RHEUMATOID ARTHRITIS

Introduction
Background

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown cause that primarily affects the peripheral joints in a symmetric pattern. Constitutional symptoms, including fatigue, malaise, and morning stiffness, are common. Extra-articular involvement of organs such as the skin, heart, lungs, and eyes can be significant. RA causes joint destruction and thus often leads to considerable morbidity and mortality. With the recent addition of new and innovative therapies, the treatment of RA is rapidly advancing.

For supplementary information, see Medscape’s Rheumatoid Arthritis Resource Center.
Pathophysiology

RA has no known cause. Although an infectious etiology has been speculated (eg, Mycoplasma organisms, Epstein-Barr virus, parvovirus, rubella), no organism has been proven responsible. RA is associated with numerous autoimmune responses, but whether autoimmunity is a secondary or primary event is still unknown.

RA has a significant genetic component, and the shared epitope of the HLA-DR4/DR1 cluster is present in up to 90% of patients with RA, although it is also present in more than 40% of controls. Synovial cell hyperplasia and endothelial cell activation are early events in the pathologic process that progresses to uncontrolled inflammation and consequent cartilage and bone destruction. Genetic factors and immune system abnormalities contribute to disease propagation.

CD4 T cells, mononuclear phagocytes, fibroblasts, osteoclasts, and neutrophils play major cellular roles in the pathophysiology of RA, while B lymphocytes produce autoantibodies (ie, rheumatoid factors [RFs]). Abnormal production of numerous cytokines, chemokines, and other inflammatory mediators (eg, tumor necrosis factor alpha [TNF-alpha], interleukin (IL)–1, IL-6, transforming growth factor beta, IL-8, fibroblast growth factor, platelet-derived growth factor) has been demonstrated in patients with RA. Ultimately, inflammation and exuberant proliferation of synovium (ie, pannus) leads to destruction of various tissues, including cartilage, bone, tendons, ligaments, and blood vessels. Although the articular structures are the primary sites involved by RA, other tissues are also affected.
Frequency
International

Worldwide, the annual incidence of RA is approximately 3 cases per 10,000 population, and the prevalence rate is approximately 1%. RA affects all populations, although the disease is much more prevalent in some groups (eg, 5-6% in some Native American groups) and much less prevalent in others (eg, black persons from the Caribbean region). First-degree relatives of individuals with RA are at an increased risk (2- to 3-fold) of the disease. Disease concordance in monozygotic twins is approximately 15-20%, suggesting that nongenetic factors play an important role. Because the worldwide frequency of RA is relatively constant, a ubiquitous infectious agent has been postulated to play an etiologic role.
Mortality/Morbidity

RA does not usually follow a benign course. It is associated with significant morbidity, disability, and mortality.

