Single-Pill Regimens for HIV-1 Infection

Posted by Sara Fazio • July 18th, 2014

In the latest Clinical Therapeutics review, a 52-year-old man with a history of HIV-1 infection and poor medication adherence presents for evaluation. A single-pill regimen is considered. For some patients with HIV-1 infection, combination regimens consisting of one pill to be taken daily can improve adherence.

With the advent and refinement of combination ART [antiretroviral therapy], the life expectancy of HIV-infected patients has risen dramatically. In addition to benefiting infected persons, ART almost completely blocks HIV-1 transmission to uninfected sexual partners. If we were able to treat most or all HIV-infected patients and thereby prevent new infections, “the beginning of the end of AIDS” would be in sight.

Clinical Pearls

• What are the currently available single-pill combinations marketed for HIV-1 treatment?

There are currently three single-pill combinations marketed for HIV-1 treatment, each containing the same combination of one nucleotide reverse-transcriptase inhibitor and one nucleoside reverse-transcriptase inhibitor (NRTIs): tenofovir disoproxil fumarate (TDF) at a dose of 300 mg and emtricitabine (FTC) at a dose of 200 mg, respectively. The first agent (Atripla, Bristol-Myers Squibb and Gilead Sciences), released in 2006, is a single pill that combines TDF-FTC with 600 mg of the nonnucleoside reverse-transcriptase inhibitor (NNRTI) efavirenz (EFV). The second agent (Complera, Gilead Sciences), approved in 2011, combines TDF-FTC with 25 mg of the NNRTI rilpivirine (RPV). The third agent (Stribild, Gilead Sciences), released in 2012, consists of TDF-FTC combined with 150 mg of the integrase strand-transfer inhibitor (INSTI) elvitegravir (EVG) and 150 mg of the pharmacoenhancer cobicistat (which boosts serum EVG levels). A fourth single-pill combination has not yet been approved for clinical use. This agent would combine two NRTIs — abacavir (ABC) at a dose of 600 mg and lamivudine (3TC) at a dose of 300 mg — with 50 mg of the recently approved INSTI dolutegravir DTG).

• In which patient populations should single-pill combinations be generally avoided?

Single-pill combinations should be avoided in patients with clinically significant renal disease because TDF, TC, and FTC all require dose reductions or elimination when the estimated creatine clearance is less than 50 ml per minute. The inability to adjust the dose of individual drug components in patients with renal insufficiency is an important limitation of single-pill combinations. In addition, patients who have drug-resistant HIV-1 infection often require agents that are not included in single-pill combinations.

Morning Report Questions

Q: When should a regimen containing a protease inhibitor be used?

A: None of the current single-pill combinations contain protease inhibitors, which should be used in patients with known viral resistance to NNRTIs or INSTIs. In addition, because transmitted resistance to protease inhibitors is uncommon and resistance to this class emerges relatively slowly, protease inhibitors are often favored when treatment decisions are required before resistance-testing results are available — for example, in the case of patients with acute HIV-1 infection or opportunistic infections. Protease inhibitors are also sometimes considered in patients with inconsistent adherence because multiple viral mutations are required to compromise the activity of these agents.

Q: How do currently available anchor medications for once daily regimens compare?

A: EFV, the anchor drug in EFV-TDF-FTC, is potent and, in recent years, the drug to which every newly developed anchor antiretroviral agent has been compared. EFV may cause neuropsychiatric effects (e.g., vivid dreams, insomnia, somnolence, and depression) or rash, although symptoms typically diminish over time. EFV is the preferred NNRTI during pregnancy, when initiated 8 weeks after conception. Rilpivirine (RPV)-based regimens are not recommended for patients whose pretherapy HIV-1 RNA level is more than 100,000 copies per milliliter or whose CD4+ T-cell count is 200 per cubic millimeter or less. RPV must be taken with a solid meal (greater than or equal to 390 kcal) and requires stomach acid for adequate absorption, precluding the concomitant use of proton-pump inhibitors. In addition to its use in initial therapy, RPV-TDF-FTC may have a role in patients with virologic suppression during treatment with a protease inhibitor-containing regimen who have a reason to change medications: in a recent trial, switching such patients to RPV-TDF-FTC maintained high rates of virologic suppression and improved lipid levels. Cobicistat-boosted EVG does not have neuropsychiatric effects and does not commonly cause rash. However, cobicistat inhibits tubular secretion of creatinine without reducing the creatine clearance. As a result, patients may have a mild increase in the serum creatinine level, typically less than 0.4 mg per deciliter (35 micromoles per liter), with this medication initially.

