and CRP at the onset of disease are predictive of more aggressive disease and potentially worse prognosis.

RFs are antibodies against the Fc portion of IgG and can be of any immunoglobulin subclass (IgA, IgG, and IgM) but are most commonly IgM. Rheumatoid factor is detectable during the course of disease in approximately 75% to 85% of patients with RA. Approximately 50% are positive in the first 6 months of illness and 85% become positive over the first 2 years. A low level of RF can also be associated with a number of other chronic inflammatory infectious and non infectious conditions as well (such as bacterial endocarditis, hepatitis C with cryoglobulinemia, aging, primary biliary cirrhosis), whereas a high level of RF is more likely indicative of RA.

In RA patients, high levels of RF are also predictive of more aggressive erosive articular disease and poorer long-term function, and are associated with more extra-articular disease such as rheumatoid nodules and lung involvement. The sensitivity and specificity of RF for the diagnosis of RA are roughly 66% and 82%, respectively. Anti-cyclic cirullinated peptide antibodies are also found in the sera of many patients with RA and are directed against the citrullinated residues of proteins.

Like RF, the higher the level of anti-CCP antibody, the higher the correlation with erosive joint disease, functional disability, and extra-articular disease. Interestingly, anti-CCP and RF have been demonstrated in sera up to 10 years before the onset of articular symptoms in some patients who later develop RA, and anti-CCP antibodies appear somewhat earlier than RF .
This important observation has potential implications for screening individuals who are at high risk for developing RA, as well as the potential for instituting preventive therapy in the preclinical stage of disease. A small portion of RA patients will remain seronegative throughout the course of their disease.

DIFFERENTIAL DIAGNOSIS

A comprehensive initial evaluation of the patient, including demographic characteristics, characterization of articular and extra-articular complaints, and careful physical examination, will guide the construction of the differential diagnosis and subsequent laboratory and radiological testing.
The most common causes of symmetrical inflammatory polyarthritis that may be confused with RA are the other systemic connective tissue disorders, psoriatic arthritis, and viral-induced arthritis (in particular, parvovirus B19– and hepatitis C–associated arthritis).

Other connective tissue disorders that can cause polyarthritis with a rheumatoid like distribution include systemic lupus erythematosus, systemic sclerosis, mixed connective tissue disease, and Sjögren’s syndrome.
In most cases, the presence of extra-articular features such as Raynaud’s phenomenon and rash, the absence of anti-CCP reactivity, and the presence of antinuclear (and other) antibodies will help to differentiate these diseases from RA.
It should be noted that RF can be present in most connective tissue diseases and occurs with particularly high frequency in Sjögren’s syndrome. Patients with connective tissue diseases who have erosive arthritis should be considered to have an overlap syndrome (e.g., “rupus” as an overlap of RA and systemic lupus).

In patients presenting with oligoarthritis, the spondyloarthropathies should be considered. These include ankylosing spondylitis, psoriatic arthritis ,reactive arthritis, and arthritis associated with inflammatory bowel disease.
Features common to these diseases include involvement of the sacroiliac joints, asymmetric peripheral joint involvement, uveitis, and Achilles tendonitis. Lyme-associated arthritis is also, in essence, a reactive arthritis, occurring weeks to months after the acute infection. Lyme arthritis tends to occur in the knee and/or ankle as a monoarthritis or oligoarthritis. Patients should be queried about tick bites and Lyme antibody testing should be obtained if suspected.


Another consideration is malignancy, which can occasionally present as polyarthralgias but true synovitis is usually absent. For example, lung cancer can cause hypertrophic osteoarthropathy. In addition, if a large protein gap is present, then one should evaluate for a monoclonal gammopathy by checking a serum protein electropheresis.
Certain metabolic disorders such as hypo- or hyperthyroidism can cause polyarthralgias. Also, hyperparathyroidism and other causes of hypercalcemia predispose to the development of pseudogout. Making the diagnosis of RA early in the course of disease is imperative so that effective treatment can be initiated in a timely manner. The goals of treatment are reduction of pain and inflammation and prevention of long-term disability and extra-articular morbidity and mortality .

Disease-ModifyingAntirheumatic Drugs

The initiation of DMARD therapy within the first 3 to 6 months of disease onset is now the standard of care for RA. The most common DMARD of choice in this setting is methotrexate (MTX) because of its proven clinical benefits and well-understood long-term efficacy and toxicity profile.
Moreover, MTX may be combined effectively with most other DMARDs, making it a highly adaptable drug. Alternatively, sulfasalazine (SSZ) and hydroxychloroquine (HCQ) may be employed for the treatment of patients with milder forms of RA.
In early disease, corticosteroids may be used to provide rapid control of the signs and symptoms of RA and serve as a bridge between the initiation of DMARD therapy and its onset of action, which is often delayed by a few months.