* Daily living activities are impaired in most individuals with RA. Spontaneous clinical remission is uncommon (approximately 5-10%). After 5 years of disease, approximately 33% of patients are unable to work; after 10 years, approximately half have substantial functional disability. Poor prognostic factors include persistent synovitis, early erosive disease, extra-articular findings (including subcutaneous rheumatoid nodules), positive serum RF findings, family history of RA, male sex, and advanced age.
* Life expectancy in patients with RA is shortened by 5-10 years, although the mortality rate may be lower in those who respond to therapy. Increased mortality rates are associated with poor functional status, age, male sex, socioeconomic factors (eg, level of education), positive RF findings, extra-articular disease, elevated acute-phase response (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]), and increased clinical severity (eg, more involved joints). Factors that increase the mortality risk include infections, cardiovascular disease, renal disease, GI bleeding, and lymphoproliferative disorders; these events may be directly due to the disease and its complications (eg, vasculitis, amyloidosis) or to therapy-induced adverse effects.
* A meta-analysis by Meune et al (2009) suggests that, despite data suggesting that the course of RA may have become milder over the past decades, the risk of cardiovascular death in patients with RA continues to be 60% higher than in the general population. In studies including 91,916 patients with RA, the overall pooled standardized mortality ratio (SMR) was 1.6 (95% confidence interval, 1.5-1.8; I(2) = 93%; P (het) <0.0001). Meta-regression analyses revealed neither any trend in SMR over time (P = 0.784) nor any relation with disease duration at the time of inclusion (P = 0.513). Meune et al conclude that reducing cardiovascular mortality should remain a major issue in RA management.1 Race RA affects all ethnic groups, although the disease is much more prevalent in some groups (eg, 5-6% in some Native American groups) and much less prevalent in others (eg, black persons from the Caribbean region). Sex RA is 2-3 times more common in females than in males. Age The frequency of RA increases with age and peaks in persons aged 35-50 years. Nevertheless, the disease is observed in both elderly persons and children. * Juvenile inflammatory arthritis (JIA) is classified as polyarticular (multiple joints), pauciarticular (<5 joints), or systemic. Systemic JIA is often associated with fever, rash, and organ involvement; it is also called Still disease. * Polyarticular RF-positive arthritis in children generally follows a clinical course that is similar to adult RA. * For additional information on juvenile rheumatoid arthritis, see the article Juvenile Rheumatoid Arthritis in eMedicine’s Pediatrics: General Medicine volume. Clinical History The American College of Rheumatology developed the following criteria for the classification of rheumatoid arthritis (RA). 1. Morning stiffness: This occurs in and around the joints and lasts at least 1 hour before maximal improvement. 2. Arthritis of 3 or more joint areas: At least 3 joint areas simultaneously have soft-tissue swelling or fluid (not bony overgrowth) observed by a physician. The 14 possible areas include the right and left proximal interphalangeal (PIP), metacarpophalangeal (MCP), wrist, elbow, knee, ankle, and metatarsophalangeal (MTP) joints. 3. Arthritis of hand joints: At least one area in a wrist, MCP, or PIP joint is swollen. 4. Symmetric arthritis (simultaneous involvement of the same joint areas on both sides of the body): Bilateral involvement of PIPs, MCPs, and MTPs is acceptable without absolute symmetry. 5. Rheumatoid nodules: Subcutaneous nodules are present over bony prominences or extensor surfaces or in juxta-articular regions. 6. Serum RF: Abnormal amounts of serum RF are demonstrated by any method for which the result has been positive in fewer than 5% of healthy control subjects. 7. Radiographic changes typical of RA on posteroanterior hand and wrist radiographs, which must include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints: Osteoarthritic changes alone do not qualify. The presence of 4 criteria supports the diagnosis of RA. Criteria 1-4 must be present for at least 6 weeks, and a physician must observe criteria 2-5. These criteria are intended as a guideline for classification of patients, often for research purposes. They do not absolutely confirm or exclude a diagnosis of RA in a particular patient, especially in those with early arthritis. Patients with RA often present with constitutional symptoms, including malaise, fever, fatigue, weight loss, and myalgias. They may report difficulty performing activities of daily living (eg, dressing, standing, walking, personal hygiene, using their hands). Most patients with RA have an insidious onset. It may begin with systemic features, such as fever, malaise, arthralgias, and weakness, before the appearance of overt joint inflammation and swelling. A small percentage of patients with RA (approximately 10%) have an abrupt onset with the acute development of synovitis and extra-articular manifestations. Spontaneous remission is uncommon, especially after the first 3-6 months. Physical Joint involvement is the characteristic feature of RA. In general, the small joints of the hands and feet are affected in a relatively symmetric distribution. The most commonly affected joints, in decreasing frequency, include the MCP, wrist, PIP, knee, MTP, shoulder, ankle, cervical spine, hip, elbow, and temporomandibular joints. Joints show inflammation with swelling, tenderness, warmth, and decreased range of motion. Atrophy of the interosseous muscles of the hands is a typical early finding. Joint and tendon destruction may lead to deformities such as ulnar deviation, boutonnière and swan-neck deformities, hammer toes, and, occasionally, joint ankylosis. Other commonly observed musculoskeletal manifestations include tenosynovitis and associated tendon rupture due to tendon and ligament involvement, most commonly involving the fourth and fifth digital extensor tendons at the wrist; periarticular osteoporosis due to localized inflammation; generalized osteoporosis due to systemic chronic inflammation, immobilization-related changes, or corticosteroid therapy; and carpal tunnel syndrome. Most patients with RA have muscle atrophy from disuse, which is often secondary to joint inflammation. * Effect of RA on organs and organ systems o Cutaneous: Subcutaneous nodules (rheumatoid nodules) develop in many patients with RA whose RF value is abnormal, often over pressure points (eg, olecranon). Vasculitic lesions of the skin may manifest as palpable purpura or skin ulceration. o Cardiac: Cardiovascular morbidity and mortality are increased in patients with RA. Nontraditional risk factors appear to play an important role. Myocardial infarction, myocardial dysfunction, and asymptomatic pericardial effusions are common; symptomatic pericarditis and constrictive pericarditis are rare. Myocarditis, coronary vasculitis, valvular disease, and conduction defects are occasionally observed. o Pulmonary: RA involvement of the lungs may take several forms, including pleural effusions, interstitial fibrosis, nodules (Caplan syndrome), and bronchiolitis obliterans-organizing pneumonia. Methotrexate (MTX) therapy can induce interstitial fibrosis that may be difficult to distinguish from that which naturally occurs in patients with RA. o GI: Intestinal involvement, as with kidney involvement, is often secondary to associated processes such as medication effects, inflammation, and other diseases. The liver is often affected in patients with Felty syndrome (ie, RA, splenomegaly, and neutropenia). o Renal: The kidneys are usually unaffected by RA directly. Secondary involvement is common, including that due to medications (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], gold, cyclosporin), inflammation (eg, amyloidosis), and associated diseases (eg, Sjögren syndrome with renal tubular abnormalities). o Vascular: Vasculitic lesions can occur in any organ but are most commonly found in the skin. Lesions may present as palpable purpura, skin ulcers, or digital infarcts. o Hematologic: Most active patients have an anemia of chronic disease. Several hematologic parameters parallel disease activity, including normochromic-normocytic anemia, thrombocytosis, and eosinophilia, although the latter is uncommon. Leukopenia is a finding in patients with Felty syndrome. o Neurologic: Nerve entrapment is common, such as with the median nerve in carpal tunnel syndrome. Vasculitic lesions, mononeuritis multiplex, and cervical myelopathy may cause serious neurologic consequences. o Ocular: Keratoconjunctivitis sicca is common in individuals with RA and is often the initial manifestation of secondary Sjögren syndrome. The eye may also have episcleritis, uveitis, and nodular scleritis that may lead to scleromalacia. The American College of Rheumatology has developed criteria to aid in determining the progression, remission, and functional status of patients with RA. * Progression of RA (clinical and radiologic staging) o Stage 1 (early RA) + No destructive changes observed upon roentgenographic examination + Radiographic evidence of osteoporosis possible o Stage II (moderate progression) + Radiographic evidence of periarticular osteoporosis, with or without slight subchondral bone destruction + Slight cartilage destruction possible + Joint mobility possibly limited; no joint deformities observed + Adjacent muscle atrophy + Extra-articular soft-tissue lesions (eg, nodules, tenosynovitis) possible o Stage III (severe progression) + Radiographic evidence of cartilage and bone destruction in addition to periarticular osteoporosis + Joint deformity (eg, subluxation, ulnar deviation, hyperextension) without fibrous or bony ankylosis + Extensive muscle atrophy + Extra-articular soft-tissue lesions (eg, nodules, tenosynovitis) possible o Stage IV (terminal progression) + Fibrous or bony ankylosis + Criteria of stage III * Remission of RA (≥5 of conditions below for at least 2 consecutive months) o Duration of morning stiffness not exceeding 15 minutes o No fatigue o No joint pain o No joint tenderness or pain with motion o No soft-tissue swelling in joints or tendon sheaths o ESR of less than 30 mm/h in a female or less than 20 mm/h in a male * Functional status of patients with RA o Class I - Completely able to perform usual activities of daily living o Class II - Able to perform usual self-care and vocational activities but limited in avocational activities o Class III - Able to perform usual self-care activities but limited in vocational and avocational activities o Class IV - Limited in ability to perform usual self-care, vocational, and avocational activities Causes The cause of RA is unknown. Genetic, environmental, hormonal, immunologic, and infectious factors may play significant roles. Socioeconomic, psychological, and lifestyle factors may influence disease outcome. * Genetic o Approximately 60% of US patients with RA carry a shared epitope of the HLA-DR4 cluster, which constitutes one of the peptide-binding sites of certain HLA-DR molecules associated with RA (eg, HLA-DR beta *0401, 0404, or 0405); in addition, HLA-DR1 (HLA-DR beta *0101) also carries this shared epitope and confers risk, particularly in certain southern European areas. o Other HLA-DR4 molecules (eg, HLA-DR beta *0402) do not share the same epitope and do not confer risk. Genes other than those of the major histocompatibility complex are also involved, and results from sequencing genes of RA families suggest the presence of several susceptibility genes and several resistance genes. * Environmental o For many decades, numerous infectious agents have been suggested to induce RA. Among these are Mycoplasma organisms, Epstein-Barr and rubella viruses, and others. o This supposition is further supported indirectly by the following: + Occasional reports of flulike disorders preceding the start of arthritis + The inducibility of arthritis in experimental animals with different bacteria or bacterial products (eg, streptococcal cell walls) + The presence of bacterial products including bacterial RNA in patients' joints + The activity of several agents that have antimicrobial effects as disease-modifying drugs (eg, gold salts, antimalarials, minocycline) * Hormonal o Sex hormones may play a role, as evidenced by the disproportionate number of females with RA, its amelioration during pregnancy, its recurrence in the early postpartum period, and its reduced incidence in women using oral contraceptives. o Hyperprolactinemia may be a risk factor for RA. * Immunologic o All of the major immunologic elements play fundamental roles in the initiation, propagation, and maintenance of the autoimmune process of RA. The exact orchestration of the cellular and cytokine events that lead to pathologic consequences, such as synovial proliferation and subsequent joint destruction, is complex. It involves T and B lymphocytes, antigen-presenting cells (eg, B cells, macrophages, dendritic cells), and numerous cytokines. Aberrant production and regulation of both pro-inflammatory and anti-inflammatory cytokines and cytokine pathways are found in RA. o T cells are assumed to play a pivotal role in the initiation of RA, and the key player in this respect is assumed to be the Th1 CD4 cells. (T helper 1 cells produce IL-2 and interferon gamma.) o These cells may subsequently activate macrophages and other cell populations, including synovial fibroblasts. Macrophages and synovial fibroblasts are the main producers of the proinflammatory cytokines TNF-alpha and IL-1. o B cells are important in the pathologic process and may serve as antigen-presenting cells. B cells also produce numerous autoantibodies (eg, RF, to citrullinated proteins) and secrete cytokines. Elimination of populations of B cells with monoclonal antibodies (eg, rituximab) offers another effective therapeutic option. While rituximab may be used as a sole agent, it is often used in combination with MTX. Rituximab has been shown to be effective in reducing the signs and symptoms in adult patients with moderately to severely active RA who have had an inadequate response to one or more TNF-antagonist therapies.2,3,4 o Experimental models suggest that synovial macrophages and fibroblasts may become autonomous and thus lose responsiveness to T-cell activities in the course of the disease. o The hyperactive and hyperplastic synovial membrane is ultimately transformed into pannus tissue and invades cartilage and bone, the latter being degraded by activated osteoclasts. o The major difference between RA and other forms of inflammatory arthritis, such as psoriatic arthritis, does not lie in their cytokine patterns but rather in the highly destructive potential of the RA synovial membrane and in the local and systemic autoimmunity. Whether these two events are linked is unclear; however, the autoimmune response conceivably leads to the formation of immune complexes that activate the inflammatory process to a much higher degree than normal. This theory is supported by the much worse prognosis of RA among patients with positive RF results. o In patients with RA, autoantibodies are directed not only against immunoglobulin G (IgG), ie, RFs, but also against various other antigens, such as nuclear antigens (RA 33, EBNA), citrullinated proteins (anti-CCP antibodies), collagen, and glucose-6-phosphate isomerase.Differential Diagnoses Amyloidosis, Overview Myelodysplastic Syndrome Calcium Pyrophosphate Deposition Disease Osteoarthritis Cryoglobulinemia Paraneoplastic Syndromes Fibromyalgia Polychondritis Hepatitis B Polymyalgia Rheumatica Hypothyroidism Psoriatic Arthritis Inflammatory Bowel Disease Sarcoidosis Lyme Disease Sjogren Syndrome Mediterranean Fever, Familial Systemic Lupus Erythematosus Multicentric Reticulohistiocytosis Whipple Disease Other Problems to Be Considered * Infectious arthritis - Bacteria (eg, Lyme disease), fungi, mycobacteria, viruses (eg, hepatitis B, rubella, parvovirus, human T-cell leukemia virus 1) * Autoimmune connective tissue diseases (eg, systemic lupus erythematosus, progressive systemic sclerosis, mixed connective tissue disease, Sjögren syndrome, vasculitis, cryoglobulinemias) * Other rheumatic diseases (eg, polyarticular gout, seronegative spondyloarthropathy [eg, ankylosing spondylitis, reactive arthritis]) * Subacute bacterial endocarditis * Hemoglobinopathies * Angioimmunoblastic lymphadenopathy Workup Laboratory Studies No pathognomonic test is available to help confirm the diagnosis of rheumatoid arthritis (RA); instead, the diagnosis is made using clinical, laboratory, and imaging features. * Markers of inflammation, such as ESR and CRP, are associated with disease activity; additionally, the CRP value over time correlates with radiographic progression. * Hematologic parameters include a CBC count and synovial fluid analysis. o Complete blood cell count + Anemia of chronic disease is common and correlates with disease activity; it improves with successful therapy. + Hypochromic anemia suggests blood loss, commonly from the GI tract (associated with NSAIDs). + Anemia may also be related to disease-modifying antirheumatic drug (DMARD) therapy. + Thrombocytosis is common and is also associated with disease activity. + Thrombocytopenia may be a rare adverse event of therapy and may occur in patients with Felty syndrome. + Leukocytosis may occur but is usually mild. + Leukopenia may be a consequence of therapy or a component of Felty syndrome, which may then respond to DMARD therapy. o Synovial fluid analysis + Inflammatory synovial fluid (WBC count >2000/µL) is present with WBC counts generally from 5,000-50,000/µL.
+ Usually, neutrophil predominance (60-80%) is observed in the synovial fluid (in contrast with mononuclear cell predominance in the synovium).
+ Because of a transport defect, the glucose levels of pleural, pericardial, and synovial fluids in patients with RA are often low compared to serum glucose levels.
* Immunologic parameters include autoantibodies (eg RF, anti-RA33, anti-CCP, antinuclear antibodies).
o Rheumatoid factor
+ RF is present in approximately 60-80% of patients with RA over the course of their disease but is present in fewer than 40% of patients with early RA.
+ RF values fluctuate somewhat with disease activity, although high-titered RF generally remains present even in patients with drug-induced remissions.
o Antinuclear antibodies: These are present in approximately 40% of patients with RA, but test results for antibodies to most nuclear antigen subsets are negative.
o Newer antibodies (eg, anti-RA33, anti-CCP): Recent studies of anti-CCP antibodies suggest a sensitivity and specificity equal to or better than those of RF, with an increased frequency of positive results in early RA. The presence of both anti-CCP antibodies and RF is highly specific for RA. Additionally, anti-CCP antibodies, as do RF, indicate a worse prognosis.

