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Rheumatoid arthritis, systemic

Description

Rheumatoid arthritis (RA) is an autoimmune disease and chronic inflammatory disorder predominantly affecting synovial joints. It is characterized by symmetric joint involvement, with swelling and tenderness along with systemic inflammation. Untreated RA can lead to destruction of cartilage and bone, causing deformities, significant disability, and premature mortality.

Clinical manifestations

Clinical presentation of RA can be variable, ranging from mild, intermittent symptoms to progressive, polyarticular arthritis with evidence of systemic inflammation. Typical presentation includes symmetrical small joint involvement with pain and swelling for more than 6 weeks. Rheumatoid arthritis characteristically affects the wrists, metacarpophalangeal joints, and proximal interphalangeal joints; other joints commonly involved include the knees, elbows, ankles, and metatarsophalangeal joints. Axial joint involvement, such as the cervical spine and the acromioclavicular, sternoclavicular, and costochondral joints, is less common but may be seen in 20%-50% of patients.

Typical RA symptoms are  pain and swelling in the joints, sometimes associated with warmth over the joint (“hot joint”) along with stiffness. The pain is inflammatory in nature, worse with inactivity and better with movement, as opposed to mechanical pain, which is worse with activity. Stiffness is a common feature of RA and may be especially prominent in the mornings, usually lasting more than an hour.

Patients may also present with intermittent symptoms, with periods of remission between episodes. One or several joints may be involved in a sequential manner, with episodes lasting up to several days with spontaneous resolution. Symptom-free periods may last from days to months with eventual recurrence of symptoms. This pattern is known as “palindromic rheumatism” and may be difficult to diagnose early in its course. Depending on the study, 15%-50% of patients with palindromic rheumatism will go on to develop classic RA.1 Less commonly, patients may present with monoarticular involvement, usually in the knee, hip, ankle, or wrist.

Examination of an inflamed joint shows tenderness and swelling from a joint effusion or synovial thickening. Synovial inflammation may also involve tendon sheaths, leading to tenosynovitis and/ or trigger finger. Over time, untreated disease with chronic inflammation leads to joint destruction and deformities. Initially a decrease in the range of motion may be seen, followed by contractures and deformities such as swan neck or Boutonniere’s deformities in the fingers, ulnar deviation, wrist subluxation, and flexion contractures of the elbows. Elbows are the most common site for development of subcutaneous rheumatoid nodules. Soft tissue involvement may be seen with rotator cuff syndrome and bursitis in the hip or knee. Hip pain may be noted in the groin (true hip involvement) or laterally (trochanteric bursitis). Chronic neck pain with subluxation at atlanto-axial joint and restricted range of motion may develop with long standing disease.

Extra-articular involvement consists of systemic features as well as organ involvement. Patients often complain of fatigue, generalized aching, loss of appetite and weight loss. Organ involvement may include subcutaneous nodules, pleuropericarditis, scleritis, episcleritis, neuropathy, rheumatoid lung disease, and vasculitis. This is usually seen in conjunction with articular symptoms or in patients with long-standing, uncontrolled disease. Secondary autoimmune conditions such as Sjogren’s syndrome may also be seen in patients with long-standing disease.

Criteria and indices

In 2010, new classification criteria for early diagnosis of RA were introduced jointly by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR).2 The old ACR criteria of 1987 included subjective elements, such as pain and stiffness, and and objective findings, such as erosions and rheumatoid factor (RF), and were criticized for their lack of sensitivity. The new criteria establish a point value between 0 and 10, with a score of 6 or higher establishing the diagnosis of RA, provided synovitis is noted in at least one joint. These criteria look at the extent and pattern of joint involvement, presence and titers of RF and cyclic citrullinated peptide (CCP) antibodies, acute phase reactants such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and duration of symptoms.

