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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.
Biosimilars for tumor necrosis factor inhibitors (August 2016)
Copies of biologic agents, termed biosimilars, including several of the tumor necrosis factor (TNF) inhibitors and other medications, have been marketed or are under development for use in the rheumatic diseases. A recent systematic review of 19 observational studies and clinical trials compared biosimilar TNF-alpha inhibitors with their reference biologic products, including infliximab, etanercept, and adalimumab, with testing done in healthy volunteers and in patients with rheumatoid arthritis, inflammatory bowel disease, and ankylosing spondylitis . Pharmacokinetic measurements were within defined equivalence margins, and similar clinical responses and adverse events were found for the tested products and their reference drugs. Additionally, similar efficacy and safety were observed in four cohort studies in which patients were switched from the reference product to a biosimilar medication. Limitations for many of the studies included small sample size and short trial duration, but collectively these data illustrate the potential utility of these agents. (See "Overview of biologic agents and kinase inhibitors in the rheumatic diseases", section on 'Biosimilars for biologic agents'.)
ORTHOPEDICS, SPINE, AND SOFT TISSUE RHEUMATIC DISORDERS
Treatment of degenerative meniscal tears (September 2016)
Acute meniscal tears often benefit from surgical treatment, but the appropriate management of chronic, degenerative tears, particularly in middle-aged adults, has been a source of debate. A recent trial randomly assigned 140 middle-aged adults (mean age 49.5) with a degenerative meniscal tear (and no evidence of osteoarthritis on magnetic resonance imaging [MRI]) to receive exercise therapy or partial meniscectomy . The trial found no clinically significant difference in knee function or pain at two years of follow-up. This finding is consistent with several other small randomized trials that have reported no clinically significant benefit from arthroscopic surgery in such patients. In the absence of persistent joint effusions or mechanical dysfunction, we suggest physical therapy as the initial management for middle-aged patients with degenerative meniscal tears. (See "Meniscal injury of the knee", section on 'Chronic degenerative meniscal injury'.)
Unloading shoes for knee osteoarthritis (July 2016)
Altered joint mechanics are thought to contribute to the development of knee osteoarthritis (OA), particularly in the medial tibiofemoral compartment in which loading is greater than in the lateral compartment during walking. As a result, there has been an interest in "unloading shoes" that have insoles with more stiffness laterally compared with medially, in an attempt to reduce the medial knee load. In a randomized trial, 160 patients with medial knee OA were assigned to wear either unloading or conventional walking shoes as much as possible every day for six months . Both groups improved from baseline, but there were no significant differences in pain or physical function between the two groups after six months. These results suggest that shoes with modified insoles do not confer additional benefit over conventional walking shoes. (See "Nonpharmacologic therapy of osteoarthritis", section on 'Insoles and footwear'.)
Tai Chi for patients with knee osteoarthritis (June 2016)
Tai Chi, a multicomponent traditional Chinese mind-body practice, combines slow and graceful movements with meditative relaxation techniques and can reduce pain and improve physical function in patients with osteoarthritis (OA), compared with control interventions. In a recent randomized trial involving over 200 patients with knee OA, a Tai Chi program (twice weekly for 12 weeks, with instruction to practice Tai Chi daily), resulted in benefit similar to an active comparator, outpatient physical therapy and a home exercise program . After 12 weeks, both groups exhibited statistically and clinically significant reduction in the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score, and differences between the groups were not statistically significant. Benefits were maintained at 52 weeks of follow-up. The Tai Chi group had greater improvements in depression and the physical quality-of-life measure. (See "Nonpharmacologic therapy of osteoarthritis", section on 'Tai Chi'.)