Table 1. Considerations for the Use of Particular Single-Pill Combinations in the Management of HIV-1 infection.

Niacin with Laropiprant in High-Risk Patients

Posted by Daniela Lamas • July 16th, 2014

Your patient, a 70-year-old man with a history of a heart attack three years ago, sits across from you at his regular outpatient follow-up appointment.

He’s doing well. He’s exercising and taking the medications you prescribed, including his statin, but he’s wondering if there’s anything more he should be doing to lower his “bad,” or LDL cholesterol and raise the “good,” or HDL, cholesterol.

A friend’s doctor prescribed him niacin, your patient tells you. Shouldn’t he take it as well?

Your patient isn’t alone. In recent years, the use of niacin as an adjunct to standard statin therapy has been increasing in the U.S. But the data on effectiveness aren’t so clear. One recent study published in NEJM in 2011, AIM-HIGH, suggested that there was actually no benefit to adding niacin for patients who were already on statins. But with concerns about how well the study was powered to determine a difference in cardiovascular events in these two groups, the question of whether patients might benefit from adding niacin to a statin remained open.

This is the question that Martin J. Landray and colleagues set out to answer. The THRIVE study, published in this week’s NEJM, reports that while adding niacin can lower levels of LDL cholesterol and raise HDL cholesterol, this comes without any clinical benefit – and with a host of adverse events.

Those eligible for the study were similar to the patient in your office – men and women 50 to 80 years old with a prior heart attack, stroke or diabetes with coronary artery disease. After an enrollment period that included standardizing background statin therapy, and a trial on niacin to make sure that patients could tolerate the drug, nearly 26,000 patients entered the study cohort. These were patients with good lipid control, with an average starting LDL of 63 mg/dL and HDL of 44 mg/dL. All received simvastatin 40 mg daily in addition to a combination of niacin and laropiprant (a medication that decreases the adverse effects, particularly flushing, associated with niacin), or placebo.

Over the four year follow-up, patients randomly assigned to the niacin group did, indeed, have lower LDL cholesterol by an average of 10 mg/dl, and 6 mg/dL higher HDL in addition to lower triglyceride levels. But these changes did not translate into clinical benefit.  When the investigators looked at their primary outcomes – major vascular events like heart attack and stroke – they found no significant difference between patients who were taking niacin, and those who weren’t. Even in subgroups of patients who might have been thought to net the most good from added niacin, such as those with low HDL and high triglycerides, the risk of serious vascular events were the same.

But the risk wasn’t. Those randomly assigned to niacin suffered a higher rate of serious adverse events, most commonly related to worsening or new onset diabetes, gastrointestinal side effects like ulcers and diarrhea, muskoskeletal adverse events like myopathy and gout, and an increase in infections and bleeding. Ultimately, those randomly assigned to niacin had a nine percent increase in the risk of death, although that did not meet statistical significance.

Of note, patients didn’t receive niacin alone, as they had in the prior AIM-HIGH study. Instead, they were given a formulation of extended-release niacin and laropripant, a prostaglandin receptor antagonist used to decrease flushing (commonly seen with niacin). This opens the question of whether some of the unanticipated adverse events were actually not due to niacin, but to laropripant, or to the combination of drugs. In a letter to the editor, the authors of the AIM-HIGH trial note that the spectrum of adverse events they saw was not entirely consistent with that described by the THRIVE investigators and suggest that some of the events seen in the THRIVE study might actually be due to the combination of drugs, rather than niacin alone.

Whether due to niacin alone or in combination, the adverse event profile is troubling. And so in an accompanying editorial, cardiologist Donald M. Lloyd-Jones recommends that while niacin should still be considered for patients who are unable to tolerate statins, or those with persistently high levels of triglycerides, “On the basis of the weight of available evidence showing net clinical harm, niacin must be considered to have an unacceptable toxicity profile for the majority of patients, and it should not be used routinely.”

