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The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.
New guidelines for management of gout (February 2017)
Several professional organizations have recently published guidelines for the management of gout, including the European League Against Rheumatism (EULAR) , an international task force , and the American College of Physicians (ACP) . The ACP guidelines depart from recommendations of the American College of Rheumatology (ACR), EULAR, the international task force, and others by suggesting a treat-to-avoid-symptoms approach (ie, monitoring the adequacy of urate-lowering drug dosing based on the frequency and severity of acute attacks) rather than a treat-to-target approach based on serum urate levels. We concur with the ACR, EULAR, and international guidelines groups, based upon the available clinical evidence and an understanding of the pathophysiology of gout, and we continue to recommend monitoring serum urate levels and using such data to make treatment choices and titrate dosing. (See "Prevention of recurrent gout: Pharmacologic urate-lowering therapy and treatment of tophi", section on 'Recommendations of major groups'.)
Relative cardiovascular safety of celecoxib, naproxen, and ibuprofen (December 2016)
The cardiovascular (CV) safety of celecoxib, the COX-2 selective nonsteroidal anti-inflammatory drug (NSAID), compared with other NSAIDs, is a matter of debate. In a randomized trial (PRECISION) involving over 24,000 patients with arthritis and either known CV disease or CV risk factors, the CV safety of celecoxib was noninferior to both naproxen and ibuprofen, two nonselective NSAIDs . Depending upon the analysis, about 2 to 5 percent of subjects experienced a CV event during follow-up, which was slightly lower than the expected event rate. Despite some limitations, this trial suggests that celecoxib in moderate doses can be administered, when indicated, without concern about increased CV risk compared with the nonselective nonsteroidal agents naproxen and ibuprofen. (See "COX-2 selective inhibitors: Adverse cardiovascular effects", section on 'Celecoxib' and "Nonselective NSAIDs: Adverse cardiovascular effects", section on 'Risk of myocardial infarction, stroke, and death'.)
ORTHOPEDICS, SPINE, AND SOFT TISSUE RHEUMATIC DISORDERS
Inpatient versus home-based physical therapy after total knee arthroplasty (March 2017)
Inpatient rehabilitation programs are widely used after total knee arthroplasty (TKA); however, there are limited data as to whether clinical outcomes are superior when compared with lower cost home-based physical therapy (PT) programs. In a trial with 165 adults who had undergone a TKA for osteoarthritis, patients were randomly assigned to either 10 days of inpatient rehabilitation followed by eight weeks of monitored home-based PT or to the monitored home-based program alone . At 26 weeks, all outcomes were similar between groups, including the six-minute walk test and measures of pain, function, and quality of life. Although more data are needed, this study suggests that inpatient rehabilitation is not superior to home-based PT for patients undergoing unilateral, uncomplicated TKA. (See "Total knee arthroplasty", section on 'Postoperative management'.)
Investigational autologous nasal chondrocyte grafts for articular cartilage defects (November 2016)
Replacing localized regions of degenerated cartilage with autologous chondrocytes grafts may be beneficial for selected patients with less severe, localized articular cartilage defects. There is an interest in using alternative sources of autologous chondrocytes with superior cartilage-forming capacity compared with articular chondrocytes. In a proof-of-concept, first-in-human trial, 10 patients with symptomatic, post-traumatic, full-thickness cartilage lesions on the femoral condyle or trochlea were treated with engineered tissue from autologous nasal cartilage . Significant improvements in pain, knee function, and quality of life were found during the 24-month follow-up period. These early data will need further validation to establish efficacy and appropriateness of this approach for treating articular cartilage defects. (See "Overview of surgical therapy of knee and hip osteoarthritis", section on 'Autologous chondrocyte implantation'.)
Vertebroplasty for osteoporotic compression fractures (November 2016)
The indications for and timing of vertebroplasty for the treatment of osteoporotic compression fractures are controversial. In a trial comparing vertebroplasty or simulated vertebroplasty (sham) in 120 patients with acute (less than six weeks) vertebral fracture and back pain, more patients in the vertebroplasty group achieved clinically significant lower pain scores at 14 days . Two previous sham-controlled trials, however, did not show a significant reduction in pain with vertebroplasty, likely due to differences in study design, including different sham procedures for the control arm and varying definitions of acute vertebral fracture. (See "Osteoporotic thoracolumbar vertebral compression fractures: Clinical manifestations and treatment", section on 'Vertebroplasty'.)
