Selected Topics in Rheumatoid Arthritis
Emory University School of Medicine, Atlanta, GA, USA
Introduction
The field of rheumatoid arthritis (RA) continues to expand, especially with the establishment of updated classification criteria, application of more specific serologies in diagnosis, understanding of broader systemic issues related to the disease, and new medications able to offer additional treatment options for patients who fail standard therapy. These major developments are reviewed in this chapter.
2010 ACR/EULAR RA Classification Criteria
- In an effort to identify early stages of disease, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) collaborated and developed new classification criteria for RA
- These new 2010 criteria replace the previously developed 1987 American Rheumatism Association’s Criteria
- The 2010 ACR/EULAR criteria include joint involvement (both size and number of joints), the presence and titers of rheumatoid factor (RF) or anti-citrullinated antibodies (ACPAs), the presence of elevated acute phase reactants, and the duration of symptoms. Each of these criteria is given a score, with a total value of greater than or equal to 6/10 being required for the diagnosis of “definite RA”
- The criteria can be applied if the patient has at least one joint with synovitis, and the synovitis cannot be better explained by another disease
- Small joint involvement as well as >10 joints involved are scored higher, increasing the likelihood of RA, however, DIPs, first CMC, and first MTP joints are excluded from assessment
- Joint “involvement” is defined as either tenderness or swelling
- Duration of symptoms >6 weeks is scored higher, increasing the likelihood of RA
- Patients with a high suspicion for RA who do not score 6 or greater on initial assessment may also fulfill the criteria prospectively, highlighting the cumulative nature of joint manifestations in RA
- In keeping with the theme of identifying RA in the early stages, the 2010 Classification criteria do not include the 1987 criteria of morning stiffness, rheumatoid nodules, and radiographic changes
- By focusing on identifying RA in early stages, experts caution that the criteria are for classification, not diagnosis, may have low specificity in clinical practice, and may incorrectly label patients as having RA instead of another inflammatory arthritis
- The criteria can be applied if the patient has at least one joint with synovitis, and the synovitis cannot be better explained by another disease
Anti-Citrullinated Antibodies
What Are They?
- In order to fully understand the significance of anti-citrullinated antibodies (ACPAs), it is important to understand the process of citrullination
- Citrullination is facilitated by enzymes called peptidyl arginine deiminases (PADs), in an environment of high calcium concentrations; PADs are able to post-translationally modify arginines into citrullines
- During apoptosis, the process of citrullination is thought to assist in the breakdown of intracellular proteins
- Normally, the breakdown products are removed by cells involved in the clearance of apoptotic debris
- In situations where apoptotic cell clearance is impaired, extracellular proteins may be exposed to PADs, which can lead to further citrullination and potential antibody formation
- Normally, the breakdown products are removed by cells involved in the clearance of apoptotic debris
- ACPA formation requires more than the mere presence of citrullinated proteins
- Genetic factors (i.e. shared epitope) and environmental factors (smoking) can lead to the increased risk of developing ACPA
What Is the Role of ACPA in the Diagnosis of RA?
- ACPA formation may precede clinical disease by several years
- Studies have shown that the sensitivity of ACPA and rheumatoid factor (RF) are comparable, but the specificity of ACPAs is favorable when compared to RF in diagnosing RA
- Importantly, ACPA is not typically present in hepatitis C, while RF is frequently elevated in hepatitis C
- The presence of ACPA has been shown to signal a worse disease prognosis as evidenced by more severe joint destruction, and extra-articular manifestations of RA
Rheumatoid Arthritis and Cardiovascular Disease
- Patients with RA are at an increased risk for developing cardiovascular (CV) disease
- It has been reported that the risk of cardiovascular disease in RA patients appears to be similar to those without RA who are 10 years older
- This increased risk appears to be independent of the traditional risk factors for CV disease
- Several studies have shown that when the traditional CV risk factors have been adjusted for, increased systemic inflammation and disease activity/severity correlate with increased risk of cardiovascular events
- It is important to look at some of the traditional risk factors of CV disease and see how they relate to patients with RA
- Hypertension
- Studies have shown that hypertension is common in RA, but the prevalence does not seem to be greater when compared to control groups without RA
- Certain medications (e.g. NSAIDs), obesity, and inactivity of patients secondary to joint damage or active disease are some of the factors that may provide challenges to appropriately treating hypertension in patients with RA
- Studies have shown that hypertension is common in RA, but the prevalence does not seem to be greater when compared to control groups without RA
- Dyslipidemia
- Multiple studies have shown that when compared to the general population, patients with RA may have lower levels of total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL).