Disease activity can be measured by various tools, including objective measures such as tender and swollen joint counts, subjective measures such as visual analogue scale and health assessment questionnaires, and disease indices such as the disease activity score (DAS)/DAS 28 and the simplified disease activity index (SDAI). Indices have the advantage of combining variables (joint counts with ESR) and decreasing variability; they are very predictive of disease activity at later points. Responses may also be measured as percent improvement as ACR20/50/70m corresponding to 20%/50%/70% improvement, respectively. Lastly, markers of inflammation (ESR, CRP) and radiographic progression are helpful in monitoring disease progression and response to therapy.

Red flags

Rheumatoid arthritis should be suspected in patients with persistent joint inflammation involving the characteristic small joints of the hands with or without evidence of systemic inflammation. Patients may respond partially to anti-inflammatory medications with recurrence or progressive worsening of symptoms.  However, nonsteroidal anti-inflammatory drugs are not appropriate as the sole medications used to treat this immune system disease.  Rapid and permanent destructive changes can occur in the joints if immunosuppressive therapy is not initiated.  Patients wtih subcutaneous nodules, pleuropericarditis, or other organ involvement along with arthritis have a worse prognosis.  All patients with rheumatoid arthritis need to be managed by a rheumatologist.

Epidemiology

Rheumatoid arthritis is the most common inflammatory arthritis and the second most common form of chronic arthritis. It affects about 1% of the population worldwide and is 3 times more common in women than men. It may occur at any age but is most common between 40-70 years of age, with prevalence rising with age.3 Geographic distribution of RA varies worldwide, with the disease being more common in North American and northern Europe as compared parts of Asia, and notably low in rural Africa. Some Native American populations have a significantly higher prevalence of more than 5%.4 These variations are suggestive of different genetic risks and environmental exposures.

Pathology and pathophysiology

The synovium is the primary site of inflammation in RA. Endothelial damage and blood vessel proliferation leads to hyperplasia of the synovial intimal lining. Proliferation of synoviocytes along with an influx of inflammatory cells (T cells, B cells, neutrophils) leads to synovitis and an increase in the amount of synovial fluid in the joint. Synovial macrophages and fibroblasts produce an overabundance of pro-inflammatory cytokines, significant ones being the interleukin (IL) family and tumor necrosis factor (TNF)-alpha. TNF-alpha further releases other cytokines and metalloproteases, which in turn can lead to synovial proliferation and joint erosions. Interleukins (IL-1, IL-6, IL-18) induce production of interferon-gamma, TNF-alpha, and proteases, as well as recruit additional inflammatory cells to the joint.5-8

Hyperplasia of synoviocytes and fibroblasts leads to synovial proliferation and formation of pannus. Pannus is the invasive region of the synovium that destroys cartilage and erodes bone. Leakage from synovial cells leads to increased formation of synovial fluid causing effusions. Further damage to bone and cartilage is brought about by release of destructive enzymes such as proteases, metalloproteinases, and cathepsins. Receptor activation of RANK ligand leads to osteoclast activation and further bone resorption. This eventually leads to cartilage destruction and bone erosions causing joint pain and deformity.

Differential diagnosis

Several forms of inflammatory arthritis can mimic RA, especially early in its course.

  • Acute viral syndromes such as parvovirus, Epstein-Barr virus (EBV), rubella, and hepatitis C can lead to polyarthritis similar to RA. These are usually self-limited and resolve within 2-4 weeks.
  • Psoriatic arthritis, reactive arthritis and other seronegative arthritides can be ruled out with clues such as rash, genitourinary and gastrointestinal infection preceding joint symptoms, enthesopathies, and dactylitis less common in RA.
  • Other connective tissue diseases such as systemic lupus erythematosus, sarcoidosis, Sjogren’s syndrome and scleroderma can cause polyarthritis but are usually associated with other characteristic symptoms such as Raynaud’s syndrome, skin tightening, and rash. The absence of anti-CCP antibodies and presence of antinuclear and other specific antibodies help differentiate these disorders.
  • Chronic tophaceous gout as well as severe osteoarthritis with hand deformities from bony proliferation may mimic RA. Osteoarthritis typically involves the distal interphalangeal joints, which are typically spared in RA.
  • Paraneoplastic syndromes may present with musculoskeletal involvement and are an important diagnostic consideration, especially in older patients, and should be considered in patients with aggressive, atypical or resistant disease.

