ACR Issues Guidelines, Recommendations for Lupus Nephritis, RA

Three new consensus documents from the ACR address critical issues in patient care: management of lupus nephritis (LN); using disease-modifying antirheumatic drugs (DMARDs) and biologics in the treatment of rheumatoid arthritis (RA); and selecting RA disease activity measures for use in clinical practice. Development of these documents was based on systematic literature review and the input of expert panels that reached consensus on the best recommendations for clinical decision making.

The previous ACR guidelines for management of systemic lupus erythematosus (SLE) were issued in 1999 and did not solely focus on LN.¹ This year’s document, developed by a 15-member panel of experts from nephrology and rheumatology, is the first ACR guideline dedicated to LN and provides detailed recommendations for screening and treatment, including mycophenolate mofetil (MMF) therapy. The recommendations cover most of the histologic types of LN, according to Bevra Hahn, MD, professor of medicine and chief of rheumatology at the David Geffen School of Medicine at the University of California, Los Angeles. Dr. Hahn was chair of the guideline development committee and first author of the document.

An update of the ACR’s 2008 RA guidelines was needed, given the availability of new agents and new vaccines, according to Jasvinder Singh, MBBS, MPH, associate professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham, and first author of the document.² The new recommendations reflect the rapid pace of change within rheumatology, and they are designed to update guidance on indications for DMARDs and biologic agents, switching between DMARDs and biologic therapies, use of biologic agents in high-risk patients, and screening for tuberculosis for patients treated with biologics or DMARDs.

A third document, with recommendations for the RA disease activity measures most valid for use in clinical practice, is the first of its kind for the ACR. The goal of the working group was to determine which of the many available measures reliably distinguish between disease activity levels in RA and are feasible for clinical practice. From the 63 tools that were identified, the committee trimmed the list to six recommended measures that are sensitive to change; accurately reflect disease activity; discriminate well between low, moderate, and high disease activity states; and include remission criteria, according to Salahuddin Kazi, MD, chief health informatics officer at the Dallas VA Medical Center and a member of the development committee and senior author of the document.

Management of Lupus Nephritis

Many of the questions that practicing physicians may have about managing LN are addressed in the American College Of Rheumatology Guidelines for Screening, Treatment, and Management of Lupus Nephritis, Dr. Hahn says.³ The guidelines cover most of the histologic types of LN and are based on recent high-quality studies. “Where not based on high-quality studies, they are based on expert opinion as influenced by other studies,” she explains.

Dr. Hahn highlighted several key points in the new guidelines:

• All patients with clinical evidence of active LN should have a renal biopsy unless it is strongly contraindicated.
• Background therapies should be used in all patients with LN: hydroxychloroquine (HCQ); angiotensin inhibitors or angiotensin receptor blockers for patients with proteinuria greater than or equal to 0.5 g per 24 hours; and statin therapy for patients with LDL cholesterol higher than 100 mg/dL.
• Women contemplating pregnancy should receive counseling from their physicians about risk.
• Specific recommendations are given for dosing MMF in patients of different races.
• African Americans and Latinos are not as likely to respond to cyclophosphamide (CYC) as well as other races do, so MMF may be the first choice for therapy.
• Two different regimens of intravenous (IV) CYC therapy are recommended: low-dose “Euro-Lupus” CYC (500 mg IV once every two weeks for a total of six doses), followed by maintenance therapy with daily oral azathioprine or daily oral MMF; and high-dose CYC (500–1,000 mg/m2 IV once a month for six doses), followed by maintenance treatment with MMF or azathioprine. If CYC is being considered for treatment, the “Euro-Lupus” dose is recommended for white patients with Western European or Southern European racial/ethnic backgrounds.
• Recommendations are given for starting doses for glucocorticoids and the situations where pulse therapy is recommended.
• Guidance is provided for switching therapies in patients who do not respond to induction therapy, including the use of rituximab in some cases.
• Either azathioprine or MMF can be used as maintenance therapy for patients who have responded to initiation therapy.

The recommended therapies for patients with LN with cellular crescents or membranous LN may be surprising to some physicians, Dr. Hahn says. For patients with cellular crescents, the new guidelines recommend either CYC or MMF for induction therapy, along with IV pulses of high-dose glucocorticoids and initiation of oral glucocorticoids at the higher range dose. Patients with membranous LN can be started on prednisone plus MMF.

These guidelines are “more mycophenolate heavy than some of the textbooks, and less cyclophosphamide centric than earlier recommendations,” says Dr. Hahn, noting that neither drug has been approved by the Food and Drug Administration for treatment of LN. However, she believes the guidelines may go a long way in persuading reluctant payers to cover these drugs for patients with LN.

Also, the guidelines are “careful to say that nothing is contraindicated, because a physician providing direct care is in the best position to decide what therapies should be initiated, modified, or discontinued,” Dr. Hahn says.