- In fact, Myasoedova et al. demonstrated that total cholesterol and LDH levels significantly decreased in the 5 years prior to the diagnosis of RA
- Multiple studies have shown that when compared to the general population, patients with RA may have lower levels of total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL).
- Diabetes mellitus (DM) and metabolic syndrome
- In a 2011 meta-analysis, Boyer et al. found that there was an increased prevalence of DM in patients with RA when compared to controls
- Multiple studies have shown an increased prevalence of the metabolic syndrome in patients with RA
- In a 2011 meta-analysis, Boyer et al. found that there was an increased prevalence of DM in patients with RA when compared to controls
- It is important to look at some of the traditional risk factors of CV disease and see how they relate to patients with RA
Treatment Advances in Rheumatoid Arthritis
Anakinra – Approved 2001
- Anakinra is an IL-1 receptor antagonist that blocks the proinflammatory activity of IL-1 by competing for its binding sites
- By blocking the effects of IL-1, anakinra reduces B and T cell activation, cytokine production, synovial proliferation, and cartilage and bone destruction typically mediated by IL-1
- Anakinra is administered subcutaneously once daily, and has been shown to have moderate efficacy in RA when compered to placebo; it has also been shown to inhibit radiographic progression
- Experts do point out that while studies show that patients do improve on anakinra, those improvements are modest compared to other biologics: ACR20 response rates in the five original randomized–control trials ranged from 38–42%
- Based on these studies, anakinra is approved for use in RA patients who have had inadequate response to conventional disease-modifying treatment
- Safety issues
- Importantly, there was no increase in infection risk associated with anakinra
- The most common adverse events were mild injection site reactions, including erythema, rash, and itching
- Lack of widespread use has been largely due to the prevalence of injection site reactions and the requirement for daily injections
- Importantly, there was no increase in infection risk associated with anakinra
Abatacept – Approved 2006
- Abatacept is a fusion protein comprised of the Fc portion of human IgG and the extracellular domain of CTLA-4
- Abatacept binds the B7 protein on antigen-presenting cells with high affinity, and thereby blocks the CD28:B7 costimulatory binding signal required for full T cell activation
- Abatacept is administered intravenously every 4 weeks, and has been shown to be superior to methotrexate alone after 12 months of treatment; studies in patients with inadequate response to anti-TNFs showed similar improvement after treatment with abatacept
- Based on these studies, it is approved for use in RA patients who have had inadequate response to methotrexate or anti-TNFs
- Safety issues
- Increased risk of serious infections, though no opportunistic infections have been reported in studies to date; routine screening for latent TB infection prior to treatment start is recommended
- Increased exacerbations and infections in patients with chronic obstructive pulmonary disease (COPD)
- Increased risk of serious infections, though no opportunistic infections have been reported in studies to date; routine screening for latent TB infection prior to treatment start is recommended
- Recently, a self-administered weekly subcutaneous formulation of abatacept has been approved, with similar efficacy and toxicity profile to the intravenous formulation
Rituximab – Approved 2006
- Rituximab is a monoclonal antibody directed against CD20 proteins expressed on the surface of B cells
- Rituximab depletes B cells that express CD20 from the peripheral blood, thereby reducing autoantibody and immune complex production as well as T cell stimulation and cytokine production involved in inflammation from RA
- Rituximab is administered intravenously on days 1 and 15, with retreatment after 6 months or longer
- Specific recommendations on the interval of retreatment have not yet been established
- Studies show rituximab and rituximab plus methotrexate to be superior to methotrexate alone in patients with inadequate response to methotrexate; similar results were reported in patients with inadequate response to anti-TNFs
- Clinical responses were of longer duration when rituximab is used in combination with methotrexate
- Based on these studies, rituximab is approved for use in patients with inadequate response to anti-TNFs
- At this point, there is no established protocol for checking peripheral B cell counts (CD19 cells) or immunoglobulin levels before or after rituximab treatment, to determine response to therapy or time to retreatment
- Early data suggest that complete B cell depletion correlates with increased response to the drug, so monitoring may have utility in this regard
- Safety issues