Etiology and risk factors

Several etiologic factors have been proposed as risks for development of RA including genetic factors, hormonal factors and environmental exposures. Genetic makeup plays a critical role in susceptibility to RA and may be responsible for up to 50% of the risk of developing RA.9 Monozygotic twins show a significantly higher concordance for the disease as compared to dizygotic twins (12-15% vs 3.5%, respectively).3,10 First-degree relatives of patients with RA have a 2-fold higher incidence of RA as compared to the general population. The strongest genetic link has been demonstrated with a unique peptide on the class II major histocompatibility complex (MHC). This amino acid sequence maps in the third hypervariability region of DR beta chains and contains amino acids 70 to 74. This “shared epitope” is over-represented in patients with RA and is associated with increased severity of RA.7,8,11 MHC has also been associated with production of antibodies against CCP.12 Several other genes are thought to contribute to increased risk of RA including immunoglobulin genotypes and cytokine polymorphisms.13

Rheumatoid factors, the classic autoantibodies in RA, are immunoglobulins with antibody specificity for the Fc region of IgG. Rheumatoid factors are not specific for RA; they are also produced in other autoimmune syndromes, chronic infections and malignancy. They may be present in 1%-4% of healthy individuals and up to 25% of people over the age of 65 years.14 Anti-CCP antibodies are more sensitive and specific in patients with RA. The process of citrullination involves the conversion of arginine to citrulline by peptidylarginine deiminases (PADIs). In RA, isoforms PADI2 and PADI4 are over-expressed in inflamed synovium, resulting in increased antibody production by resident B cells.15 The presence and higher titers of anti-CCP antibodies correlates with more aggressive disease.

Non-genetic risks include hormonal factors like estrogen and progesterone through an effect on humoral and cell mediated immunity. Seventy-five percent of pregnant women with RA experience spontaneous remission, but often with disease flare within weeks post-delivery. Exposure to cigarette smoke has been correlated with higher risk of RA and development of anti-CCP antibodies with more aggressive disease.16 Infectious agents have also been implicated, including viruses such as EBV, parvovirus B19, and retroviruses. The proposed mechanism is through molecular mimicry and stimulation of innate immune system.7,8

Radiographic and laboratory findings

Laboratory tests constitute an important part of the initial workup and should include routine tests such as complete blood count with differential and comprehensive metabolic panel along with inflammatory markers such as ESR and CRP. Normocytic anemia may be seen as a result of chronic inflammation. Leucopenia should raise the suspicion of Felty’s syndrome (neutropenia and splenomegaly). Low albumin and high gamma globulin are suggestive of chronic inflammation. Elevated ESR and CRP are suggestive of active inflammation and may be followed as response to treatment along with clinical assessment.

Rheumatoid factors may be detected in up to 90% of patients with RA, although they may be seen in several other conditions as noted above. Anti-CCP antibodies are more sensitive (80%-90%) and specific (90%) for RA, and their presence is very suggestive of RA.17 Rheumatoid factors and anti-CCP antibodies may be detectable for up to 10 years prior to the onset of the disease. A small portion of patients with RA will remain seronegative, and the absence of RF and anti-CCP does not completely rule out an RA diagnosis. Antinuclear antibodies may be seen in 20%-30% of patients with RA, usually associated with high RF titers.10 Synovial fluid analysis, although not specific, can also be helpful. A synovial fluid white cell count of > 2,000 cells/mm3 is typically noted, indicative of an inflammatory process. Gram stain and culture help rule out infectious etiologies.