Imaging Studies

* Radiography: Note that erosions may be present in the feet, even in the absence of pain and in the absence of erosions in the hands.
o Extremities - Hands, wrists, knees, feet, elbows, shoulders, hips, cervical spine
o Others when indicated
* MRI: This modality is used primarily in patients with abnormalities of the cervical spine; early recognition of erosions based on MRI images has been sufficiently validated.
* Ultrasonography: This allows recognition of effusions in joints that are not easily accessible (eg, hip joints, shoulder joints in obese patients) and cysts (Baker cysts). High-resolution sonograms may allow visualization of tendon sheaths, changes and degree of vascularization of the synovial membrane, and even erosions; however, this needs further validation. Ultrasonography may be used as an office-based procedure.
* Bone scanning: Findings may help to distinguish inflammatory from noninflammatory changes in patients with minimal swelling.
* Densitometry: Findings are useful for helping diagnose changes in bone mineral density indicative of osteoporosis.

Other Tests

* HLA-DR4 (shared epitope) may constitute a helpful marker in early undifferentiated arthritis.

Procedures

* Joint aspiration, diagnostic arthroscopy (histology), and biopsies (eg, skin, nerve, fat, rectum, kidney) may be considered if vasculitis or amyloidosis is suggested.

Histologic Findings

The lymphoplasmacytic infiltration of the synovium with neovascularization seen in RA is similar to that seen in other conditions characterized by inflammatory synovitis. Early rheumatoid nodules are characterized by small-vessel vasculitis and later by granulomatous inflammation.Treatment
Medical Care

The optimal care of patients with rheumatoid arthritis (RA) requires an integrated approach of pharmacologic and nonpharmacologic therapies.