Treatment of RA

The 2012 Update of the 2008 American College of Rheumatology Recommendations for the Use of Disease-Modifying Antirheumatic Drugs and Biologic Agents in the Treatment of Rheumatoid Arthritis recommends that targeting low disease activity or remission should be the goal of treatment for every patient with established RA or early RA, according to Dr. Singh.⁴

Two expert panels developed the recommendations. A nonvoting working group and core expert panel of clinicians and methodologists selected the topic areas, conducted the literature review, synthesized the evidence, and created clinical scenarios that represented the spectrum of care to be addressed by the guideline. A task force panel of 11 internationally recognized expert clinicians, patient representatives, and methodologists with expertise in RA treatment rated the scenarios and provided formal input about recommendations.

Most important in these recommendations is the specific guidance about when to start, resume, add, or switch DMARD therapy or biologic agents, and how to switch between various biologic agents, says Dr. Singh. The updated recommendations also provide guidance on using biologic agents when the patient has a diagnosis of hepatitis, malignancy, or congestive heart failure. Other key points included in the document:

• Tuberculosis (TB) screening to identify latent TB infection should be done in all patients with RA who are being considered for therapy with biologic agents, regardless of the presence of risk factors for latent TB.
• Specific recommendations for vaccinations, including the pneumococcal, influenza, hepatitis B, human papillomavirus, and herpes zoster vaccines, are given for patients starting or currently receiving DMARDs or biologic agents.
• New biologics launched since the 2008 recommendations—tocilizumab, certolizumab pegol, and golimumab—are included in the treatment algorithm.

More aggressive treatment is advised for patients with early RA in this document compared with the 2008 recommendations. This type of recommendation is given due to an expectation that earlier treatment can lead to better outcomes, that prevention of joint damage is an important goal, and that early intensive therapy can help preserve physical function and improve quality of life. Dr. Singh notes that the illustrative figures included in the 2012 recommendations can provide the practitioner with “more elaborative information than that achieved in the text itself,” with details given about treatment regimens and switching between therapies. We “provide guidance for practitioners who will still make individual decisions with their patients depending on their patients’ preferences and risk factors and other disease factors that may make them choose one medication over another,” he says.

Choosing Disease Activity Measures

Rheumatoid Arthritis Disease Activity Measures: American College of Rheumatology Recommendations for Use in Clinical Practice highlights six disease-activity measures that are feasible to perform in a clinical setting; give a real-time score rather than a relative change measure; have defined ranges for low, moderate, and high disease activity; and include remission criteria.⁵ This document “acknowledges that you should measure disease activity in a formal fashion rather than as a gestalt,” Dr. Kazi says.

Sixty-three disease-activity measurement tools were identified through a systematic review of the literature. Using exclusion criteria and comments from an expert advisory panel, that list was narrowed to 14 measures. After practicing rheumatologists rated nine of the 14 measures as useful and feasible, the working group identified six that had the best psychometric properties, including reliability, validity, and responsiveness. Those selected for the final list include the Clinical Disease Activity Index (CDAI), Disease Activity Score with 28-joint counts (DAS28), Patient Activity Scale (PAS), PAS-II, Routine Assessment of Patient Index Data with three measures (RAPID-3), and Simplified Disease Activity Index (SDAI).

Three of the six are patient-reported measures: PAS, PAS-II, and RAPID-3. The CDAI adds assessment by the physician, and SDAI and DAS28 include both physician assessment and laboratory values. Each of the six measures is also a composite measure, which can “reduce the risk that any one aspect of a patient’s disease drives the disease activity in one direction or another…to help prevent extreme results,” Dr. Kazi explains. The selection of six disease-activity measures should help “sort out the muddle that was out there with 63 possible tools,” he says. These six should also provide maximum flexibility to rheumatologists, with some measures completed by the patient in the waiting room, and others completed by both patient and physician.

“These measures are not perfect and are not a substitute for clinical judgment, but they can provide an additional tool to identify the patient’s current state of disease activity and provide a language that allows some consistency between physicians,” Dr. Kazi says. “We are doing our patients a favor by using a measure that is transportable from practice to practice.”

Other key points in the recommendations:

• Systematic use of these tools can help implement “treat-to-target” goals;
• Patient-reported measures take fewer than three minutes to complete and have simple mathematical scoring, but lack formal joint assessment;
• Patient-/provider-reported CDAI does not require an acute-phase reactant, but does require that providers conduct detailed joint counts consistently; and
• Both the SDAI and DAS28, conducted by the physician, include tender and swollen joints counts and an acute-phase reactant.

Dr. Kazi says physicians should find a disease activity measure “that works for your practice. Be consistent with it, and use it consistently and longitudinally with the same patient. We look at so many things to decide how a patient is doing, and this is one more tool that can help us take better care of patients.”

Kathy Holliman is a medical journalist based in New Jersey.

References

1. Guidelines for referral and management of systemic lupus erythematosus in adults. American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Arthritis Rheum. 1999;42:1785-1796.
2. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59:762-784.
3. Hahn BH, McMahon M, Wilkinson A, et al. American college of rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken). 2012;64:797-808.
4. Singh JA, Furst DE, Bharat A, et al. 2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64:625-639.
5. Anderson J, Caplan L, Yazdany J, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res (Hoboken). 2012;64:640-647.