Acetaminophen for knee and hip osteoarthritis (May 2016)
Treatment with acetaminophen (paracetamol, N-acetyl-p-aminophenol [APAP]) appears to be slightly more effective than no treatment in relieving overall pain from osteoarthritis (OA), but generally less effective than nonsteroidal antiinflammatory drugs (NSAIDs). This was recently illustrated in a 2016 network meta-analysis of randomized trials involving nearly 60,000 patients with knee or hip OA receiving either APAP, one of seven NSAIDs, or placebo . The summary estimates of benefit with APAP were extremely low, although statistically significant, for the highest dose of APAP, but less than the predefined minimum clinically important effect. These results do not exclude the possibility that some patients respond, while many others do not. In patients with OA lacking signs or symptoms of inflammation, we initiate pharmacologic therapy with acetaminophen on an as-needed basis. If this is inadequate, we advise a trial of acetaminophen on a scheduled basis up to three to four times daily. Such use is consistent with evidence supporting its modest benefit compared with placebo and its relative safety. (See "Initial pharmacologic therapy of osteoarthritis", section on 'Noninflammatory OA'.)
AAP guidance on use of biologic response modifiers (July 2016)
Biologic response modifiers (BRMs) are immunosuppressive agents that are used to treat autoimmune disorders such as juvenile idiopathic arthritis and inflammatory bowel disease. Patients receiving BRMs have an increased risk of infection, particularly mycobacterial, viral, and fungal infections. Thus, the American Academy of Pediatrics has published guidance for clinicians using these agents . A thorough history is recommended to help determine infectious risk, with performance of screening tests as indicated depending upon the history and biologic agent chosen. Administration of routine immunizations at least two weeks prior to starting a BRM is advised for inactivated or subunit vaccines and at least four weeks prior for live vaccines, if treatment can be safely delayed. Administration of live vaccines is not recommended during treatment with BRMs. An infectious disease specialist should be consulted if a live vaccine is deemed necessary while a patient is on biologic therapy. Inactivated and subunit vaccines can be given while on therapy, and an annual inactivated influenza vaccine is recommended. (See "Systemic juvenile idiopathic arthritis: Treatment", section on 'Biologic therapy'.)
Rituximab versus a tumor necrosis factor inhibitor for biologic-naive rheumatoid arthritis (July 2016)
A small number of trials have directly compared different biologic agents for rheumatoid arthritis (RA) following an inadequate response to initial disease-modifying antirheumatic drug (DMARD) therapy. In a randomized, open-label noninferiority trial involving nearly 300 biologic-naïve patients with active seropositive RA and an inadequate response to nonbiologic DMARDs, treatment with rituximab, the B cell depleting anti-CD20 monoclonal antibody, had comparable efficacy at one year to a TNF inhibitor (either etanercept or adalimumab) . Several issues limit interpretation of the trial, including very slow recruitment despite a large number of participating centers, suggesting that patients in the trial may not be representative of the full range of biologic-naïve patients encountered in clinical practice. Additional studies are also needed to better establish the relative safety of rituximab in this setting with regard to long-term use and rare but serious adverse effects. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy", section on 'Efficacy of rituximab versus TNF inhibitor'.)
Tocilizumab versus methotrexate for initial therapy of rheumatoid arthritis (July 2016)
Several biologic agents have been compared with methotrexate (MTX) as initial disease-modifying antirheumatic drug (DMARD) therapy for rheumatoid arthritis (RA). In a recent randomized trial involving over 300 DMARD-naïve patients with active early RA and using a treat-to-target strategy, initial treatment with tocilizumab, an interleukin-6 receptor blocking monoclonal antibody, with or without MTX, was more effective than MTX alone in achieving sustained (≥24 weeks) remission while on the initial trial regimen . However, results for the entire two-year trial period, after modifications in the treatment regimens for inadequate response, were more similar, and the trial design had limitations that might have favored the tocilizumab arms. For multiple reasons, MTX remains our initial DMARD of choice for most patients, although the findings provide support for tocilizumab as another possible option in selected patients. (See "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults", section on 'Tocilizumab'.)