* Nonpharmacologic
o Education is important in helping patients to understand their disease and to learn how to cope with its consequences.
o Physiotherapy and physical therapy are initiated to help improve and sustain range of motion, to increase muscle strength, and to reduce pain.
o Occupational therapy is initiated (1) to help patients to use joints and tendons efficiently without stressing these structures, (2) to help decrease tension on the joints with specially designed splints, and (3) to cope with daily life through adaptations to the patients' environment and the use of different aids.
o Orthopedic measures include reconstructive and replacement-type surgical measures.
* Pharmacologic
o The American College of Rheumatology is developing RA recommendations and algorithms for the use of nonbiological and biological DMARDs for patients with RA.
o DMARDs represent the most important measure in the successful treatment of RA. DMARDs can retard or prevent disease progression and, thus, joint destruction and subsequent loss of function.
o Successful DMARD therapy may eliminate the need for other anti-inflammatory or analgesic medications.
o Until the full action of DMARDs takes effect, anti-inflammatory or analgesic medications may be required as bridging therapy to reduce pain and swelling.
o DMARDs can be classified into xenobiotic and biological agents.
o Xenobiotic agents include the following:
+ The xenobiotic DMARDs, ie, gold salts (eg, aurothiomalate, auranofin, others), D-penicillamine, chloroquine and hydroxychloroquine, sulfasalazine (SSZ), methotrexate (MTX), azathioprine, and cyclosporin A, have been widely used to treat RA; some have been used for decades.
+ MTX and SSZ are the most active compounds in terms of frequency of remissions and time to onset of action and provide the best risk-benefit ratios. MTX alone or in combination with other agents has become the standard of care for moderate-to-severe RA.
+ Minocycline may act as a DMARD through its action as a matrix metalloproteinase inhibitor.
+ Leflunomide is the most recent addition to the xenobiotics and has an activity that is similar to that of SSZ and MTX.
+ SSZ is dosed up to 2-4 g/d, while MTX is administered up to 25 mg once a week (PO, IV, IM, or SC). Both SSZ and MTX are started at lower dosages and are increased to full dosages within approximately 4-6 weeks. Monitoring of CBC counts and liver enzymes is important because of the drugs' hematologic and hepatic toxicities. Approximately 1% of patients develop agranulocytosis to SSZ or pneumonitis to MTX. Leflunomide is usually initiated with a loading dose of 100 mg/d for 3 days and is then continued at 20 mg/d. CBC counts and liver enzymes also must be monitored. Most of these drugs have been shown to improve signs and symptoms (as well as quality of life) and to significantly retard radiographic progression of RA.
+ Visser et al (2009) conducted a systematic review to assess the evidence for the optimal treatment of RA with MTX. The study sought to establish the optimal dosage and route of administration of MTX. In the review of 1748 articles identified in the literature, 38 met inclusion criteria. The analysis concluded that an initial MTX dose of 15 mg/week orally with escalation of 5 mg/month to achieve target doses of 25-30 mg/week or maximum tolerable doses was the optimal, evidence-based dosing strategy. Starting at higher initial doses or too rapid of escalation is limited by toxicity. Conversion from oral to subcutaneous administration of MTX is suggested for patients who have an inadequate response to oral therapy.5
+ Combination therapy appears to be helpful in patients whose RA insufficiently or completely fails to respond to monotherapy with a DMARD. Several compounds have been successfully combined without unexpected added risks; these usually include MTX as one of the drugs, ie, MTX plus SSZ plus an antimalarial, MTX plus leflunomide, or MTX plus biologics. In general, the same precautions are needed as with the single compounds, although liver and bone marrow toxicity may be increased if compounds affecting these organs are combined.
+ The most important and most common adverse events relate to liver and bone marrow toxicity (MTX, SSZ, leflunomide, azathioprine, gold compounds, D-penicillamine), renal toxicity (cyclosporine A, parenteral gold salts, D-penicillamine), pneumonitis (MTX), allergic skin reactions (gold compounds, SSZ), autoimmunity (D-penicillamine, SSZ, minocycline), and infections (azathioprine, cyclosporine A). Antimalarials may cause ocular toxicity. Wolfe and Marmor studied nearly 4,000 patients with RA or SLE who had used the antimalarial hydroxychloroquine and concluded that the risk of hydroxychloroquine toxicity was relatively low but increased (>1%) after 7 years of therapy.6 Nevertheless, these drugs, when used with appropriate clinical and laboratory control monitoring, are usually well tolerated. Adverse events typically become rarer after the first 2-3 months. Most adverse events are reversible with drug cessation or with dose reduction.
+ In clinical trials, 30-70% of patients using DMARDs, either alone or in combination therapy, achieve partial responses according to the American College of Rheumatology's disease activity score. Currently, predicting which patients will not respond is not possible. In clinical practice, attempting to reduce disease activity as much as possible by (1) increasing the dose of medication (eg, MTX), (2) switching to other DMARDs in those who do not respond or in those with responses regarded as insufficient, or (3) initiating combination therapy is important. Because patients may require 2-3 months to achieve a full response to DMARDs, decisions regarding changes in medication are often delayed until that time.
o Biological agents include the following:
+ The recognition of TNF-alpha and IL-1 as central proinflammatory cytokines has led to the development of agents that block these cytokines or their effects. The TNF blockers include etanercept, infliximab, and adalimumab. Etanercept, a bivalent p 75–TNF receptor linked to the Fc portion of human IgG, is administered at 25 mg SC twice weekly or 50 mg SC weekly, with or without concomitant MTX. Infliximab, a chimeric monoclonal antibody against TNF-alpha, is administered at doses of 3 mg/kg IV at weeks 0, 2, and 6 and then every 4-8 weeks, usually with MTX. Adalimumab, a recombinant human IgG1 monoclonal antibody specific for human TNF monoclonal antibody, is administered 40 mg SC every 2 weeks.
+ These agents are expensive. Consensus statements do not recommend their use until at least one xenobiotic DMARD, usually MTX, has been administered without sufficient success. In clinical trials, up to 70% of patients achieve significant responses, but remissions are not usually observed.7
+ These agents bind TNF and thus prevent its interaction with its receptors; infliximab binds to cells that express membrane TNF, while etanercept binds lymphotoxin (formerly termed TNF-beta) in addition to soluble TNF-alpha. Failure to respond to one TNF blocker does not preclude response to another. As with xenobiotics, the decision to continue or stop biological agents can often be made within 3 months after initiation of therapy.
+ Adverse effects associated with the biological agents include the generation of antibodies against these compounds, emergence of antinuclear antibodies, occasional drug-induced lupuslike syndromes, and infections (including tuberculosis). Rarely, demyelinating disorders and bone marrow suppression may occur. Acute and chronic infections, demyelinating disorders, and recent malignancies are contraindications for TNF blockers. Thoroughly searching for latent tuberculosis using chest radiography and/or purified protein derivative (PPD) testing is recommended before these agents are started.
+ Another biological agent is anakinra (IL-1 receptor antagonist [IL-1ra]). IL-1ra occupies the IL-1 receptor without triggering it and prevents receptor binding of IL-1. It is given at a dose of 100 mg/d SC. In clinical trials, a significant response was observed in approximately 40% of patients with RA.
+ Abatacept is a selective costimulation modulator that inhibits T-cell activation by binding to CD80 and CD86, thereby blocking their interaction with CD28. CD28 interaction provides a signal needed for full T-cell activation that is implicated in RA pathogenesis. It is dosed according to body weight (vida infra); after initial infusion, repeat on week 2 and week 4, then every 4 weeks following.
+ Fleischmann et al examined safety and efficacy of certolizumab monotherapy in 220 patients RA in whom DMARD therapy had failed. Patients were randomized 1:1 to receive certolizumab 400 mg or placebo every 4 weeks for 24 weeks. At 24 weeks, 45.5% of the certolizumab group achieved a 20% improvement according to the American College of Rheumatology criteria (ACR20), whereas 9.3% of the placebo group achieved ACR20 (P <0.001). Statistically significant differences between certolizumab and placebo were observed as early as week 1 through week 24 (P <0.001).8 + Smolen et al evaluated the effect of certolizumab plus MTX versus placebo plus MTX in patients with RA. The primary endpoint was ACR20 response at week 24. Patients (n=619) were randomized to receive certolizumab 400 mg at weeks 0, 2, and 4 followed by 200 mg or 400 mg plus MTX every 2 weeks, or placebo plus MTX every 2 weeks. Significantly more patients who received certolizumab 200 mg or 400 mg achieved ACR20 compared with those who received placebo (P <0.001), with rates of 57.3%, 57.6%, and 8.7%, respectively. Radiographic progression was significantly inhibited with certolizumab 200 mg (0.2), 400 mg (-0.4) compared with placebo (1.2). When compared with placebo plus MTX, certolizumab plus MTX significantly relieved signs and symptoms, improved physical function, and inhibited radiographic progression in patients with RA.9 + In addition to improving signs and symptoms and quality of life, all biologic agents significantly retard radiographic progression of joint erosions. + Golimumab, a new human anti–TNF-alpha monoclonal antibody, inhibits TNF-alpha bioactivity, thereby modulating immune activity in patients with RA. Emery et al (2009) conducted a 52-week, randomized, double-blind, placebo-control study, followed by an open-label extension through 5 years to assess the safety and efficacy of golimumab in MTX-naive patients with RA. Patients (n=637) were randomized to receive placebo plus MTX (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus MTX (group 3), or golimumab 100 mg plus MTX (group 4). Intent-to-treat analysis showed no significant differences in the primary endpoint between group 1 and groups 3 and 4 combined, indicating efficacy of golimumab in RA. The incidence of serious adverse events was similar among all treatment groups.10 + Treatment with rituximab may deplete CD20+ B cells, and Bingham et al investigated whether this may affect patients' response to immunization. In a controlled trial in 103 patients, responses to pneumococcal polysaccharide vaccine were lesser in patients with RA receiving rituximab and methotrexate than in those receiving methotrexate alone (57% vs 82%, respectively, showed a 2-fold rise in titer in response to ≥1 serotype). Decreased response to keyhole limpet hemocyanin (KLH) (neoantigen) was also seen in the rituximab-treated patients (47% vs 93%). However, the ability to maintain a positive delayed-type hypersensitivity to a Candida albicans skin test was comparable in both groups, as was response to tetanus toxoid. They concluded that, to maximize immunization responses, polysaccharide and primary immunizations should be administered before starting rituximab treatment.11 o Glucocorticoids + Glucocorticoids are potent anti-inflammatory drugs and are commonly used in patients with RA to bridge the time until DMARDs are effective. + Doses of up to 10 mg of prednisone per day are typically used, but some patients may require higher doses. + Timely dose reductions and cessation are important because of the adverse effects associated with long-term steroid use. o Nonsteroidal anti-inflammatory drugs + NSAIDs interfere with prostaglandin synthesis through inhibition of the enzyme cyclooxygenase (COX), thus reducing swelling and pain. However, they do not retard joint destruction and, therefore, when used alone, are not sufficient to treat RA. Similar to glucocorticoids, they can be reduced in dose or discontinued with successful DMARD therapy. + Several dozen NSAIDs are available and can be classified into different groups of compounds. Commonly used NSAIDs include ibuprofen, naproxen, ketoprofen, piroxicam, and diclofenac. + In the early 1990s, 2 isoforms of COX were discovered, ie, COX-1 and COX-2. Traditional NSAIDs inhibit both COX-1 and COX-2. + The coxibs (COX-2 inhibitors), a new group of compounds, have recently been developed. These compounds have a significant preference for COX-2 over COX-1. COX-1 has a protective role, particularly in the stomach, while COX-2 is strongly up-regulated during inflammation. + Coxibs, with their selectivity for COX-2, have been shown to be clinically efficacious and are accompanied by significantly reduced GI toxicity, the major adverse event related to the use of nonselective COX inhibitors (ie, NSAIDs). Other adverse effects, such as water retention, hypertension, and abnormal transaminase levels, are observed with both nonselective and COX-2–selective drugs. Whether and to what degree nonaspirin NSAIDs, coxibs, or both have cardiovascular toxicity has not been definitively settled. + COX-2 inhibitors and traditional NSAIDs plus a proton-pump inhibitor have similar upper GI toxicity. A study by Chan et al (2010) compared the risk of clinical outcomes across the entire GI tract between the 2 drug regimens. A lower incidence of GI toxicity with COX-2 inhibitors was observed and a significantly greater number of patients in the NSAID/proton-pump inhibitor group withdrew early because of GI adverse events compared with the COX-2 inhibitor group (P =0.0006).12 o Analgesics + Acetaminophen/paracetamol, tramadol, codeine, opiates, and various other analgesic medications can also be used to reduce pain. + These agents do not affect swelling or joint destruction. o Experimental therapies + Despite significant advances over the past decades, RA continues to be an incurable disease. The disease remains active in many patients whose conditions partially or completely fail to respond to DMARDs. Therefore, a vigorous search is underway for new therapeutic agents. + Although not truly experimental because it has been approved for use in RA, an immunoadsorbent column (Prosorba) is used on occasion to treat patients with resistant RA. Weekly exchanges are given for 12 weeks. + New TNF blockers are in clinical trials and include certolizumab, a Fab pegylated fragment of a humanized monoclonal antibody. + Several new CD20 B-cell–targeted biologic agents are under investigation, including atacicept, AMG 623, B3-FCc, Br3-Fc, belimumab, epratuzumab, ofatumumab, ocrelizumab, and TRU-015. + Biologics capable of blocking IL-6 (tocilizumab) or interfering with T-cell/non–T-cell interactions look to be very promising. + Xenobiotics directed at molecules involved in transduction of TNF, those involved with the receptor for the lymphotoxin-b receptor, or IL-1–mediated signals (eg, AMG 108, an IL-1ra) could prove helpful. + Inhibition of matrix metalloproteinases, although initially unsuccessful, could prove to be efficacious, as could agents that inhibit activation of osteoclasts. + Apheresis procedures are being investigated. + High-dose immunosuppression combined with autologous stem cell transplantation has been used in study protocols for patients whose conditions are resistant to other therapies. o Early therapy + Many studies have revealed that early treatment of RA (ie, within months of onset) with DMARDs can not only more efficiently retard disease progression than later treatment, but may also induce more remissions. Thus, early therapy with DMARDs has become the standard of care. + Importantly, note that patients with early forms of arthritis should be evaluated by, and if necessary, referred to physicians who are experienced in the diagnosis and treatment of RA. + In a study by van Vollenhoven et al, patients with early RA were administered MTX (up to 20 mg/wk). Study participants not achieving low disease activity after 3-4 months were randomized to receive either sulfasalazine and hydroxychloroquine or infliximab in addition to MTX. Of 487 patients who were initially enrolled, 258 had not achieved low disease activity with MTX and were then randomized to receive additional treatment (in addition to MTX) with sulfasalazine and hydroxychloroquine (n=130) or infliximab (n=128). In the sulfasalazine and hydroxychloroquine group, 32 of 130 (25%) achieved the primary outcome defined as a good response according to the European League Against Rheumatism (EULAR). In the infliximab group, 50 of 128 (39%) attained the primary outcome. The authors concluded that, in early RA that fails MTX treatment, the addition of a tumor necrosis factor antagonist is superior to addition of conventional DMARDs.13 + Secchiero et al sought to determine the relationship between therapeutic response to DMARDs and serum concentrations of TNF-related apoptosis-inducing ligand (TRAIL) and osteoprotegerin in patients with early RA.14 TRAIL and osteoprotegerin serum concentrations were measured at baseline and at 1 year. Patients who had a clinical response (as measured by the 28-joint count Disease Activity Score) were noted to have significantly higher baseline concentrations of TRAIL after 1 year of therapy compared with patients who did not have a clinical response to DMARDs. The authors suggest that TRAIL concentrations may be an important factor in therapeutic response to DMARD in patients with early RA. Surgical Care Cervical spine involvement usually affects C1-C2 and may potentially cause serious neurologic consequences. Patients who are to undergo intubation or procedures that may involve manipulation of the neck should undergo careful evaluation of the cervical spine. Patients with RA often need multiple operations over time (eg, synovectomy, tendon corrections, joint replacements). Consultations * Orthopedists * Physical and rehabilitative medicine specialists Medication Optimal care of patients with rheumatoid arthritis (RA) requires an integrated approach of pharmacologic and nonpharmacologic therapies. Disease-modifying antirheumatic drugs Xenobiotics include gold salts (eg, aurothiomalate, auranofin, others), D-penicillamine, chloroquine and hydroxychloroquine, SSZ, MTX, azathioprine, and cyclosporin A and have been widely used to treat RA. Leflunomide (Arava) First new DMARD approved in more than 10 years. Blocks autoimmune antibodies and reduces inflammation. Inhibits dihydroorotate dehydrogenase, an enzyme in the de novo pyrimidine synthesis pathway. Studies indicate that it reduces symptoms, possibly better than MTX, and may even slow progression of RA. Use with caution in renal insufficiency * Dosing * Interactions * Contraindications * Precautions Adult Initial: 100 mg/d PO for 3 d Maintenance dose: 10-20 mg/d PO Pediatric Not established * Dosing * Interactions * Contraindications * Precautions Cholestyramine and charcoal reduce effects; concomitant rifampin increases toxicity * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity * Dosing * Interactions * Contraindications * Precautions Pregnancy X - Contraindicated; benefit does not outweigh risk Precautions Serious adverse reactions include hepatotoxicity and immunosuppression; other reactions include nausea, diarrhea, abdominal pain, rash, bronchitis, headache, hypertension, dizziness, and alopecia; caution if impaired liver or renal function or if immunodeficient; leflunomide is a prodrug and active metabolite has a very long plasma half-life (approximately 15 d); with serious toxicity, can be cleared more quickly using cholestyramine 8 mg tid Methotrexate (Rheumatrex, Folex PFS) Unknown mechanism of action in treatment of inflammatory reactions, although it is a known inhibitor of dihydrofolate reductase and causes extracellular release of adenosine, a known inhibitor of immune and inflammatory pathways. Ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Gradually adjust dose to attain satisfactory response. * Dosing * Interactions * Contraindications * Precautions Adult 7.5-25 mg PO/IV/IM/SC qwk Pediatric Not established * Dosing * Interactions * Contraindications * Precautions Oral aminoglycosides may decrease absorption and blood levels of concurrent oral MTX; charcoal lowers levels; coadministration with etretinate may increase hepatotoxicity; folic acid or its derivatives contained in some vitamins may decrease response; probenecid, NSAIDs, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, can increase plasma levels; may decrease phenytoin plasma levels; may increase plasma levels of thiopurines * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; alcoholism; hepatic inflammation or insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency * Dosing * Interactions * Contraindications * Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions Monitor CBC counts monthly and liver and renal function every 1-3 mo during therapy (monitor more frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels, eg, renal insufficiency, dehydration); has toxic effects on hematologic, GI, and pulmonary systems; discontinue if significant drop in blood counts occurs; fatal reactions reported when administered concurrently with NSAIDs or in setting of significantly impaired renal function; folic acid supplementation (1 mg/d) may decrease adverse GI effects Sulfasalazine (Azulfidine, Azulfidine EN-tabs) Acts locally to decrease inflammatory response and systemically inhibits prostaglandin synthesis. * Dosing * Interactions * Contraindications * Precautions Adult Initial: 1 g PO tid/qid Maintenance: 2 g/d PO in divided doses Pediatric <2 years: Not established >2 years: 40-60 mg/kg/d PO in 3-6 divided doses, followed by maintenance dose of 20-30 mg/kg/d divided qid