Radiographs may be normal in the initial stages of the disease, with the earliest changes being peri-articular osteopenia and soft tissue swelling. With disease progression, symmetric loss of joint space and peri-articular erosions may be noted, along with subluxation and deformities. Ultrasound and magnetic resonance imaging (MRI) are more sensitive for detecting early disease, including soft tissue inflammation, such as tenosynovitis, synovial effusion, and hypertrophy, as well as other signs of inflammation including bone marrow edema and early erosions.

Treatment options

The goal in treating RA is to achieve and maintain disease remission with early diagnosis and aggressive treatment, a “step-down” approach. The different classes of medications include non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, disease-modifying anti-rheumatic drugs (DMARDs), and biologic therapies. NSAIDs (naproxen, celecoxib, ibuprofen) are not sufficient therapy alone and are used as co-therapies for analgesia. Corticosteroids are used as “bridge” therapy due to their fast action and potent anti-inflammatory effects. They are often the initial medication prescribed, and are also effective in disease flares. Long-term use is limited due to significant toxicity, including risk of infections and bone loss.

Disease-modifying anti-rheumatic drugs are oral agents and are considered the first line of therapy in RA. Methotrexate is the mainstay of therapy for most patients. It inhibits the enzyme dihydrofolate reductase, necessary for DNA synthesis, and is efficacious due to an anti-inflammatory effect by its actions on several cytokines. Leflunomide is an alternative oral agent that inhibits the enzyme dihydroorotate dehydrogenase involved in pyrimidine synthesis. Both medications have been shown to prevent disease progression and structural joint damage as noted on clinical as well as radiographic assessment. Hydroxychloroquine and sulfasalazine are used in milder forms of RA or in combination with other DMARDs.

The advent of biologic agents has dramatically changed the course of RA due to their significant benefit on symptoms as well as substantial ability to retard radiographic progression. The first of this class to be approved were anti-TNF agents, which target TNF, an important pro-inflammatory cytokine. Etanercept is a TNF receptor fusion protein whereas infliximab, adalimumab, certolizumab, and golimumab are monoclonal antibodies against TNF. These medications are administered subcutaneously with the exception of infliximab, which is given by intravenous infusion.

Abatacept is CTLA-4 recombinant fusion protein that prevents co-stimulation from T cells. It is used in patients considered TNF failures, and it is shown to improve symptoms of RA as well as prevent radiographic progression. Anakinra is a recombinant anti-IL-1 receptor antagonist with modest effect in RA. Rituximab is an anti-CD20 monoclonal antibody that depletes B cells and is often used in refractory RA.  Tocilizumab, a monoclonal antibody against IL-6 receptor, is the most recent addition to the list of biologic agents for RA. Though very effective, the newer biologic agents may be associated with significant potential toxicity, including increased risk for serious infections, reactivation of latent tuberculosis, certain malignancies, and precipitation of other autoimmune conditions.

Outcomes

Rheumatoid arthritis is a chronic medical condition and requires lifelong treatment. Untreated or under-treated RA results in progressive joint damage. Chronic pain due to ongoing inflammation can significantly affect productivity and quality of life. Significant hand deformities and joint contractures can render a patient incapable of performing activities of daily living. Patients with untreated disease are also more likely to develop systemic symptoms and organ involvement including weight loss, pulmonary disease, neuropathy, and vasculitis. Patients with RA and chronic pain are noted to have higher rates of depression. Osteoporosis and cardiovascular (CV) disease are common co-morbidities, with CV disease being the most common cause of death in patients with RA. Lastly, patients with RA have a higher risk of malignancy, especially lymphoma.

Holistic medicine

Non-pharmacologic measures form an important aspect of treatment of RA. Exercise is essential in maintaining joint mobility and muscle strength as well as management of fatigue. Weight loss decreases joint load in overweight patients and improves pain. Yoga, tai chi, and relaxation techniques may reduce pain. Alternative medicine, such as Ayurvedic therapy or acupuncture, and natural supplements, such as plant or fish oil,s have been suggested but there are inadequate data supporting their efficacy. Treatment of depression is important in the overall well-being of a patient with RA.