Internet-delivered therapy for chronic knee pain (February 2017)
Nonpharmacologic interventions are known to be effective in the treatment of chronic knee pain and osteoarthritis (OA), but implementation of such therapies is often limited. In a trial of 148 adults with chronic knee pain and disability, patients were randomized to either a novel internet-based intervention or a control group . Both groups had access to internet-based educational material, but the intervention group also received interactive online training in pain-coping skills as well as videoconferencing sessions with a physiotherapist for home exercise. At three months, the intervention group reported improved pain and function compared with the control group, which was sustained for at least six months. More data are needed to evaluate internet-based strategies as a practical way to deliver care for OA patients.
Lack of benefit of chondroitin and glucosamine for knee osteoarthritis (January 2017)
The use of glucosamine and chondroitin for osteoarthritis (OA) has been controversial, with most studies showing little to no evidence of clinically meaningful benefit. In a multicenter randomized trial, 164 patients with moderate to severe knee osteoarthritis were treated with either placebo or chondroitin sulfate plus glucosamine . At six months' follow-up, the mean reduction in the global pain score was greater in the placebo group, and there were no between-group differences in patient-reported function or other outcomes. Although the study was limited by the small size and potentially inadequate dosing of chondroitin and glucosamine, it is likely that the combination of glucosamine and chondroitin is no better than placebo in patients with knee osteoarthritis.
Effect of antihypertensive drug class on fracture rates (January 2017)
Thiazide diuretics stimulate distal tubular reabsorption of calcium, leading to a decrease in urinary calcium excretion and a possible benefit on bone mineral density. The rates of hip or pelvic fractures among patients treated with thiazide-like diuretics, angiotensin converting enzyme (ACE) inhibitors, or calcium channel blockers were compared in a post-hoc analysis of the ALLHAT trial . At approximately five years, those randomly assigned chlorthalidone had fewer hip or pelvic fractures as compared with those assigned to either lisinopril or amlodipine. Thus, if monotherapy is appropriate in a patient with hypertension and osteoporosis, thiazide-like diuretics may have advantages over ACE inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers. (See "Choice of drug therapy in primary (essential) hypertension", section on 'Thiazide diuretics'.)
Methotrexate for moderate oligoarticular juvenile idiopathic arthritis (February 2017)
Methotrexate is used as part of initial therapy in oligoarticular juvenile idiopathic arthritis (JIA) for those with severe disease activity and poor prognostic risk factors, but it is not clear if it should be used in patients with moderate disease. In a randomized, open-label trial of over 200 children with moderate oligoarticular JIA, the addition of oral methotrexate to glucocorticoid injections did not improve the proportion of children who achieved inactive disease or clinical remission at 12 months, although it did increase the time to flare (by approximately four months) . Further study is needed to determine if methotrexate should be used for the initial therapy of children with moderate-risk JIA, including whether oral methotrexate is as effective as subcutaneous administration in this setting. (See "Oligoarticular juvenile idiopathic arthritis", section on 'Initial therapy'.)
Adjuvant glucocorticoids for initial treatment of Kawasaki disease (January 2017)
The use of glucocorticoids to treat children with Kawasaki disease has been a subject of debate. In a meta-analysis of comparative studies examining initial treatment with glucocorticoids plus intravenous immune globulin (IVIG) compared with IVIG alone, combination therapy was associated with a lower rate of coronary artery abnormalities, with the greatest benefit in patients predicted to be at high risk for IVIG resistance at baseline . The Kobayashi criteria can be used to determine this risk status in Japanese children but are not reliable in other populations. When increased risk for IVIG resistance cannot be determined, we do not recommend routine use of glucocorticoids for initial therapy. (See "Kawasaki disease: Initial treatment and prognosis", section on 'Glucocorticoids'.)