* Dosing
* Interactions
* Contraindications
* Precautions

Decreases effects of iron, digoxin, and folic acid; conversely, increases effect of oral anticoagulants, oral hypoglycemic agents, and MTX

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity to sulfa drugs or any component; GI or GU obstruction

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions

Caution in patients with renal or hepatic impairment, blood dyscrasias, or urinary obstruction; adverse effects include anorexia, nausea/vomiting, diarrhea (enteric-coated tabs may reduce adverse GI effects), photosensitivity, headache, dizziness, urticaria/pruritus, hemolytic anemia, interstitial nephritis, acute nephropathy, hematuria, cirrhosis, jaundice, and hepatic necrosis (rare)

Hydroxychloroquine (Plaquenil)

Inhibits chemotaxis of eosinophils, inhibits locomotion of neutrophils, and impairs complement-dependent antigen-antibody reactions. Hydroxychloroquine sulfate (200 mg) is equivalent to 155-mg hydroxychloroquine base and 250-mg chloroquine phosphate.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

400-600 mg PO qd with food or milk
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Serum levels increase with cimetidine; magnesium trisilicate may decrease absorption

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; psoriasis; retinal and visual field changes attributable to 4-aminoquinolones

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; not recommended for long-term use in children; visual symptoms or muscular weakness may occur; perform periodic (q6mo) ophthalmologic examinations; test periodically for muscle weakness
Biologicals

Various biologic agents are used to rheumatic actions on joints and may include TNF–alpha inhibition and targeted monoclonal antibodies.

Data accumulated from 3 Swedish registries analyzed the cancer risk in 6,366 patients with RA taking TNF blockers. Data were compared with 61,160 patients with RA who were biologics-naive, 5,989 patients starting methotrexate, 1,838 patients starting DMARD combination therapy, and the general Swedish population. Results showed that, among patients taking TNF blockers (25,693 person-years of follow-up in 6,366 patients over 6 y), 240 developed first-time cancer, yielding a relative risk (RR) of 1.00 (confidence interval, 95%; 0.86-1.15) compared with the biologics-naive cohort. Similar RRs were shown with the other cohorts. The authors did not observe an increased risk for cancer with TNF blockers in this study.15

A meta-analysis conducted by Wiens et al (2010) evaluated the efficacy of adalimumab (n=1524), etanercept (n=1029), infliximab (n=1116), and placebo (n=2834) for the treatment of rheumatoid arthritis. American College of Rheumatology improvement criteria were used to assess efficacy. Etanercept and adalimumab demonstrated higher efficacy with short-term treatment (ie, 12-30 wk), whereas adalimumab was most effective for long-term therapy (ie, 1-3 y).16

Tsuzaka et al found that the baseline ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) mRNA level may be used as a biomarker for prediction of the response to infliximab in patients with rheumatoid arthritis. ADAMTS5 is said to play a significant role in cartilage deterioration. Low baseline ADAMST5 levels were significantly lower in the good responder group compared with those in the nonresponder and moderate responder groups.17

According to a study by Caporali et al, anti-TNF-alpha therapy is safe and hepatitis B reactivation did not occur in carriers of antibodies to hepatitis B core antigen (anti-HBc) who were affected by chronic inflammatory arthropathies.18

Rituximab (Rituxan)

Chimeric IgG1-kappa monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. The Fab domain of rituximab binds to CD20 antigen on B lymphocytes, and the Fc domain recruits immune effector functions to mediate B-cell lysis in vitro. Possible mechanisms of cell lysis include complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Rituximab in combination with methotrexate is indicated to reduce signs and symptoms in adult patients with moderately to severely active RA who have had an inadequate response to one or more TNF antagonist therapies.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Give two 1-g IV infusions 2 wk apart
Glucocorticoids administered as methylprednisolone 100 mg IV or equivalent 30 min prior to each infusion are recommended to reduce incidence and severity of infusion reactions
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

No formal drug interaction studies performed with rituximab; renal toxicity reported with drug in combination with cisplatin in clinical trials (in clinical trials involving patients with RA, concomitant administration of methotrexate or cyclophosphamide did not alter pharmacokinetics of rituximab)

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity or IgE-mediated hypersensitivity to murine proteins or any component of product

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Safety and efficacy of re-treatment not established in controlled trials; not recommended in patients with RA and no prior inadequate response to one or more TNF antagonists; has caused severe infusion reactions (in some cases, reactions were fatal); hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death has been reported in some patients with hematologic malignancies treated with rituximab; hypersensitivity reactions (non–IgE-mediated reactions reported); mucocutaneous reactions, some with fatal outcome, have been reported in patients treated with rituximab; vaccination with live-virus vaccines not recommended

Infliximab (Remicade)

Chimeric IgG1k monoclonal antibody that neutralizes cytokine TNF-alpha and inhibits its binding to TNF-alpha receptor. Reduces infiltration of inflammatory cells and TNF-alpha production in inflamed areas. Used with MTX in patients who have inadequate response to MTX monotherapy.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

3 mg/kg IV at weeks 0, 2, and 6; then q4-8wk, usually with MTX; some patients require higher doses (4-5 mg/kg)
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

None reported

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; active infection; demyelinating disorders or multiple sclerosis; tuberculosis

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

TNF-alpha modulates cellular immune responses; anti–TNF therapies, such as infliximab, may adversely affect normal immune responses and allow development of superinfections; may increase risk of reactivation of TB in patients with certain granulomatous infections; PPD-positive patients require TB prophylaxis; may cause anti-DNA antibodies and drug-induced lupus; caution in congestive heart failure

Etanercept (Enbrel)

Soluble p75 TNF receptor fusion protein (sTNFR-Ig). Inhibits TNF binding to cell surface receptors, which, in turn, decreases inflammatory and immune responses.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

25 mg SC twice weekly or 50 mg SC once weekly with or without concomitant administration of MTX
Pediatric

Administer as in adults

* Dosing
* Interactions
* Contraindications
* Precautions

None reported

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; active infection; sepsis; concurrent live vaccination; demyelinating disorders or multiple sclerosis; tuberculosis

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions

Caution in impaired renal function and asthma; discontinue administration if serious infection develops; adverse effects may include injection-site pain, localized erythema, rash, URI symptomology, GI upset, nausea, vomiting, rhinitis, cough, and drug-induced lupus; caution in congestive heart failure

Adalimumab (Humira)

Recombinant human IgG1 monoclonal antibody specific for human TNF. Indicated to reduce inflammation and inhibit progression of structural damage in moderate-to-severe rheumatoid arthritis. Reserved for those who experience inadequate response to one or more DMARDs. It can be used alone or in combination with MTX or other DMARDs. Binds specifically to TNF-alpha and blocks interaction with p55 and p75 cell-surface TNF receptors.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