Miscellany

  • Rheumatoid arthritis is an autoimmune inflammatory polyarthritis usually with insidious presentation. Early diagnosis is key, with due attention to rule out similar presentations of other conditions.
  • Although primarily a joint disease, extra-articular manifestations may be seen and indicate active disease.
  • Although the exact cause is unknown, several inflammatory pathways have been identified with further research specifically targeting the involved cytokines.
  • Management of comorbidities (depression, osteoporosis, CV disease) plays an important role in disease outcomes.

Key terms

  • Inflammatory arthritis
  • Inflammation
  • Synovium
  • Rheumatoid factor
  • Disease-modifying anti-rheumatic drugs
  • Biologic antirheumatic agents

Skills and competencies

  • Examination of a joint with recognition of effusions and synovitis
  • Recognition of soft tissue involvement such as tenosynovitis, bursitis
  • Awareness and recognition of systemic signs such as scleritis, pleuritis, rashes

References

  1. Koskinen E, Hannonen P, Sokka T. Palindromic rheumatism: longterm outcomes of 60 patients diagnosed in 1967-84. J Rheumatol 2009; Sep;36(9):1873-5.
  2. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO,3rd, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; Sep;62(9):2569-81.
  3. Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet 2001; Sep 15;358(9285):903-11.
  4. Costenbader KH, Chang SC, Laden F, Puett R, Karlson EW. Geographic variation in rheumatoid arthritis incidence among women in the United States. Arch Intern Med 2008; Aug 11;168(15):1664-70.
  5. Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet 2010; Sep 25;376(9746):1094-108.
  6. Feldmann M, Brennan FM, Maini RN. Rheumatoid arthritis. Cell 1996; May 3;85(3):307-10.
  7. Rheumatoid Arthritis in ACP Medicine. Available at: http://www.acpmedicine.com/acp/chapters/ch1502.htm#. Accessed 04/10, 2012.
  8. Waldburger J, Firestein G. Rheumatoid Arthritis. ; 2008. p. 122,123-132.
  9. van der Woude D, Houwing-Duistermaat JJ, Toes RE, Huizinga TW, Thomson W, Worthington J, et al. Quantitative heritability of anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis. Arthritis Rheum 2009; Apr;60(4):916-23.
  10. tehlirian C, Bathon J. Rheumatoid Arthritis Clinical and Laboratory Manifestations. Primer on the Rheumatic Diseases; 2008. p. 114,114-121.
  11. Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 1987; Nov;30(11):1205-13.
  12. van der Helm-van Mil AH, Verpoort KN, Breedveld FC, Huizinga TW, Toes RE, de Vries RR. The HLA-DRB1 shared epitope alleles are primarily a risk factor for anti-cyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis. Arthritis Rheum 2006; Apr;54(4):1117-21.
  13. Cvetkovic JT, Wallberg-Jonsson S, Stegmayr B, Rantapaa-Dahlqvist S, Lefvert AK. Susceptibility for and clinical manifestations of rheumatoid arthritis are associated with polymorphisms of the TNF-alpha, IL-1beta, and IL-1Ra genes. J Rheumatol 2002; Feb;29(2):212-9.
  14. Dorner T, Egerer K, Feist E, Burmester GR. Rheumatoid factor revisited. Curr Opin Rheumatol 2004; May;16(3):246-53.
  15. Vossenaar ER, Nijenhuis S, Helsen MM, van der Heijden A, Senshu T, van den Berg WB, et al. Citrullination of synovial proteins in murine models of rheumatoid arthritis. Arthritis Rheum 2003; Sep;48(9):2489-500.
  16. Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 2006; Jan;54(1):38-46.
  17. Schellekens GA, Visser H, de Jong BA, van den Hoogen FH, Hazes JM, Breedveld FC, et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 2000; Jan;43(1):155-63.
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