Sarilumab, an anti-IL-6 receptor antibody for treatment of rheumatoid arthritis (April 2017)
Emerging data indicate that sarilumab, an investigational human monoclonal antibody directed against the membrane-bound and soluble interleukin (IL)-6 receptor, is effective for the treatment of rheumatoid arthritis (RA). In a trial of 546 patients with RA who had an inadequate response or intolerance to tumor necrosis factor (TNF) inhibitors, sarilumab improved clinical response rates and physical function compared with placebo when given together with conventional disease-modifying antirheumatic drugs . In a separate trial of 369 patients with active RA who had failed or did not tolerate methotrexate, sarilumab was superior to the TNF inhibitor, adalimumab, as monotherapy . Sarilumab has similar safety and tolerability to the humanized anti-IL-6 receptor monoclonal antibody, tocilizumab, which is commercially available for the treatment of RA and other disorders. (See "Cytokine networks in rheumatic diseases: Implications for therapy", section on 'Anti-interleukin-6 receptor antibodies'.)
Sirukumab, an anti-IL-6 antibody for the treatment of rheumatoid arthritis (April 2017)
Sirukumab is a human anti-interleukin (IL)-6 monoclonal antibody under development for the treatment of rheumatoid arthritis (RA). In a randomized trial involving almost 900 patients with active RA refractory or intolerant to at least one tumor necrosis factor (TNF) inhibitor, sirukumab was more likely than placebo to result in a clinical response . Notably, two or more biologic agents, including non-TNF drugs, had previously been administered in the majority of patients, and most patients were receiving continued therapy with a conventional disease-modifying antirheumatic drug, usually methotrexate. Adverse reactions were similar between groups, other than injection-site erythema, which was more common with sirukumab. Further studies are ongoing with several antibodies that target IL-6 directly; it remains to be seen if this offers a strategic advantage over targeting of the receptor. (See "Cytokine networks in rheumatic diseases: Implications for therapy", section on 'Anti-interleukin-6 antibodies'.)
Baricitinib, an oral JAK-1/JAK-2 inhibitor for the treatment of rheumatoid arthritis (March 2017)
A series of recent randomized trials have documented the efficacy and relative safety of baricitinib, a small molecule, orally administered, Janus kinase (JAK)-1 and JAK-2 inhibitor, as a treatment for rheumatoid arthritis (RA). These include a trial involving almost 600 patients with active RA who were naïve (or had minimal exposure) to both conventional nonbiologic disease-modifying antirheumatic drugs (DMARDs) and biologic DMARDs, in which baricitinib was superior to methotrexate as monotherapy ; a trial involving almost 700 patients with inadequate responses to prior DMARD therapy, in which responses were greater with the addition of baricitinib compared with placebo ; and a trial involving over 1300 patients with active RA and an inadequate response to methotrexate (MTX), in which the addition of baricitinib was more effective than adalimumab and placebo . Baricitinib was associated with minor increases in serum creatinine and LDL cholesterol and small reductions in blood neutrophil counts. Baricitinib has been approved in Europe for use either alone or in combination with MTX and is undergoing regulatory review in the United States. (See "Cytokine networks in rheumatic diseases: Implications for therapy", section on 'Baricitinib'.)
Adalimumab versus certolizumab pegol in rheumatoid arthritis with inadequate methotrexate response (March 2017)
The relative efficacy of the five available tumor necrosis factor (TNF) inhibitors has not been well studied in patients with rheumatoid arthritis (RA). Now, a randomized trial involving over 900 patients with active RA and an inadequate response to methotrexate (MTX) alone has directly compared the combination of MTX with either of two TNF inhibitors (adalimumab and certolizumab pegol) and found neither combination superior to the other . There was no difference between the groups in the proportion of patients achieving a clinical response at week 12, the number with low disease activity at week 104, other major clinical outcome measures, or adverse effects. We continue to suggest choosing a TNF inhibitor based on factors such as patient preferences regarding route of administration and frequency of treatment, comorbidities, and local regulatory and coverage constraints. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy", section on 'MTX plus TNF inhibitor'.)