40 mg SC q2wk; may increase to 40 mg SC qwk in some patients not taking concomitant MTX
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

May interfere with immune response to live virus vaccine (MMR) and reduce efficacy; MTX decreases clearance (available data do not support adjusting dose of either HUMIRA or MTX)

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; active infection; demyelinating disorders or multiple sclerosis; tuberculosis

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions

Causes immunosuppression; may reactivate tuberculosis infection; increases risk for lymphoma development; associated with CNS demyelination (rare); discontinue if serious infection develops; autoantibody development may occur, causing lupuslike syndrome; caution in congestive heart failure

Golimumab (Simponi)

TNF-alpha inhibitor. Decreases inflammation caused by overproduction of TNF associated with chronic inflammatory diseases. Indicated for moderate-to-severe RA, active psoriatic arthritis, and active ankylosing spondylitis. Available as 50-mg/mL, single-dose Simponi SmartJect (Autoinjector) or a prefilled syringe.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

50 mg SC monthly in conjunction with methotrexate
Pediatric

<18 years: Not established * Dosing * Interactions * Contraindications * Precautions Higher incidence of serious infections may occur when coadministered with abatacept, anakinra, or rituximab (do not administer concurrently); may decrease humoral response to live-virus vaccines (eg, MMR) * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; active infections * Dosing * Interactions * Contraindications * Precautions Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals Precautions Similar to other TNF-alpha inhibitors, may cause reactivation of tuberculosis or hepatitis B; test patients for latent tuberculosis before initiating treatment; serious infections (eg, bacterial sepsis, severe invasive fungal infections, opportunistic infections) may occur; do not initiate if infection exists, and discontinue if serious infection or sepsis develops; lymphoma incidence increased over general population; may exacerbate existing demyelinating disease or cause new onset of demyelinating disease; may worsen heart failure or may cause new onset of heart failure; common adverse effects include upper respiratory tract infection, sore throat, and nasal congestion Nonsteroidal anti-inflammatory drugs These agents interfere with prostaglandin synthesis through inhibition of the COX enzyme, thus reducing swelling and pain. However, they do not retard joint destruction and alone are not sufficient to treat RA. As with glucocorticoids, dose can be reduced or drug discontinued with successful DMARD therapy. Coxibs and NSAIDs have been given a "black box" warning by the US Food and Drug Administration regarding their potential for increased serious cardiovascular thrombotic events. NSAIDs may increase the risk of serious cardiovascular thrombotic events, MI, and stroke, which can be fatal. NSAIDs also increase the risk of serious adverse GI effects, including stomach or intestinal bleeding, ulceration, and perforation, which can be fatal. Elderly patients are at greater risk for serious GI events. Several dozen NSAIDs are available, which can be classified into different groups of compounds. Commonly used NSAIDs include ibuprofen, naproxen, ketoprofen, piroxicam, and diclofenac. Selective COX-2 inhibitors may be considered for patients at risk for GI bleeding. Combination products that include an NSAID and a proton pump inhibitor are also an option. Ibuprofen (Motrin, Advil) Indicated for patients with mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis. * Dosing * Interactions * Contraindications * Precautions Adult 200-400 mg PO q4-6h while symptoms persist; not to exceed 3.2 g/d Pediatric <6 years: Not established 6 months to 12 years: 4-10 mg/kg/dose PO tid/qid >12 years: Administer as in adults

* Dosing
* Interactions
* Contraindications
* Precautions

Administration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of MTX toxicity; phenytoin levels may be increased when administered concurrently

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; peptic ulcer disease, recent GI bleeding or perforation, renal insufficiency, or high risk of bleeding

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in coagulation abnormalities or during anticoagulant therapy

Celecoxib (Celebrex)

Primarily inhibits COX-2. COX-2 is considered an inducible isoenzyme, induced during pain and inflammatory stimuli. Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeutic concentrations, COX-1 isoenzyme is not inhibited, thus GI toxicity may be decreased. Seek lowest dose for each patient.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Up to 200 mg/d bid PO
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Coadministration with fluconazole may cause increase in celecoxib plasma concentrations because of inhibition of celecoxib metabolism; coadministration with rifampin may decrease celecoxib plasma concentrations

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions

May cause fluid retention and peripheral edema; caution in compromised cardiac function, hypertension, and conditions predisposing to fluid retention; caution in severe heart failure and hyponatremia because may deteriorate circulatory hemodynamics; NSAIDs may mask usual signs of infection; caution in the presence of existing controlled infections; evaluate therapy when symptoms or lab results suggest liver dysfunction

Ketoprofen (Orudis, Oruvail)

For relief of mild to moderate pain and inflammation. Small dosages are initially indicated in small and elderly patients and in those with renal or liver disease. Doses of more than 75 mg do not increase therapeutic effects. Administer high doses with caution and closely observe patient for response.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

25-50 mg PO q6-8h prn; not to exceed 300 mg/d
Pediatric

<3 months: Not established 3 months to 12 years: 0.1-1 mg/kg PO q6-8h >12 years: Administer as in adults

* Dosing
* Interactions
* Contraindications
* Precautions

Coadministration with aspirin increases risk of inducing serious NSAID-related side effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in coagulation abnormalities or during anticoagulant therapy

Naproxen (Naprosyn)

For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis.
NSAIDs decrease intraglomerular pressure and decrease proteinuria.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

250-500 mg PO bid; may increase to 1.5 g/d for limited periods
Pediatric

<2 years: Not established >2 years: 2.5 mg/kg/dose PO; not to exceed 10 mg/kg/d

* Dosing
* Interactions
* Contraindications
* Precautions

Coadministration with aspirin increases risk of inducing serious NSAID-related side effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and may require discontinuation of drug

Esomeprazole and naproxen (Vimovo)

Naproxen component is indicated for relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis. Naproxen is an NSAID that inhibits inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis.
Esomeprazole component is indicated to decrease risk of gastric ulcers in patients at risk of developing NSAID-associated gastric ulcers. Esomeprazole is the S-isomer of omeprazole, a proton pump inhibitor. Inhibits gastric acid secretion by inhibiting H+/K+-ATPase enzyme system at secretory surface of gastric parietal cells.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

1 tab PO bid at least 30 min ac
Delayed-release tab; swallow whole and do not chew, crush, dissolve, or split
Available in 2 dosage strengths: Esomeprazole 20 mg and naproxen 375 mg per tab or esomeprazole 20 mg and naproxen 500 mg per tab
Pediatric

<18 years: Not established * Dosing * Interactions * Contraindications * Precautions Concomitant use of NSAIDs may reduce antihypertensive effect of ACE inhibitors, diuretics, and beta-blockers; NSAIDs increase lithium plasma levels; concomitant use with methotrexate may increase methotrexate toxicity; concomitant use with warfarin may result in increased risk of bleeding complications (monitor INR and prothrombin time); esomeprazole inhibits gastric acid secretion and may interfere with absorption of drugs for which gastric pH is an important determinant of bioavailability (eg, ketoconazole, iron salts, digoxin, atazanavir, nelfinavir); esomeprazole inhibits CYP2C19 and therefore may alter serum levels/activity of CYP2C19 substrates; esomeprazole is extensively metabolized by CYP2C19 and CYP3A4 * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; NSAIDs are contraindicated for perioperative pain in the setting of coronary artery bypass graft surgery (increased risk of MI and stroke); NSAIDs are contraindicated during late pregnancy (risk of premature closure of ductus arteriosus) * Dosing * Interactions * Contraindications * Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions May cause anaphylactoid reaction; not recommended with severe hepatic impairment or moderate-to-severe renal impairment; common adverse effects (>5%) include erosive gastritis, dyspepsia, gastritis, diarrhea, gastric ulcer, upper abdominal pain, and nausea
NSAIDs carry black box warning regarding GI hemorrhage and serious thrombotic sequelae

Piroxicam (Feldene)

Decreases activity of cyclo-oxygenase, which in turn inhibits prostaglandin synthesis. These effects decrease formation of inflammatory mediators.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

10-20 mg/d PO qd
Pediatric

0.2-0.3 mg/kg/d PO qd; not to exceed 15 mg/d

* Dosing
* Interactions
* Contraindications
* Precautions

Coadministration with aspirin increases risk of inducing serious NSAID-related side effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; active GI bleeding

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; reversible leukopenia may occur (discontinue if there is persistent leukopenia, granulocytopenia, or thrombocytopenia)

Diclofenac (Voltaren)

Designated chemically as 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt, with an empirical formula of C14 H10 Cl2 NO2 NA. One of a series of phenylacetic acids that has demonstrated anti-inflammatory and analgesic properties in pharmacological studies. Believed to inhibit the enzyme cyclooxygenase, which is essential in the biosynthesis of prostaglandins. Can cause hepatotoxicity; hence, liver enzymes should be monitored in the first 8 weeks of treatment.
Rapidly absorbed; metabolism occurs in liver by demethylation, deacetylation, and glucuronide conjugation. Delayed-release, enteric-coated form is diclofenac sodium, and immediate-release form is diclofenac potassium. Has relatively low risk for bleeding GI ulcers.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

25 mg PO bid/tid
If well tolerated, increase by 25 or 50 mg at weekly intervals until satisfactory response is obtained or total daily dose of 150-200 mg PO is reached
Higher doses generally do not increase effectiveness
Pediatric

<12 years: Not established >12 years: Administer as in adults

* Dosing
* Interactions
* Contraindications
* Precautions

Coadministration with aspirin increases risk of inducing serious NSAID-related side effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding) may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; do not administer into CNS or give to patients with peptic ulcer disease, recent GI bleeding or perforation, renal insufficiency, and those at high risk of bleeding

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; low white blood cell counts occur rarely, and usually return to normal in ongoing therapy; discontinuation of therapy may be necessary if there is persistent leukopenia, granulocytopenia, or thrombocytopenia
Analgesics

Acetaminophen/paracetamol, tramadol, codeine, opiates, and various other analgesic medications can be used to reduce pain. These agents do not affect swelling or joint destruction.