Baricitinib, investigational oral agent for rheumatoid arthritis (April 2016)
The Janus kinases (JAK) are cytoplasmic protein tyrosine kinases that are critical for signal transduction of several important cytokines. JAK inhibitors block these pathways by binding to a common gamma chain used by these receptors. One of these agents, tofacitinib, preferentially inhibits JAK1 and JAK3 and is available for the treatment of rheumatoid arthritis (RA); others, including baricitinib, which inhibits JAK1 and JAK2, are in development. In a recently published randomized trial of over 500 patients with active RA refractory to one or more tumor necrosis factor inhibitors (and to other biologic agents in some cases), patients were significantly more likely to achieve an ACR20 response at 12 weeks with baricitinib, a once-daily oral agent, compared with placebo . Physical function also improved. Additional data regarding efficacy and safety are needed, and further trials are ongoing. (See "Cytokine networks in rheumatic diseases: Implications for therapy", section on 'Baricitinib'.)
SCLERODERMA AND OTHER SYSTEMIC RHEUMATIC DISEASES
Guidelines for the treatment of systemic sclerosis (October 2016)
The British Society for Rheumatology (BSR) and the British Health Professionals in Rheumatology (BHSR) have published a comprehensive set of guidelines for the management of systemic sclerosis (SSc) . Some of the key points include the importance of making an early diagnosis and considering treatment with an immunosuppressive agent in patients with diffuse cutaneous SSc of less than three years duration. They also review the major therapies for treating of organ-based disease and emphasize the importance of referring patients to specialty centers with access to multidisciplinary care. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults", section on 'General principles of management'.)
Tocilizumab for systemic sclerosis (May 2016)
New strategies under investigation for the treatment of systemic sclerosis (SSc, scleroderma) include the anti-interleukin (IL)-6 receptor antibody, tocilizumab, based upon the association of high IL-6 expression with disease severity and poor outcome, evidence of a role for IL-6 in the microvasculopathy in SSc, and case reports suggesting potential benefit from the drug. In a recent phase 2 randomized trial involving nearly 90 patients with SSc for five years or less, patients receiving tocilizumab failed to achieve a statistically significant reduction in the modified Rodnan skin score (mRSS) at weeks 24 and 48, compared with those receiving placebo, although scores did improve and several secondary endpoints favored tocilizumab . A larger, phase 3 trial is ongoing to further evaluate the potential role of such therapy in practice. (See "Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)", section on 'Other biologic agents'.)
Macitentan ineffective for ischemic digital ulcers in systemic sclerosis (May 2016)
Inhibition of vasoconstrictor endothelin-1 (ET-1) by the drug bosentan was previously shown to reduce the frequency of recurrent digital ulcers associated with systemic sclerosis (SSc, scleroderma) and to improve pulmonary hypertension (PH). Despite this, another potent nonselective ET-1 antagonist, macitentan, did not reduce the frequency of new ischemic digital ulcers over 16 weeks, compared with placebo, in two randomized trials involving a total of over 550 patients with SSc, although the number of new ulcers was lower than expected among the participants in both trials . However, macitentan has been shown to be beneficial in PH. The basis for the differences between these two ET-1 inhibitors is unknown. (See "Treatment of the Raynaud phenomenon resistant to initial therapy", section on 'Recurrent digital ulcers in scleroderma'.)
SYSTEMIC LUPUS ERYTHEMATOSUS AND SJOGREN'S SYNDROME
Screening and prevention of hydroxychloroquine retinopathy (August 2016)
Antimalarial agents hydroxychloroquine (HCQ) and chloroquine are widely used for the treatment of systemic lupus erythematosus, rheumatoid arthritis, and other inflammatory and dermatologic conditions, and are generally thought to be safe. Retinal toxicity is a known risk, however, and measures to minimize this potential toxicity are necessary. Recently, the American Academy of Ophthalmology issued revised recommendations for screening and prevention of retinopathy . Key changes include the following:
●The maximum daily dose of HCQ should not exceed 5 mg/kg (previously 6.5 mg/kg), and the maximum daily dose of chloroquine should not exceed 2.3 mg/kg (previously 3 mg/kg).