SCLERODERMA AND OTHER SYSTEMIC RHEUMATIC DISEASES
Management of microvascular damage in systemic sclerosis (December 2016)
Vasoactive drugs are used for systemic sclerosis (SSc) patients with severe Raynaud phenomenon (RP) and digital ulcers. For prevention of recurrent digital ulcers, there may be a benefit from combination therapy with intravenous iloprost and bosentan. In a prospective observational study with 30 SSc patients receiving intravenous iloprost for severe secondary RP, half of the patients were also given bosentan following the development of digital ulcers or pulmonary arterial hypertension . After four years of follow-up, the iloprost plus bosentan group showed evidence of a significant improvement in digital microvasculature structure and function, which also corresponded with a significant reduction in the incidence of new digital ulcers. This limited study needs confirmation but suggests that combination therapy may be helpful in complex SSc patients with recurrent digital ulcers. (See "Treatment of the Raynaud phenomenon resistant to initial therapy", section on 'Recurrent digital ulcers in systemic sclerosis'.)
SYSTEMIC LUPUS ERYTHEMATOSUS AND SJOGREN'S SYNDROME
Guidelines on women's health in systemic lupus erythematosus and antiphospholipid syndrome (March 2017)
Both systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) affect women of child-bearing age, and the management of these diseases in the setting of pregnancy can pose unique challenges. These include the effect of pregnancy on maternal disease, the impact of disease activity on fetal health, and the safety of medications during pregnancy and breastfeeding. The European League Against Rheumatism (EULAR) has published new recommendations for the management of women's health in patients with SLE and APS, which provide guidance for family planning, assisted reproduction, pregnancy monitoring, treatment during pregnancy, hormone replacement therapy and menopause, and malignancy screening . (See "Pregnancy in women with systemic lupus erythematosus", section on 'Pregnancy planning'.)
Adverse events with short-term oral glucocorticoid use in adults (April 2017)
Chronic steroid use is associated with a wide spectrum of adverse effects. However, there is a paucity of clinical data on the adverse effects associated with short-term use. A retrospective cohort study and self-controlled case series assessed the risk of three adverse events (sepsis, venous thromboembolism [VTE], and fracture) in over 300,000 adults younger than 65 who received at least one short-term (<30 days) outpatient prescription for oral glucocorticoids over a three-year period . The most common indications for use were upper respiratory tract infections, spinal conditions, and allergies. Within 30 days of drug initiation, there was a two- to fivefold increase in the rates of sepsis, VTE, and fracture, which then decreased over the subsequent 31 to 90 days. These findings suggest that even short courses of oral steroids are associated with adverse effects that should be considered before prescribing. (See "Major side effects of systemic glucocorticoids", section on 'Dose effects'.)
Anakinra for familial Mediterranean fever (January 2017)
Anti-interleukin (IL)-1 therapy has been the preferred second-line therapy for patients with familial Mediterranean fever (FMF) based on data from case reports and case series. In the first randomized trial to evaluate anti-IL-1 therapy in colchicine-resistant FMF, 24 patients from a single center received daily injections of either anakinra or placebo and were followed for four months . Patients in the anakinra group had fewer attacks per month, significant improvement in quality of life, and no severe adverse events. Thus, anakinra appears to be a safe and effective alternative for patients who do not respond to or cannot tolerate colchicine. (See "Management of familial Mediterranean fever", section on 'Interleukin-1 inhibition'.)
Adalimumab for noninfectious uveitis (November 2016)
Patients with noninfectious uveitis can benefit from effective and safe glucocorticoid-sparing therapy. Two well-designed, randomized trials showed that adalimumab was effective in the treatment of noninfectious intermediate, posterior, and pan-uveitis [24,25]. In these trials, adalimumab improved the time-to-treatment failure in patients with uveitis who followed a tapering schedule for oral glucocorticoids. Both the European Medicines Agency and the US Food and Drug Administration recommended approval of adalimumab for adults with these forms of uveitis. (See "Uveitis: Treatment", section on 'Anti-tumor necrosis factor-alpha'.)
- Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis 2017; 76:29.
- Kiltz U, Smolen J, Bardin T, et al. Treat-to-target (T2T) recommendations for gout. Ann Rheum Dis 2016; 76:632.
- Qaseem A, Harris RP, Forciea MA, Clinical Guidelines Committee of the American College of Physicians. Management of Acute and Recurrent Gout: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med 2017; 166:58.
- Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. N Engl J Med 2016; 375:2519.
- Buhagiar MA, Naylor JM, Harris IA, et al. Effect of Inpatient Rehabilitation vs a Monitored Home-Based Program on Mobility in Patients With Total Knee Arthroplasty: The HIHO Randomized Clinical Trial. JAMA 2017; 317:1037.