To your patient, then: Stick with your current meds and skip the niacin. For now, that’s the best answer we have.

Letrozole or Clomiphene for Infertility in PCOS

Posted by Sara Fazio • July 11th, 2014

This double-blind, multicenter, randomized trial showed that letrozole, as compared with clomiphene, was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome.

The PCOS, which is diagnosed on the basis of hyperandrogenism, oligo-ovulation with associated oligomenorrhea, and polycystic ovaries on ultrasonography, affects 5 to 10% of reproductive-age women and is the most common cause of anovulatory infertility.

Clinical Pearls

What are the potential drawbacks to the use of clomiphene citrate for ovulation induction?

Clomiphene citrate, a selective estrogen-receptor modulator that antagonizes the negative feedback of estrogen at the hypothalamus with a consequent increase in ovarian stimulation by endogenous gonadotropin, has been used for this indication for decades.  Clomiphene has drawbacks, including its overall poor efficacy (only a 22% rate of live birth with up to six cycles of clomiphene in our previous study), a relatively high multiple-pregnancy rate (3 to 8%) as compared with the rate associated with unassisted conception   (<1%), and an undesirable side-effect profile, including mood changes and hot flashes.

What was the primary outcome of this study comparing clomiphene to letrozole for ovulation induction in infertile women with the polycystic ovary syndrome?

The group of women who received letrozole had more cumulative live births than the group of women who received clomiphene (103 of 374 women [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth with letrozole, 1.44; 95% confidence interval, 1.10 to 1.87).   There were no significant between-group differences in live-birth rates according to treatment cycle. The live-birth rates after an anovulatory cycle were similar with and without progestin-induced withdrawal bleeding in both treatment groups.

Table 2. Outcomes with Regard to Live Birth, Ovulation, Pregnancy, Pregnancy Loss, and Fecundity.

Figure 1. Kaplan-Meier Curves for Live Birth.

Morning Report Questions

Q: What were secondary study outcomes?

A: The rates of pregnancy loss after conception were similar in the two treatment groups. The ovulation rate was significantly higher with letrozole than with clomiphene at each monthly visit (P<0.01 for all comparisons) beginning with the second visit. Among patients who ovulated, there was a significantly greater chance of singleton pregnancy with letrozole than with clomiphene (P=0.03). The sex ratio at birth favored girls.

Table 2. Outcomes with Regard to Live Birth, Ovulation, Pregnancy, Pregnancy Loss, and Fecundity. 

Q: How did adverse events compare between the two treatment groups?

A: Three serious adverse events related to ovarian-cyst formation occurred during infertility treatment: two with letrozole (a ruptured corpus luteum cyst in one patient and hospitalization for the drainage and removal of an ovarian cyst in another patient) and one with clomiphene (ovarian torsion). Clomiphene was associated with a significantly higher incidence of hot flushes; letrozole was associated with significantly higher incidences of fatigue and dizziness. During pregnancy, the most common complication was gestational diabetes, followed by preeclampsia or eclampsia, preterm labor, and premature rupture of membranes, with no significant differences between treatment groups. There were five major congenital anomalies (four with letrozole and one with clomiphene); the between-group difference was not significant (P=0.65).

Table 3. All Serious Adverse Events, plus Other Adverse Events with Significant Differences between the Treatment Groups.

CNS Fungal Infections

Posted by Sara Fazio • July 11th, 2014

Molds are ubiquitous in soil, water, and decaying vegetation and can cause devastating infections that are difficult to treat. This review summarizes the epidemiologic profiles, clinical characteristics, and treatment of mold infections of the central nervous system.

Molds are ubiquitous organisms found in soil, water, and decaying vegetation. All have septate, angular, branching hyphae in tissue, with the exception of those in the order Mucorales, which have broad, ribbonlike, nonseptate or hyposeptate hyphae.

Clinical Pearls

What is the typical mechanism by which fungal infections reach the CNS?

