Disease Activity Assessment

Multiple indices have been developed to measure disease activity in RA. Some specific indices, such as the Disease Activity Score 28 (DAS28) and the Simplified Disease Activity Index (SDAI), require laboratory testing in addition to physical examination, whereas the Clinical Disease Activity Index (CDAI), the Rheumatoid Arthritis Disease Activity Index (RADAI), the Patient Activity Scale (PAS), and the Routine Assessment Patient Index Data (RAPID) rely on a combination of patient- and physician-reported activity measures in addition to examination of the joints.¹ A recent report found that the patient-administered RADAI correlated well with the DAS28 in assessing disease activity in patients experiencing an RA flare.² The new ACR recommendations provide cut points for low, moderate, and high disease activity across the various instruments (Table 1).¹ No recommendations favoring any specific indices were made, but, in general, quantification of disease activity is necessary to make evidenced-based decisions about treatment.¹ According to Dr. Saag, not all rheumatologists are currently using a disease activity instrument, because of the time involved and other challenges such as additional laboratory testing required.¹ The ACR Task Force specifically chose not to recommend the use of any particular disease activity instruments, since certain measures work better than others in different clinical practice settings. New performance measures developed by the National Committee on Quality Assurance (NCQA) recommend that disease activity be assessed and classified every 12 months at minimum.¹ As Dr. Saag noted, assessing and classifying disease activity provides objective evidence that can be used to guide the appropriate initiation of specific therapies, particularly biologic therapies.

Table 1. Instruments and disease activity cut points for RA.¹

In addition to measures of disease activity, the recommendations cite various factors that have been determined to be prognostic in RA. These include active disease with high counts for tender and swollen joints, the presence of joint erosion, elevated levels of rheumatoid factor, the presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies, elevated erythrocyte sedimentation rate (ESR), elevated C-reactive protein (CRP) levels, worse physical functioning as indicated by scores on the Health Assessment Questionnaire, and the presence of the HLA-DRB1 genotype.¹ The presence of anti-CCP antibodies prior to and at the time of disease onset has been associated with a more aggressive form of RA; the presence of both anti-CCP antibodies and rheumatoid factor has predicted disease progression on radiographic examination when combined with swollen joint count and Larsen score.⁴ Levels of anti-CCP antibodies also correlate with therapeutic response; ie, antibody levels decrease in patients responding to treatment.⁴ Persistently elevated ESR (≥52 mm/hr) and CRP level (≥3 mg/dL) during treatment with methotrexate has been associated with greater progression on radiography.⁵ Patient health status, as indicated by scores on the Health Assessment Questionnaire in the first 3 months of the disease, has been identified as a strong predictor of patient outcomes 10 years later.⁶

Contraindications

Conditions considered to be therapeutic contraindications for using nonbiologic and biologic DMARDs were defined primarily on the basis of evidence from observational studies, and to a lesser extent on evidence from randomized clinical trials (Table 2).¹

Table 2. Recommendations for contraindications to nonbiologic and biologic DMARD in rheumatoid arthritis.¹ (Click image to view larger)

Infectious diseases and pneumonitis. Therapy with leflunomide, methotrexate, or biologic agents should not be initiated, nor should therapy with these agents be resumed, in patients with infectious diseases or pneumonitis. Such conditions include active bacterial infection or bacterial infection requiring antibiotic therapy, active tuberculosis or latent tuberculosis prior to preventive therapy, active herpes zoster infection, or active life-threatening fungal infections.¹ In general, patients with RA have an elevated risk for herpes zoster relative to the general population (3 cases per 1,000 person-years), but the level of risk is similar to that for people with depressed immunity from human immunodeficiency virus (HIV) infection, transplantation, cancer, or other immunosuppressive disorders and treatments (12–14 cases per 1,000 person-years).⁷ Use of oral corticosteroids and of biologic and traditional DMARDs is associated with a slight increase in the risk of herpes zoster (odds ratio [OR] = 1.54 for biologics and 1.37 for traditional DMARDs).⁸ In patients with severe upper respiratory tract infections (viral or bacterial) or nonhealed skin ulcers, use of biologic agents is contraindicated.¹ A recent meta-analysis of clinical trials in which RA patients were treated with anti-tumor necrosis factor (anti-TNF) antibodies found an elevated incidence of serious bacterial infections, ie, requiring antimicrobial therapy or hospitalization.⁹ Risk of serious infection was significantly increased with high doses of anti-TNF therapy (OR versus placebo = 2.3; 95% CI, 1.5–3.6) but only reached borderline significance for low doses (OR verus placebo = 1.8; 95% CI, 1.1–3.1).⁹ The Task Force Panel made no recommendations for or against using DMARDs in patients with HIV infection. Methotrexate was contraindicated in cases of RA-associated pneumonitis or interstitial lung disease of unknown cause.¹