Acetaminophen (Tylenol, Feverall, Tempra)

Used for analgesia in patients with documented hypersensitivity to aspirin or NSAIDs, with upper GI disease, or who are taking oral anticoagulants.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

325-650 mg PO q4-6h or 1000 mg tid/qid; not to exceed 4 g/d
Pediatric

<12 years: 10-15 mg/kg/dose PO q4-6h prn; not to exceed 2.6 g/d >12 years: 325-650 mg PO q4h; not to exceed 5 doses in 24 h

* Dosing
* Interactions
* Contraindications
* Precautions

Rifampin can reduce analgesic effects; coadministration with barbiturates, carbamazepine, hydantoins, and isoniazid may increase hepatotoxicity

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; known G-6-PD deficiency

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions

Hepatotoxicity possible in persons with chronic alcoholism following various dose levels; severe or recurrent pain or high or continued fever may indicate serious illness; contained in many OTC products, and combined use with these products may result in cumulative doses exceeding recommended maximum dose

Tramadol (Ultram)

Inhibits ascending pain pathways, altering perception of and response to pain. Also inhibits reuptake of norepinephrine and serotonin.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

50-100 mg PO q4-6h; not to exceed 400 mg/d
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Decreases carbamazepine effects significantly; cimetidine increases toxicity, risk of serotonin syndrome with coadministration of antidepressants

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; opioid-dependency; concurrent use of MAOIs or within 14 d; use of SSRIs, TCAs, or opioids or acute alcohol intoxication; history of seizures (it may lower seizure threshold)

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Can cause dizziness, nausea, constipation, sweating, or pruritus; additive sedation with alcohol and TCAs; abrupt discontinuation can precipitate opioid withdrawal symptoms; adjust dose in liver disease, myxedema, hypothyroidism, or hypoadrenalism; pregnancy and breastfeeding; seizure; development of tolerance or dependency with extended use
Immunomodulators

These agents interfere with cytokine actions responsible for inflammation.

Anakinra (Kineret)

Competitively and selectively inhibits IL-1 binding to type I receptor (IL-1RI). IL-1 is found in excess in patients with RA and is produced in response to inflammatory stimuli. By blocking IL-1 binding, inflammation and pain associated with RA are inhibited. Indicated for RA in patients in whom one or more DMARDs have failed. Should be administered at approximately the same time every day.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

100 mg/d SC
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

None reported; higher rate of serious infections and neutropenia possible when coadministered with TNF blocking agents (eg, etanercept, infliximab); may decrease response to live virus vaccines

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity to product or Escherichia coli –derived products; active infections

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions

Serious infections may occur (discontinue treatment if serious infection develops); neutropenia may occur (especially if administered concomitantly with TNF blocking agents); most common adverse effect is local reaction at site of injection; caution in breastfeeding

Abatacept (Orencia)

Selective costimulation modulator that inhibits T-cell activation by binding to CD80 and CD86, thereby blocking CD28 interaction. CD28 interaction provides a signal needed for full T-cell activation that is implicated in RA pathogenesis. Indicated for reducing signs and symptoms of RA, slowing progression of structural damage, and improving physical function in adults with moderate-to-severe RA who have inadequate response to DMARDs, methotrexate, or TNF antagonists. May be used as monotherapy or with DMARDs (other than TNF antagonists, because of increased risk of serious infections [4.4% vs 0.8%]). Not recommended for concomitant use with anakinra (insufficient experience).

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Dose according to body weight; after initial administration, repeat at 2 and 4 wk after first infusion, then q4wk; infuse over 30 min
<60 kg: 500 mg IV 60-100 kg: 750 mg IV >100 kg: 1 g IV
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

In clinical trials, coadministration with TNF antagonists resulted in increased risk of serious infections; do not administer concurrently with live virus vaccines (eg, MMR) or within 3 mo of discontinuation

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Discontinue if serious infection occurs; patients with COPD developed adverse effects more frequently, including COPD exacerbations, cough, rhonchi, and dyspnea; serious adverse reactions include serious infections (3% vs 1.9% placebo); malignancy frequency was similar to that of placebo (1.3% vs 1.1% placebo), with the exception of lung cancer (0.2% vs 0% placebo); common adverse effects include headache, upper respiratory tract infection, nasopharyngitis, and nausea

Tocilizumab (Actemra)

Interleukin 6 (IL-6) receptor inhibitor. IL-6 inhibition results in a decreased C-reactive protein level to within reference range, decreased values in other pharmacodynamic parameters (eg, rheumatoid factor, erythrocyte sedimentation rate, amyloid A), and increased hemoglobin value. Indicated for moderate-to-severe active RA in adults who have had an inadequate response to 1 or more TNF-antagonist therapies. May be used alone or in combination with methotrexate or other disease-modifying antirheumatic drugs.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

4 mg/kg IV q4wk initially; may increase to 8 mg/kg q4wk based on clinical response; not to exceed 800 mg/dose q4wk; administer IV infusion over 1 h (do not administer as bolus or push)
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Not studied with TNF antagonists; do not give live vaccines concurrently; inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those prior to therapy, leading to increased metabolism of drugs that are CYP450 substrates; affects multiple CYP450 enzymes, and resultant enzyme restoration may increase metabolism and decrease effectiveness of certain drugs (eg, oral contraceptives, lovastatin, simvastatin, atorvastatin, warfarin, cyclosporine, theophylline, omeprazole); effect may last for several weeks after stopping therapy

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Boxed warning
Serious infections can occur; if serious infection develops, discontinue until infection is controlled; monitor for tuberculosis before and throughout therapy

Precautions
Anaphylaxis or serious hypersensitivity has been reported; common adverse effects (ie, >5%) include upper respiratory tract infections, nasopharyngitis, headache, hypertension, and increased ALT level; do not use in the presence of any active infection (including localized); caution in GI perforation; monitor neutrophil, platelet, lipid, and liver function test values
Recommended not to initiate if absolute neutrophil count <2000/mm3, platelet count <100,000/mm3, or AST/ALT value >1.5 times the upper limit of normal
Glucocorticoids

These agents are potent anti-inflammatory drugs commonly used in patients with RA to bridge the time until DMARDs are effective. Doses of up to 10 mg/d of prednisone are typically used, but some patients may require higher doses. Adverse events associated with long-term steroid use make dose reductions and cessation important in due course.

Prednisone (Deltasone, Meticorten, Orasone)

Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

10-60 mg/d PO or divided bid/qid; generally, maintenance dose should be <10 mg/d; alternatively, may be given IM, IV, or intra-articularly
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI ulceration

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions

Hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, and infections may occur with glucocorticoid use; abrupt discontinuation may cause adrenal crisis

Methylprednisolone (Depo-Medrol, Medrol, Solu-Medrol)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

100 mg IV or equivalent
Pediatric

Not establishedFollow-up
Deterrence/Prevention

* Rheumatoid arthritis (RA) is a progressive inflammatory disease.
o The current approach to management of RA emphasizes aggressive control of inflammation to prevent long-term damage using early DMARD therapy, including the use of single or combination DMARDs.
o Early use of DMARDs had traditionally been avoided until patients show signs of joint damage; however, this strategy has proved ineffective over several years. Patients experience poor long-term outcomes, including severe functional declines, radiographic progression of disease, work disability, and premature mortality.
* Two issues appear to be sources of confusion regarding long-term outcomes of treatment.
o First, a small percentage of patients who meet diagnostic criteria for RA have a self-limited process with spontaneous remission. Thus, in the absence of signs of progression, some patients are diagnosed with, and subsequently treated for, other conditions.
o Second, measures of inflammatory activity, such as joint swelling or ESRs, are often used to assess inflammatory activity. However, these indices are less-useful endpoints for evaluation than severe long-term outcomes, such as work disability or joint deformity and radiographic changes (the latter two are irreversible). During a period in which inflammatory markers may be stable or even improved, radiographic progression and functional decline can occur.
* The older traditional DMARDs, injectable gold salts and penicillamine, rarely induce sustained remission and are usually discontinued within 2 years. Because better agents are available, they are rarely used.
* DMARDs, such as MTX and SSZ, have greater long-term effectiveness but still rarely induce true remission.
* Optimal control may require combination therapy. Recent studies have shown that MTX combined with other DMARDs is more effective and has acceptable toxicity compared with monotherapy. Although the combination is not commonly used, cyclosporine with MTX results in greater clinical improvement than MTX alone. Triple therapy with MTX, SSZ, and hydroxychloroquine may provide substantially greater clinical improvement than MTX alone or SSZ plus hydroxychloroquine.19 In combination with infliximab, MTX provides a superior response to monotherapy.20 In combination with etanercept, MTX provides a higher rate of meaningful clinical response. Toxicities of these drug combinations are rarely more significant than those occurring with any of the individual agents used alone.
* The goal of contemporary management of RA should be complete remission or no evidence of disease activity.
o Achieving this goal likely requires ongoing drug therapy, probably using a combination of MTX with some other DMARD, although some patients may still respond satisfactorily to monotherapy.
o More long-term studies are needed to evaluate potential important adverse effects associated with combination therapy before definite recommendations can be made.