●Real body weight should be used to calculate dose limits instead of ideal body weight.
In addition to exceeding the recommended daily dose, major risk factors for retinal toxicity include antimalarial use for greater than five years, renal disease, concomitant tamoxifen use, and the presence of macular disease. All patients should undergo a baseline eye examination before or within a year of beginning treatment with an antimalarial drug and, if normal, at least annually after five years of exposure for patients without major risk factors. For the treatment of rheumatic diseases, we typically use standard daily doses of HCQ (non-weight-based, eg, up to 400 mg) in individuals weighing 80 kg or more. In patients weighing less than 80 kg, we use a lower daily dose of HCQ up to the maximum of 5 mg/kg of real body weight. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Ocular health'.)
Rhabdomyolysis and sickle cell trait (August 2016)
Sickle cell trait is a benign carrier condition with a normal life expectancy. However, concerns have been raised regarding an increased risk of rhabdomyolysis and sudden death with prolonged physical activity. These risks were addressed in a cohort study of almost 50,000 black soldiers in the United States army for whom sickle cell trait status and other clinical information was available . While the risk of rhabdomyolysis was increased (hazard ratio, 1.5), this magnitude of risk is similar to that conferred by obesity or smoking and less than that due to antipsychotic or statin medications. Mortality was not increased over that in black soldiers without sickle cell trait, and the sole death from rhabdomyolysis occurred in an individual without sickle cell trait. Interventions to reduce exertion-related injuries should be aimed at all athletes and members of the military, regardless of sickle cell trait status. (See "Sickle cell trait", section on 'Rhabdomyolysis and sudden death during strenuous physical activity'.)
Tocilizumab as a glucocorticoid-sparing agent in polymyalgia rheumatica (June 2016)
Similar to giant cell arteritis (GCA), interleukin (IL)-6 levels are known to be elevated in the peripheral blood of patients with active polymyalgia rheumatica (PMR). Several case series have suggested that tocilizumab, a humanized IL-6 receptor monoclonal antibody, may be an effective steroid-sparing agent; however, these were mostly retrospective experiences in patients with concurrent GCA and/or long-standing PMR. In a small prospective study of nine newly diagnosed PMR patients (without concurrent GCA) who were administered monthly tocilizumab for one year alongside a standardized rapid glucocorticoid taper, all nine patients achieved a relapse-free remission off glucocorticoids at six months and remained in remission at 15 months follow-up, reporting only mild adverse effects of tocilizumab . However, larger randomized trials are required to define the role of tocilizumab in clinical practice. (See "Treatment of polymyalgia rheumatica", section on 'IL-6 receptor blockade'.)
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- Kise NJ, Risberg MA, Stensrud S, et al. Exercise therapy versus arthroscopic partial meniscectomy for degenerative meniscal tear in middle aged patients: randomised controlled trial with two year follow-up. BMJ 2016; 354:i3740.
- Hinman RS, Wrigley TV, Metcalf BR, et al. Unloading Shoes for Self-management of Knee Osteoarthritis: A Randomized Trial. Ann Intern Med 2016; 165:381.
- Wang C, Schmid CH, Iversen MD, et al. Comparative Effectiveness of Tai Chi Versus Physical Therapy for Knee Osteoarthritis: A Randomized Trial. Ann Intern Med 2016; 165:77.
- da Costa BR, Reichenbach S, Keller N, et al. Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis. Lancet 2016; 387:2093.
- American Acedemy of Pediatrics Clinical Report: Infectious complications with the use of biologic response modifiers in infants and children. http://pediatrics.aappublications.org/content/pediatrics/early/2016/07/14/peds.2016-1209.full.pdf (Accessed on July 19, 2016).
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- Khanna D, Denton CP, Merkel PA, et al. Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic Sclerosis: DUAL-1 and DUAL-2 Randomized Clinical Trials. JAMA 2016; 315:1975.
- Marmor MF, Kellner U, Lai TY, et al. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision). Ophthalmology 2016; 123:1386.
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