Hematologic and oncologic conditions. For patients in whom lymphoproliferative disease or myelodysplasia has been diagnosed or treated within the previous 5 years, methotrexate, leflunomide, and anti-TNF agents are contraindicated.¹ The meta-analysis of anti-TNF trials noted above reported a significant dose-dependent effect for malignancy-related adverse effects with the use of these agents.⁹ In comparisons with placebo, the OR was higher for high-dose anti-TNF therapy (OR = 4.3; 95% CI, 1.6–11.8) than for low-dose anti-TNF therapy (OR = 1.4; 95% CI, 0.3–5.7).⁹ The ACR Task Force Panel did not endorse any specific recommendations regarding other malignancies and the use of biologic or nonbiologic DMARDs.¹ A recent study suggests that anti-TNF therapy does not increase the risk for nonhematologic or lymphoproliferative malignancies in RA patients.⁹ If white blood cell counts are <3,000/mm³, methotrexate and leflunomide are contraindicated, except in cases in which large granular lymphocyte syndrome accompanies RA.¹

Cardiac conditions. Cardiac contraindications for DMARDs are limited to patients who have moderate or severe heart failure (New York Heart Association class III or IV). Only anti-TNF therapies are specifically contraindicated in patients with moderate or severe heart failure; this recommendation is based on level B evidence from the Anti-TNF Therapy Against Congestive Heart Failure (ATTACH) and Randomized Etanercept Worldwide Evaluation (RENEWAL) trials, in which patients treated with high doses of anti-TNF therapy for moderate to severe chronic heart failure experienced a worsening in their clinical status.^10,11

Hepatitis. In patients with acute hepatitis B or C, treatment with methotrexate, leflunomide, sulfasalazine, minocycline, and biologic agents is contraindicated, because of the risk of increased activation of the virus as a result of immune suppression.^1,12 In patients with chronic liver disease (including hepatitis B and C) Child-Pugh score, which reflects the severity of liver impairment, is the key factor in clinical decision making.¹ Methotrexate and leflunomide are contraindicated for patients in all Child-Pugh classes.¹ Biologic therapy, minocycline, and sulfasalazine are contraindicated for Child-Pugh class B and C regardless of hepatitis treatment status.¹

Neurologic conditions. In patients with multiple sclerosis or demyelination disorders, anti-TNF agents are contraindicated, based on limited observations from randomized controlled trials.^1,13,14

Monitoring

Safety monitoring during the use of DMARDs for RA has three components: baseline laboratory testing, tuberculosis screening, and vaccination updates. For initiating or resuming treatment with biologic or nonbiologic DMARDs, measurement of complete blood count, liver transaminase levels, and serum creatinine levels, as well as screening for hepatitis B and C in high-risk patients, is recommended.¹

Tuberculosis screening is recommended for all patients who will be receiving biologic agents, regardless of risk factors. For patients with a history of relevant risk factors, a chest radiograph is also recommended. Conditions that are relevant risk factors for tuberculosis include HIV infection, silicosis, diabetes mellitus, a history of gastrectomy or jejunoileal bypass, and carcinoma of the head, neck, or lungs. Patients who have undergone organ transplantation or who have been treated with >5 mg/day of prednisone for >1 month or with other immunosuppressive drugs are also at risk. Individuals who are recent immigrants (<5 years) from countries of high tuberculosis prevalence are considered at risk, as are residents and employees of high-congregate settings such as jails, nursing homes, hospitals, other health care facilities, and homeless shelters. Other categories of high-risk individuals include mycobacetriology laboratory personnel and intravenous drug users.¹ Patients receiving biologic therapy should undergo annual vaccination for pneumonia and influenza, in accordance with guidelines from the Centers for Disease Control and Prevention, and should also receive the hepatitis B vaccination series. Use of live vaccines including varicella-zoster, oral polio, and rabies is contraindicated.¹

Use of Biologic Agents in RA

The ACR recommendations regarding the use of biologic DMARDs in RA were aggregated based on the duration of RA, ie, early disease (<6 months) versus later disease (>6 months), and disease activity, ie, low or moderate versus high activity. Most therapies are supported by level C evidence for use during early RA; Table 1 shows cut points for high and low disease activity as measured by other instruments. The presence of features of poor prognosis in early RA is also a key clinical decision-making factor. Features for poor prognosis include functional limitations as determined by the Health Assessment Questionnaire or other measurement; extra-articular disease (ie, rheumatoid nodules), secondary Sjögren’s syndrome, RA vasculitis, RA lung disease, or Felty’s syndrome. Bony erosions as demonstrated by radiography, and laboratory findings of positive rheumatoid factor and positive anti-CCP antibodies, are additional indicators of poor prognosis.