METHOTREXATE

the mainstay of DMARD therapy for RA is methotrexate (MTX). MTX inhibits dihydrofolate reductase, an enzyme needed for DNA synthesis.
Its therapeutic action was originally thought to be due to suppression of lymphocyte proliferation.
However, MTX’s mechanism of action is most likely due to its anti-inflammatory effects, although the specific mechanisms remain unclear. Inside cells, MTX is converted to a polyglutamated form that inhibits the enzyme 5- aminoimidazole-4-carboxamidoribonucleotide (AICAR) transformylase.

Importantly, women of childbearing age must use appropriate contraceptive measures because of the known teratogenic effects of MTX. Because MTX is partially eliminated through the kidney, this DMARD is generally avoided in patients with a serum creatinine of greater than 2.0 mg/dL.
Suppression of bone marrow occurs more commonly if renal insufficiency is present. In addition, MTX may cause an increase in serum transaminases and, rarely, liver fibrosis. Periodic laboratory monitoring of complete blood counts and liver enzymes are recommended in all patients taking MTX .and it should be used with folic acid.

LEFLUNOMIDE

represents an alternative oral agent to MTX. It inhibits an enzyme involved in pyrimidine synthesis, orotic acid dehydrogenase.
Leflunomide is taken once a day orally, in doses of 10 or 20 mg. Leflunomide’s active metabolite has a long half-life of 15 to 18 days, which is a notable feature of its pharmacokinetics. Its proven to reduce structural damage.
Its use is limited to some extent by gastrointestinal side effects and potential for teratogenicity. Similar to MTX, leflunomide therapy has been associated with elevated serum transaminases and should be monitored by regular liver enzyme testing.


HYDROXYCHLOROQUINE AND SULFASALAZINE
They are typically used to treat milder forms of RA and in combination with other DMARDs.
The mechanism of action of HCQ is not well understood but may, in part, be due to the fact that it concentrates inside cells, principally within acidic cytoplasmic vesicles.
In lysosomes, accumulation of HCQ raises the intravesical pH and may thereby interfere with the processing of autoantigenic peptides .
The clinical efficacy of HCQ therapy has been shown in a randomized, controlled trial of patients with relatively mild disease of less than 5 years’ duration . To date, no studies have shown that HCQ alone can decrease the rate of structural damage in RA.

Biological agents

TUMOR NECROSIS FACTOR (TNF)ANTAGONISTS
Etanercept, infliximab, adalimumab and other are TNF inhibitors approved for the treatment of RA. These biologic agents have revolutionized the treatment of RA because of their substantial benefits on the signs and symptoms of this disease,
as well as their ability to significantly retard the radiographic progression of joint damage. These drugs were engineered to specifically inhibit TNF, which is a critical mediator of joint inflammation. TNF has been shown to be a pivotal proinflammatory cytokine that regulates the production of other proinflammatory cytokines, such as IL-1 and IL-6.

Etanercept and adalimumab have caused injection site reactions but they are rarely severe enough to limit therapy. Infliximab has been associated with infusion reactions, which can range from rash to urticaria and fever, and rarely to anaphylaxis
Neutralizing antibodies can develop in infliximab-treated individuals that may inhibit the efficacy of the drug and predispose to infusion reactions.
There is also an increased risk of serious bacterial and opportunistic infections, especially reactivation of latent tuberculosis. A long-term study of etanercept therapy for RA showed that the rate for serious infection was 4.2 per 100,000 patient years, which remained relatively stable throughout the time period
reactivated TB have been reported with infliximab therapy. There have also been cases of TB reported with the use of adalimumab.

Use of anti-TNF agents may also confer an increased risk for lymphoproliferative disorders, namely lymphoma. malignancies, including nonmelanoma skin cancers, suggesting a possible relationship between TNF blockers and an increased risk for solid tumors
Other rare side effects of note include demyelinating disorders and drug-induced lupus reactions. The anti-TNF agents should not be used in patients with New York Heart Association (NYHA) class III to V heart failure because these drugs may exacerbate heart failure.

COMORBIDITIES

Osteoporosis is a major comorbidity in RA and can result from both the disease itself and the use of corticosteroids. Most patients are routinely advised to take calcium and vitamin D to prevent osteoporosis.
Cardiovascular (CV) disease is the number one cause of death in RA patients. Indeed, RA itself is a CV risk factor. It is unclear if intensive treatment of RA influences this risk, though available data suggest that MTX and anti-TNF treatment reduces the rate of CV events. Low dose aspirin should be considered in patients over the age of 50 years as primary prevention for CV disease.
Cholesterol levels should be regularly monitored and cholesterol-lowering medications prescribed as needed. Other CV risk factors, such as hypertension, diabetes, and obesity, should be treated according to usual recommendations.