Kenneth G. Saag

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

The American College of Rheumatology (ACR) most recently published recommendations for use of disease modifying anti-rheumatic drugs (DMARDs) and biologics in the treatment of rheumatoid arthritis (RA) in 2008 (1). These recommendations covered indications for use, monitoring of side-effects, assessment of the clinical response to DMARDs and biologics, screening for tuberculosis (TB), and assessment of the roles of cost and patient preference in decision-making for biologic agents (1). Recognizing the rapidly evolving knowledge in RA management and the accumulation of new evidence regarding the safety and efficacy of existing and newer therapies, the ACR commissioned an update of the 2008 recommendations in select topic areas. The 2012 revision updates the 2008 ACR recommendations in the following areas: (1) indications for DMARDs and biologics; (2) switching between DMARD and biologic therapies; (3) use of biologics in high-risk patients (those with hepatitis, congestive heart failure, and malignancy); (4) screening for TB in patients starting or currently receiving biologics; and (5) vaccination in patients starting or currently receiving DMARDs or biologics (Table 1). Table 1 Overview Comparison of Topics and Medications Included in the 2008 and 2012 ACR RA Recommendations METHODS We utilized the same methodology as described in detail in the 2008 guidelines (1) to maintain consistency and to allow cumulative evidence to inform this 2012 recommendation update. These recommendations were developed by two expert panels: (1) a non-voting working group and Core Expert Panel (CEP) of clinicians and methodologists responsible for the selection of the relevant topic areas to be considered, the systematic literature review, and the evidence synthesis and creation of “clinical scenarios”; and (2) a Task Force Panel (TFP) of 11 internationally-recognized expert clinicians, patient representatives and methodologists with expertise in RA treatment, evidence-based medicine and patient preferences who were tasked with rating the scenarios created using an ordinal scale specified in the Research and Development/University of California at Los Angeles (RAND/UCLA) Appropriateness method (2–4). This method solicited formal input from a multi-disciplinary TFP panel to make recommendations informed by the evidence. The methods used to develop the updated ACR recommendations are described briefly below. Systematic Literature Review – Sources, Databases and Domains Literature searches for both DMARDs and biologics relied predominantly on PubMed searches) with medical subject headings (MeSH) and relevant keywords similar to those used for the 2008 ACR RA recommendations (see Appendices 1 and 2). We included randomized clinical trials (RCTs), controlled clinical trials (CCTs), quasi-experimental designs, cohort studies (prospective or retrospective), and case-control studies, with no restrictions on sample size. More details about inclusion criteria are listed below and in Appendix 3. The 2008 recommendations were based on a literature search that ended on February 14, 2007. The literature search end date for the 2012 Update was February 26, 2010 for the efficacy and safety studies and September 22, 2010 for additional qualitative reviews related to TB screening, immunization and hepatitis (similar to the 2008 methodology). Studies published subsequent to that date were not included. For biologics, we also reviewed the Cochrane systematic reviews and overviews (published and in press) in the Cochrane Database of Systematic Reviews to identify additional studies (5–8) and further supplemented by hand-checking the bibliographies of all included articles. Finally, the CEP and TFP confirmed that relevant literature was included for evidence synthesis. Unless they were identified by the literature search and met the article inclusion criteria (see Appendix 3), we did not review any unpublished data from product manufacturers, investigators, or the Food and Drug Administration (FDA) Adverse Event Reporting System. We searched the literature for the eight DMARDs and nine biologics most commonly used for the treatment of RA. Literature was searched for eight DMARDS including azathioprine, cyclosporine, hydroxychloroquine, leflunomide, methotrexate, minocycline, organic gold compounds and sulfasalazine. As in 2008, azathioprine, cyclosporine and gold were not included in the recommendations based on infrequent use and lack of new data (Table 1). Literature was searched for nine biologics including abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab and tocilizumab; anakinra was not included in the recommendations due to infrequent use and lack of new data. Details of the bibliographic search strategy are listed in Appendix 1.

American College of Rheumatology 2008 Recommendations for the Use of Nonbiologic and Biologic Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis

Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) are intended to provide guidance for particular patterns of practice and not to dictate the care of a particular patient. The ACR considers adherence to these guidelines and recommendations to be voluntary, with the ultimate determination regarding their application to be made by the physician in light of each patient’s individual circumstances. Guidelines and recommendations are intended to promote beneficial or desirable outcomes but cannot guarantee any specific outcome. Guidelines and recommendations developed or endorsed by the ACR are subject to periodic revision as warranted by the evolution of medical knowledge, technology, and practice.

2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.

To develop a new evidence‐based, pharmacologic treatment guideline for rheumatoid arthritis (RA).