Complications

* RA itself is not fatal, but complications of the disease may shorten survival by years in some individuals. In general, RA is progressive and cannot be cured; in some, the disease gradually becomes less aggressive and symptoms may even improve. However, if bone and ligament destruction and any deformities have occurred, the effects are permanent.
* Joint disability and pain with daily life are common. Affected joints can become deformed, and the performance of even ordinary tasks may be very difficult or impossible. According to one survey, 70% of patients with RA believe the disease prevents them from living a fully productive life. In 2000, a study in England found that approximately one third of individuals stop working within 5 years of the onset of disease.
* RA is a systemic disease that can affect other parts of the body in addition to joints. These effects include the following:
o Peripheral neuropathy: This condition affects nerves, most often those in the hands and feet. It can result in tingling, numbness, or burning.
o Anemia
o Scleritis: This is an inflammation of the blood vessels in the eye that can result in corneal damage, scleromalacia, and, in severe cases of nodular scleritis, perforation.
o Infections: Patients with RA have a higher risk for infections. The immunosuppressive drugs required for treatment further increase that risk.
o GI problems: Although patients with RA may experience stomach and intestinal distress, lower rates of stomach and colorectal cancers have been reported among patients with RA.
o Osteoporosis: Osteoporosis is more common than average in postmenopausal women with RA. The hip is particularly affected. The risk for osteoporosis also appears to be higher than average in men with RA who are older than 60 years.
o Lung disease: One small study found a very high prevalence of lung disease (pulmonary inflammation and fibrosis) in patients newly diagnosed with RA. However, the association between a history of smoking and a higher risk for RA may at least partially account for this finding. Cigarette smoking, in any case, may increase the severity of the disease.
o Heart disease: RA can affect the blood vessels and independently increases the risk for coronary ischemic heart disease.
o Sjögren syndrome: Keratoconjunctivitis sicca is a common complication of RA. Oral sicca and salivary gland enlargement are less common.
o Felty syndrome: This condition is characterized by the combination of splenomegaly, leukopenia (neutropenia), and recurrent bacterial infections. Felty syndrome sometimes responds to DMARD therapy.
o Lymphoma and other cancers: Alterations in the immune system associated with RA may play a role in the higher risk for lymphoma observed in patients with RA. Aggressive treatments for RA that suppress the immune system may help prevent this cancer, but more research is needed to evaluate this possibility. Other cancers that may occur with increased frequency in patients with RA include prostate and lung cancers.
o Macrophage activation syndrome: This is a life-threatening complication of RA and requires immediate treatment with high-dose steroids and cyclosporin A. Patients with RA should be aware of symptoms, which include persistent fever, weakness, drowsiness, and lethargy.

Prognosis

* The clinical course of RA is generally one of exacerbations and remissions. Approximately 40% of patients with RA become disabled after 10 years, but outcomes are highly variable.21 Some patients experience a relatively self-limited disease, and others have a chronic progressive illness.
* Improvements in the detection of early joint injury have provided a previously unappreciated view of the ubiquity and importance of early joint damage. Nonetheless, predicting the course of an individual case of RA at the outset remains difficult, although the HLA-DRB1*04/04 genotype, a high serum titer of autoantibodies (eg RF, anti-CCP), extra-articular manifestations, a large number of involved joints, age younger than 30 years, female sex, and systemic symptoms all correlate with an unfavorable prognosis in terms of joint damage and disability. Insidious onset is also an unfavorable sign.
* The absence of RF does not necessarily portend a good prognosis. Outcome is compromised when diagnosis and treatment are delayed. Other laboratory markers of a poor prognosis include early radiologic evidence of bony injury, persistent anemia of chronic disease, elevated levels of the C1q component of complement, and the presence of anti-CCP antibodies.
* RA that remains persistently active for more than one year is likely to lead to joint deformities and disability. Periods of activity lasting only weeks or a few months followed by spontaneous remission portend a better prognosis.
* The overall mortality rate in patients with RA is reportedly 2.5 times that of the general population. In those with severe articular and extra-articular disease, the mortality rate approaches that of patients with 3-vessel coronary disease or stage IV Hodgkin disease. Much of the excess mortality derives from infection, vasculitis, and poor nutrition. With the exception of lymphoma, mortality from cancer is unchanged.
* Most data on disability rates derive from specialty units caring for referred patients with severe disease. Little information is available on patients cared for in primary care community settings. Estimates suggest that more than half of these patients remain fully employed, even after 10-15 years of disease, with a third having only intermittent low-grade disease and another third experiencing spontaneous remission.
* A study of prognosis in patients with RA by Balsa et al (2010) found a decreased risk of severe disability in homozygous and heterozygous carriers of the 33T allele in the IL-4 gene; the model also included absence of anti-CCP antibodies and the single-nucleotide polymorphism rs2476601 on the PTPN22 gene. In contrast, homozygous and heterozygous carriers of the 1858T allele on the PTPN22 gene had a decreased probability of remission.22

Patient Education

Patient education and counseling are well worth the time invested because they help to reduce pain, disability, and frequency of physician visits. They represent the most cost-effective intervention for RA.

* Informing the patient of the diagnosis
o With a potentially disabling disease such as RA, the act of informing the patient of the diagnosis takes on major importance. The goal is to satisfy the patient's informational needs regarding the diagnosis, prognosis, and treatment in appropriate detail. Careful questioning and empathic listening are required to understand the patient's perspective, requests, and fears.
o Telling patients more than they are intellectually or psychologically prepared to handle (a common practice) risks making the experience so intense as to trigger withdrawal. Conversely, failing to address issues of importance to the patient compromises the development of trust. The patient needs to know that the primary physician understands the situation and is available for support, advice, and therapy as the need arises. Encouraging the patient to ask questions helps to communicate interest and caring.
* Discussing prognosis and treatment
o Patients and families do best when they know what to expect and can view the illness realistically. Uncertainty greatly contributes to the disease of RA. Many patients fear crippling consequences and dependency.
o The most common disease manifestations should be described. Without building false hopes, the physician can point out that spontaneous remissions can occur and that more than two thirds of patients live independently without major disability. In addition, emphasize that much can be done to minimize discomfort and to preserve function. A review of available therapies and their efficacy helps to overcome feelings of depression stemming from an erroneous expectation of inevitable disability.
o Even in patients with severe disease, guarded optimism is now appropriate, given the host of effective and well-tolerated disease-modifying treatments that are emerging.
o Abandonment is a major fear. Patients are relieved to know that they will be closely observed by the primary physician and health care team, working in conjunction with a consulting rheumatologist and physical/occupational therapist, all of whom are committed to maximizing the patient's comfort and independence and to preserving joint function.
* Dealing with misconceptions
o Several common misconceptions deserve attention. A substantial proportion of patients and their families feel that they have done something to cause the illness. Explaining that no known controllable precipitants exist helps to eliminate much unnecessary guilt and self-recrimination.
o Dealing in an informative, evidence-based fashion with a patient who expresses interest in alternative and complementary forms of therapy can help limit expenditures on ineffective treatments.
o Another misconception is that a medication must be expensive to be helpful. Generic NSAIDs, low-dose prednisone,23 and the first-line disease-modifying agents are quite inexpensive, yet remarkably effective for relieving symptoms, a point that bears emphasizing. The sense that one must be treated with the latest TNF inactivator can be addressed by a careful review of the overall treatment program and the proper role of such agents in the patient's plan of care.
o The active participation of the patient and family in the design and implementation of the therapeutic program helps to boost morale and to ensure compliance, as does explaining the rationale for the therapies used.
* Preserving a sense of self-worth
o A major goal is to preserve the patient's sense of worth and independence. However, when fatigue, morning stiffness, or specific joint disease interferes with a patient's capacity to carry out the usual responsibilities at work and at home, counseling will be necessary to recommend modification of work responsibilities and perhaps retraining. Recognition and treatment of concomitant depression is important.
o With the use of occupational therapy, the treatment effort is geared to helping the patient maintain a meaningful work role within the limitations of the illness.
o The family plays an important part in striking the proper balance between dependence and independence. Household members should avoid overprotecting the patient (eg, refraining from intercourse out of fear of hurting the patient) and should work to sustain the patient's pride and ability to contribute to the family. Allowing the patient with RA to struggle with a task is sometimes constructive.
o In a systematic literature review and meta-analysis, Baillet et al determined that cardiorespiratory aerobic exercise is safe for people with stable rheumatoid arthritis and may actually improve muscle strength.24
* Supporting the patient with debilitating disease
o Persons with long-standing severe disease who have already sustained much irreversible joint destruction benefit from an emphasis on comfort measures, supportive counseling, and attention to minimizing further debility. Such patients need help in grieving for their disfigurement and loss of function.
o An accepting, unhurried, empathic manner allows the patient to express feelings. The seemingly insignificant act of touching does much to restore a sense of self-acceptance. Attending to pain with increased social support, medication, and a refocusing of attention to function are useful. A trusting and strong patient-doctor relationship can do much to sustain a patient through times of discomfort and disability.
* For excellent patient education resources, visit eMedicine's Arthritis Center and Muscle Disorders Center. Also, see eMedicine's patient education articles Rheumatoid Arthritis, Juvenile Rheumatoid Arthritis, Understanding Rheumatoid Arthritis Medications, Chronic Fatigue Syndrome, and Chronic Pain.

Miscellaneous
Medicolegal Pitfalls

* Failure to properly monitor patients for adverse effects of DMARD therapy
* Failure to control overuse of corticosteroids, with resultant toxicity