- Mumme M, Barbero A, Miot S, et al. Nasal chondrocyte-based engineered autologous cartilage tissue for repair of articular cartilage defects: an observational first-in-human trial. Lancet 2016; 388:1985.
- Clark W, Bird P, Gonski P, et al. Safety and efficacy of vertebroplasty for acute painful osteoporotic fractures (VAPOUR): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2016; 388:1408.
- Bennell KL, Nelligan R, Dobson F, et al. Effectiveness of an Internet-Delivered Exercise and Pain-Coping Skills Training Intervention for Persons With Chronic Knee Pain: A Randomized Trial. Ann Intern Med 2017; 166:453.
- Roman-Blas JA, Castañeda S, Sánchez-Pernaute O, et al. Combined Treatment With Chondroitin Sulfate and Glucosamine Sulfate Shows No Superiority Over Placebo for Reduction of Joint Pain and Functional Impairment in Patients With Knee Osteoarthritis: A Six-Month Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Arthritis Rheumatol 2017; 69:77.
- Puttnam R, Davis BR, Pressel SL, et al. Association of 3 Different Antihypertensive Medications With Hip and Pelvic Fracture Risk in Older Adults: Secondary Analysis of a Randomized Clinical Trial. JAMA Intern Med 2017; 177:67.
- Ravelli A, Davì S, Bracciolini G, et al. Intra-articular corticosteroids versus intra-articular corticosteroids plus methotrexate in oligoarticular juvenile idiopathic arthritis: a multicentre, prospective, randomised, open-label trial. Lancet 2017; 389:909.
- Chen S, Dong Y, Kiuchi MG, et al. Coronary Artery Complication in Kawasaki Disease and the Importance of Early Intervention : A Systematic Review and Meta-analysis. JAMA Pediatr 2016; 170:1156.
- Fleischmann R, van Adelsberg J, Lin Y, et al. Sarilumab and Nonbiologic Disease-Modifying Antirheumatic Drugs in Patients With Active Rheumatoid Arthritis and Inadequate Response or Intolerance to Tumor Necrosis Factor Inhibitors. Arthritis Rheumatol 2017; 69:277.
- Burmester GR, Lin Y, Patel R, et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis 2017; 76:840.
- Aletaha D, Bingham CO 3rd, Tanaka Y, et al. Efficacy and safety of sirukumab in patients with active rheumatoid arthritis refractory to anti-TNF therapy (SIRROUND-T): a randomised, double-blind, placebo-controlled, parallel-group, multinational, phase 3 study. Lancet 2017; 389:1206.
- Fleischmann R, Schiff M, van der Heijde D, et al. Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease-Modifying Antirheumatic Drug Treatment. Arthritis Rheumatol 2017; 69:506.
- Dougados M, van der Heijde D, Chen YC, et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis 2017; 76:88.
- Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis. N Engl J Med 2017; 376:652.
- Smolen JS, Burmester GR, Combe B, et al. Head-to-head comparison of certolizumab pegol versus adalimumab in rheumatoid arthritis: 2-year efficacy and safety results from the randomised EXXELERATE study. Lancet 2016; 388:2763.
- Trombetta AC, Pizzorni C, Ruaro B, et al. Effects of Longterm Treatment with Bosentan and Iloprost on Nailfold Absolute Capillary Number, Fingertip Blood Perfusion, and Clinical Status in Systemic Sclerosis. J Rheumatol 2016; 43:2033.
- Andreoli L, Bertsias GK, Agmon-Levin N, et al. EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann Rheum Dis 2017; 76:476.
- Waljee AK, Rogers MAM, Lin P, et al. Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ 2017.
- Ben-Zvi I, Kukuy O, Giat E, et al. Anakinra for Colchicine-Resistant Familial Mediterranean Fever: A Randomized, Double-Blind, Placebo-Controlled Trial. Arthritis Rheumatol 2017; 69:854.
- Jaffe GJ, Dick AD, Brézin AP, et al. Adalimumab in Patients with Active Noninfectious Uveitis. N Engl J Med 2016; 375:932.
- Nguyen QD, Merrill PT, Jaffe GJ, et al. Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial. Lancet 2016; 388:1183.