American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid‐induced osteoporosis

Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) are intended to provide guidance for particular patterns of practice and not to dictate the care of a particular patient. The ACR considers adherence to these guidelines and recommendations to be voluntary, with the ultimate determination regarding their application to be made by the physician in light of each patient’s individual circumstances. Guidelines and recommendations are intended to promote beneficial or desirable outcomes but cannot guarantee any specific outcome. Guidelines and recommendations developed or endorsed by the ACR are subject to periodic revision as warranted by the evolution of medical knowledge, technology, and practice.

2011 American College of Rheumatology Recommendations for the Treatment of Juvenile Idiopathic Arthritis: Initiation and Safety Monitoring of Therapeutic Agents for the Treatment of Arthritis and Systemic Features

Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) are intended to provide guidance for particular patterns of practice and not to dictate the care of a particular patient. The ACR considers adherence to these guidelines and recommendations to be voluntary, with the ultimate determination regarding their application to be made by the physician in light of each patient’s individual circumstances. Guidelines and recommendations are intended to promote beneficial or desirable outcomes but cannot guarantee any specific outcome. Guidelines and recommendations developed or endorsed by the ACR are subject to periodic revision as warranted by the evolution of medical knowledge, technology, and practice.

Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: A randomized, double-blind, placebo-controlled extension trial

OBJECTIVE To evaluate the continued efficacy and safety of alendronate (ALN) for up to 2 years in patients receiving glucocorticoids. METHODS This is a 12-month extension of a previously completed 1-year trial of daily ALN, performed to evaluate the effects of ALN over a total of 2 years in 66 men and 142 women continuing to receive at least 7.5 mg of prednisone or equivalent daily. All patients received supplemental calcium and vitamin D. The primary end point was the mean percentage change in lumbar spine bone mineral density (BMD) from baseline to 24 months. Other outcomes included changes in hip and total body BMD, biochemical markers of bone turnover, radiographic joint damage of the hands, and vertebral fracture incidence. RESULTS The mean (+/-SEM) lumbar spine BMD increased by 2.8 +/- 0.6%, 3.9 +/- 0.7%, and 3.7 +/- 0.6%, respectively, in the groups that received 5 mg, 10 mg, and 2.5/10 mg of ALN daily (P < or = 0.001) and decreased by -0.8 +/- 0.6% in the placebo group (P not significant) over 24 months. In patients receiving any dose of ALN, BMD was increased at the trochanter (P < or = 0.05) and maintained at the femoral neck. Total body BMD was increased in patients receiving 5 or 10 mg ALN (P < or = 0.01). These 2 dose levels of ALN were more effective than placebo at all sites (P < or = 0.05). Bone turnover markers (N-telopeptides of type I collagen and bone-specific alkaline phosphatase) decreased 60% and 25%, respectively, during treatment with ALN (P < or = 0.05). There were fewer patients with new vertebral fractures in the ALN group versus the placebo group (0.7% versus 6.8%; P = 0.026). The safety profile was similar between treatment groups. CONCLUSION Alendronate is an effective, well-tolerated therapy for the prevention and treatment of glucocorticoid-induced osteoporosis, with sustained treatment advantages for up to 2 years.

Low dose long-term corticosteroid therapy in rheumatoid arthritis: An analysis of serious adverse events

PURPOSE The purpose of this study was to better define the toxicity of low dose (less than or equal to 15 mg/d prednisone or equivalent) long-term (greater than 1 year) corticosteroids in the treatment of rheumatoid arthritis (RA). PATIENTS AND METHODS We examined an historical cohort of 112 RA patients on low dose (6.1 +/- 3.1 mg/d, mean +/- SD) long-term (6.2 +/- 4.6 years) prednisone (CS) and compared them to 112 matched RA patients not using prednisone (CO). CS were matched one-to-one with CO for sex (75% women), age (+/- 5 yrs), race (98% white), and duration of disease (+/- 5 yrs). Subjects were determined by review of unselected medical records from three distinct rheumatology practice settings. For CS, charts were abstracted from the date of prednisone start for predefined adverse events (AEs). RESULTS Ninety-two (92) AEs were noted in CS versus 31 in CO and included: fracture (CS:21 versus CO:8), serious infections (CS:14 versus CO:4), gastrointestinal (GI) bleed or ulcer (CS:11 versus CO:4), and cataracts (CS:17 versus CO:5). At time of first AE, CS prednisone average dose was 7.0 +/- 2.6 mg with a duration of 4.9 +/- 3.9 years. Stepwise multiple logistic regression analysis was used to create a model which included all clinically relevant variables and all parameters significantly different at the cohort inception. Prednisone average dose of greater than 10 to less than or equal to 15 mg/d correlated most strongly with the development of an AE (Odds Ratio (OR) = 32.3, 95% Confidence Interval (CI) 4.6, 220). Average prednisone 5 to 10 mg (OR = 4.5, 95% CI 2.1, 9.6), RA nodules (OR = 3.9, 95% CI 1.9, 8.0), and bony erosions (OR = 2.4, 95% CI 1.2, 4.7) also entered the final model. Kaplan Meier survival curves for the development of the first AE showed a dose-response relationship between prednisone and AE occurrence, independent of rheumatoid nodules. Subset analyses utilized a nested case control design for the development of three serious AEs: fractures, serious infections, and GI events. These analyses revealed possible relationships between prednisone use and the development of each specific AE (prednisone use OR: fracture 3.9, 95% CI 0.8, 18.1; infection 8.0, 95% CI 1.0, 64.0; and GI event 3.3, 95% CI 0.9, 12.1). CONCLUSIONS Although disease severity is an important confounding factor, low dose long-term prednisone use equal to or greater than 5 mg/d is correlated with the development of specific adverse events in a dose-dependent fashion.

Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data

Adverse effects of glucocorticoids have been abundantly reported. Published reports on low dose glucocorticoid treatment show that few of the commonly held beliefs about their incidence, prevalence, and impact are supported by clear scientific evidence. Safety data from recent randomised controlled clinical trials of low dose glucocorticoid treatment in RA suggest that adverse effects associated with this drug are modest, and often not statistically different from those of placebo.

The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine.

The goal of our study was to estimate the prevalence of osteoporosis and low bone mass based on bone mineral density (BMD) at the femoral neck and the lumbar spine in adults 50 years and older in the United States (US). We applied prevalence estimates of osteoporosis or low bone mass at the femoral neck or lumbar spine (adjusted by age, sex, and race/ethnicity to the 2010 Census) for the noninstitutionalized population aged 50 years and older from the National Health and Nutrition Examination Survey 2005–2010 to 2010 US Census population counts to determine the total number of older US residents with osteoporosis and low bone mass. There were more than 99 million adults aged 50 years and older in the US in 2010. Based on an overall 10.3% prevalence of osteoporosis, we estimated that in 2010, 10.2 million older adults had osteoporosis. The overall low bone mass prevalence was 43.9%, from which we estimated that 43.4 million older adults had low bone mass. We estimated that 7.7 million non‐Hispanic white, 0.5 million non‐Hispanic black, and 0.6 million Mexican American adults had osteoporosis, and another 33.8, 2.9, and 2.0 million had low bone mass, respectively. When combined, osteoporosis and low bone mass at the femoral neck or lumbar spine affected an estimated 53.6 million older US adults in 2010. Although most of the individuals with osteoporosis or low bone mass were non‐Hispanic white women, a substantial number of men and women from other racial/ethnic groups also had osteoporotic BMD or low bone mass.

Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomised controlled trial

BACKGROUND Persistent use of glucocorticoid drugs is associated with bone loss and increased fracture risk. Concurrent oral bisphosphonates increase bone mineral density and reduce frequency of vertebral fractures, but are associated with poor compliance and adherence. We aimed to assess whether one intravenous infusion of zoledronic acid was non-inferior to daily oral risedronate for prevention and treatment of glucocorticoid-induced osteoporosis. METHODS This 1-year randomised, double-blind, double-dummy, non-inferiority study of 54 centres in 12 European countries, Australia, Hong Kong, Israel, and the USA, tested the effectiveness of 5 mg intravenous infusion of zoledronic acid versus 5 mg oral risedronate for prevention and treatment of glucocorticoid-induced osteoporosis. 833 patients were randomised 1:1 to receive zoledronic acid (n=416) or risedronate (n=417). Patients were stratified by sex, and allocated to prevention or treatment subgroups dependent on duration of glucocorticoid use immediately preceding the study. The treatment subgroup consisted of those treated for more than 3 months (272 patients on zoledronic acid and 273 on risedronate), and the prevention subgroup of those treated for less than 3 months (144 patients on each drug). 62 patients did not complete the study because of adverse events, withdrawal of consent, loss to follow-up, death, misrandomisation, or protocol deviation. The primary endpoint was percentage change from baseline in lumbar spine bone mineral density. Drug efficacy was assessed on a modified intention-to-treat basis and safety was assessed on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00100620. FINDINGS Zoledronic acid was non-inferior and superior to risedronate for increase of lumbar spine bone mineral density in both the treatment (least-squares mean 4.06% [SE 0.28] vs 2.71% [SE 0.28], mean difference 1.36% [95% CI 0.67-2.05], p=0.0001) and prevention (2.60% [0.45] vs 0.64% [0.46], 1.96% [1.04-2.88], p<0.0001) subgroups at 12 months. Adverse events were more frequent in patients given zoledronic acid than in those on risedronate, largely as a result of transient symptoms during the first 3 days after infusion. Serious adverse events were worsening rheumatoid arthritis for the treatment subgroup and pyrexia for the prevention subgroup. INTERPRETATION A single 5 mg intravenous infusion of zoledronic acid is non-inferior, possibly more effective, and more acceptable to patients than is 5 mg of oral risedronate daily for prevention and treatment of bone loss that is associated with glucocorticoid use.