- Slight increased risk of serious infections, though no opportunistic infections have been reported in studies to date; routine screening for latent TB infection prior to treatment start is not required
- Infusion reactions are common and typically improve with subsequent infusions; acetaminophen, diphenhydramine, and pretreatment corticosteroids can be helpful
- Fatal infusion reactions have been reported in four patients receiving rituximab for RA
- Case reports in patients with lymphoma, lupus, or RA treated with rituximab suggest a small but increased risk of progressive multifocal leukoencephalopathy (PML), however the long-term overall risk of PML in patients receiving rituximab for RA or other rheumatic diseases is unknown
- Slight increased risk of serious infections, though no opportunistic infections have been reported in studies to date; routine screening for latent TB infection prior to treatment start is not required
Tocilizumab – Approved 2010
- Tocilizumab is a monoclonal antibody directed against the IL-6 receptor
- Tocilizumab blocks the proinflammatory functions of IL-6, including the stimulation of T and B cells and macrophages to promote the transition from acute to chronic inflammation
- Tocilizumab is administered intravenously every 4 weeks, and has been shown to be superior to methotrexate in studies of methotrexate-naïve patients; it has also been shown to be superior in inadequate responders to methotrexate or anti-TNFs
- Based on these studies, it is approved for use either in combination with methotrexate, or as monotherapy, for patients who have had inadequate response to anti-TNFs
- Safety issues
- Like other biologics, tocilizumab carries an increased risk of serious bacterial, invasive fungal, mycobacterial, and opportunistic infections; all patients should be screened for latent TB prior to starting the medication
- Neutropenia, thrombocytopenia, and liver enzyme elevation have been reported; dose reduction is recommended in these situations
- Increased incidence of gastrointestinal (GI) perforations were noted in patients receiving tocilizumab, typically colonic perforations in the setting of known diverticulitis, though upper GI perforation did occur in two patients
- Lipid profile abnormalities were noted including elevated total cholesterol, LDL, HDL, and triglycerides; routine lipid monitoring is recommended while on tocilizumab though guidelines for initiation of lipid-lowering medications in this setting have not been established
- Tocilizumab has not been studied and is not recommended for patients with hepatitis B or hepatitis C infection, patients with creatinine clearance <50 mL/min, or patients with transaminases >1.5× upper limit of normal
- Like other biologics, tocilizumab carries an increased risk of serious bacterial, invasive fungal, mycobacterial, and opportunistic infections; all patients should be screened for latent TB prior to starting the medication
Appropriate Immunizations and Screening in RA Patients
Tuberculosis Screening
- Screen to identify LTBI (latent TB infection) in all RA patients being considered for use of a biologic agent, regardless of the presence or absence of risk factors
- Risk factors for TB (CDC guidelines)
- Close contacts of persons known or suspected to have active TB
- Foreign-born persons from areas that have high incidence of active TB (Africa, Asia, eastern Europe, Latin America, Russia)
- Persons who visit areas with high prevalence of active TB, especially if for frequent or prolonged visits
- Residents and employees of congregate settings whose clients are at an increased risk for active TB (correctional facilities, long-term care facilities, homeless shelters)
- Healthcare workers who serve clients who are at an increased risk for active TB
- Populations defined locally as having increased incidence of LTBI or active TB (possibly including medically underserved, low-income populations or persons who abuse drugs/alcohol)
- Infants, children, and adolescents exposed to adults who are at an increased risk of LTBI or active TB
- Close contacts of persons known or suspected to have active TB
- Options for screening for LTBI
- Tuberculin skin test (TST)
- Interferon-gamma-release assays (IGRAs) – preferred if there is a history of BCG vaccination
- If TST or IGRA is positive or if clinically indicated for another reason, obtain chest x-ray
- If chest x-ray is positive, obtain sputum for AFB (acid-fast bacilli) to rule out active TB (may require specialist referral)
- For LTBI or active TB, refer to an infectious diseases specialist or the Health Department for treatment
- If TST or IGRA is positive or if clinically indicated for another reason, obtain chest x-ray
- Tuberculin skin test (TST)
- Timing of biologics when TB is present
- LTBI: complete treatment for LTBI for 1 month prior to staring biologic therapy
- Active TB: complete treatment for active TB prior to starting biologic therapy
- LTBI: complete treatment for LTBI for 1 month prior to staring biologic therapy
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