Early RA. In early RA characterized by low or moderate disease activity, nonbiologic DMARDs are recommended as first-line therapy. For patients who have had RA for <6 months and exhibit high disease activity of 3 to 6 months’ duration, biologic therapy with anti-TNF agents (interchangeably) and in combination with methotrexate is recommended.¹ In patients with disease duration of <6 months with features of poor prognosis, biologic therapy (anti-TNF agents) and combination therapy with methotrexate is recommended (Figure 1).¹ For patients who have cost or insurance limitations, nonbiologic DMARD regimens such as methotrexate combined with sulfasalazine, methotrexate alone, or methotrexate combined with hydroxychloroquine are recommended.¹ Methotrexate or leflunomide monotherapy and methotrexate plus hydroxychloroquine combination therapy are also recommended.¹ A baseline safety evaluation including a complete blood count, liver transaminase levels, and serum creatinine level, along with ongoing monitoring, is recommended. The intervals for follow-up monitoring vary according to the treatment.

Figure 1. Algorithm for using biologic therapy in patients with early RA (<6 months).¹

Later RA. Recommendations for the use of methotrexate and all biologic therapies in later disease are based on stronger evidence (level A) than for the early-disease recommendations.¹ In patients who have had RA for >6 months, biologic therapy is recommended under two scenarios: (1) lack of response to methotrexate monotherapy, with residual disease activity and features of poor prognosis; and (2) inadequate response to sequential stepped monotherapy with nonbiologic DMARDs, with partial disease activity, regardless of prognostic features (Figure 2).¹ For patients with later disease who do not respond to methotrexate therapy, anti-TNF monotherapy is recommended if disease activity is high and is accompanied by features of poor prognosis. Nonbiologic DMARDs are recommended for patients who do not respond to methotrexate therapy but exhibit low disease activity or moderate disease activity lacking features of poor prognosis.¹ For patients with later RA who had inadequate response to methotrexate or sequential monotherapy and still showed moderate or high disease activity, regardless of prognostic features, biologic therapy is recommended. Anti-TNF therapies are recommended for patients without features of poor prognosis, whereas anti-TNF agents, abatacept, or rituximab were recommended when features of poor prognosis are present.

Figure 2. Algorithm for using biologic DMARDs in patients with later RA (>6 months).¹

What Is Not Presented in the ACR Recommendations

Nonmedical therapies and anti-inflammatory pharmacologic interventions including glucocorticoids and nonsteroidal anti-inflammatory agents and other analgesics are not addressed in the new recommendations.¹ Likewise, biologic agents used infrequently (eg, anakinra) or DMARDs that are not recommended for patients who are to start or resume therapy (anakinra, azathioprine, cyclosporine, or organic gold) are excluded as well.¹ Switching to or adding alternative DMARDs in patients already receiving biologic and nonbiologic DMARDs is not addressed because of the absence of clinical data.¹ Clinical questions remain regarding differentiation between anti-TNF agents, as well as the optimal order for treatment sequencing in cases of ineffective response to anti-TNF agents.

Conclusions

The updated ACR recommendations for treating RA include, for the first time, the use of nonbiologic and biologic DMARDs. The recommendations address the use of measurement-based care, contraindications, safety monitoring, and the distinction between early and late disease as it relates to the appropriate treatment of RA. Rheumatologists have several options for measuring disease activity. The six scales in current use involve different methodologies, some requiring laboratory data (DAS and SDAI), and others based on patient report and examination (CDAI, RADAI, PAS, RAPID). The recommendations specify the cut points for high, moderate, and low disease activity for all six scales. Clinicians thus have versatile options at their disposal for measuring disease activity and can choose the instrument that best suits the needs of their practice. Documenting RA disease activity on an ongoing basis can be useful in navigating the increasingly stringent environment regarding insurance reimbursement for DMARD therapies.

Recommendations regarding contraindications for DMARDs exist for a few disease classes. Contraindications are indicated for active fungal and bacterial infections, acute herpes zoster infection, and active or latent tuberculosis; DMARD treatment can be reconsidered once the infection has fully resolved. DMARD contraindications are also recommended for patients with lymphoproliferative malignancies diagnosed within the preceding 5 years. No other malignancies are recommended as contraindications. Cardiac contraindication is limited to patients with class III or IV heart failure. DMARDs are contraindicated in active hepatitis B or C; for chronic hepatitis, Child-Pugh class dictates the use of DMARD therapy. Multiple sclerosis and demyelination disorders are contraindications for anti-TNF therapy.

Tuberculosis screening and follow-up screening in high-risk patients is recommended for patients treated with biologic therapies. Regular vaccination for pneumonia, influenza, and hepatitis B is recommended with the use of most DMARDs. In patients with early disease, anti-TNF therapy combined with methotrexate is recommended for patients with high disease activity and factors indicative of poor prognosis. In patients with later disease, biologic therapy is recommended for patients who have an inadequate response to methotrexate or sequential monotherapy with nonbiologic agents and in patients exhibiting moderate or high disease activity. The issue of switching biologic therapy remains unresolved. With the inclusion of biologic therapy in the updated 2008 ACR recommendations for the management of RA patients, the best practices relevant to the use of DMARDs are now more accurately reflected.

References

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