The respiratory tract is usually the portal of entry, with subsequent hematogenous dissemination to the CNS. However, direct inoculation of CNS or paraspinal tissue as a result of surgery, trauma, intravenous drug use, or contaminated medical supplies may also occur in immunocompetent persons. Organisms may also spread to the CNS from adjacent structures, including the sinuses, mastoid, and orbit. Infection of the ethmoid sinuses may lead to cavernous sinus thrombosis as a result of invasion of the emissary veins that drain the sinuses. Hyphae can invade from the ethmoid sinuses through the lamina papyracea and into the periorbital space, thus threatening the eye, extraocular muscles, and posterior apical structures, including the optic nerve. Angioinvasion is common in immunocompromised patients and accounts for the hematogenous dissemination from the lungs that causes focal neurologic deficits.

What are the characteristics of CNS aspergillosis?

The risk factors for CNS aspergillosis include neutropenia, systemic glucocorticoid treatment, mastoidectomy, spinal anesthesia, and paraspinal glucocorticoid injections. Focal neurologic deficits and seizures caused by stroke or mass effect are the most common clinical manifestations of CNS aspergillosis. Meningeal signs are uncommon, and their presence is indicative of a subarachnoid hemorrhage. CNS aspergillosis should be high on the list of disorders in the differential diagnosis for patients with immunosuppression and focal brain lesions, especially those with characteristic pulmonary infiltrates in whom focal neurologic deficits or focal seizures develop. Recovery of aspergillus from pulmonary lesions with the use of bronchoalveolar lavage or fine-needle aspiration should be pursued when possible. An enzyme immunoassay for detection of galactomannan in serum or bronchoalveolar lavage fluid should be performed when feasible. Galactomannan and 1,3-(beta)-d-glucan may be found in the serum or CSF of patients with CNS aspergillosis. Voriconazole is the first-line treatment for CNS aspergillosis.

Morning Report Questions

Q: What are typical features of cerebral mucormycosis?

A: Cerebral mucormycosis, which is perhaps the most aggressive mold infection of the CNS, constitutes a medical emergency. Diabetes mellitus and iron-overload conditions are distinctive risk factors for the development of mucormycosis. In patients with neutropenia or patients receiving glucocorticoid therapy, mold infections of the CNS develop as sino-orbital infections or through hematogenous dissemination of pulmonary mucormycosis. In contrast, patients with diabetes mellitus usually present with sino-orbital mucormycosis and seldom present with pulmonary or disseminated infection. Among intravenous drug users, CNS mucormycosis is a relatively common cause of intracerebral fungal abscesses. Perhaps more than any other infection, mucormycosis of the ethmoid sinuses may involve all structures along its invasive path, including the orbit and eye, bone, and brain tissue. Because venous drainage of the ethmoid sinuses extends into the cavernous sinuses, ethmoidal mucormycosis carries a high risk of cavernous sinus thrombosis. Successful management of rhinocerebral mucormycosis depends not only on early diagnosis but also on primary antifungal therapy with amphotericin B, reversal of host impairments and timely surgical intervention, when indicated.

Q: What are the features of CNS infection with fusarium species?

A: CNS fusariosis develops predominantly in patients with prolonged neutropenia. These organisms are highly angioinvasive and cause hemorrhagic infarction with strokelike events. Portals of entry include the lungs, sinuses, vascular catheters, and distinctively, periungual lesions (paronychia in patients with neutropenia). Fusarium species are also most frequently associated with fungemia, multiple erythematous nodular cutaneous lesions, and septic arthritis. A definitive mycologic diagnosis can be rapidly established by biopsy and culture of cutaneous lesions. As compared with other mold infections of the CNS, disseminated fusariosis is more commonly associated with bilateral endophthalmitis, which may lead to blindness. Fusarium species vary in their susceptibility to antifungal agents. Voriconazole is licensed for second-line therapy; however, amphotericin B also has been used successfully.

Take the Case Challenge

Posted by Jennifer Zeis • July 10th, 2014

A 41-year-old man was admitted to the hospital in midsummer because of fever, rash, pancytopenia, and abnormal results of liver-function tests. What is the diagnosis? What diagnostic tests are indicated?

Read the case description for the next Case Record of the Massachusetts General Hospital, and then vote and comment now on NEJM.org. In a few days, find the answer in the full text of the Case Record to be published July 24.

Follow the conversation with #NEJMCases on Twitter or Facebook.

Dupilumab as a Treatment for Atopic Dermatitis

Posted by Rachel Wolfson • July 9th, 2014

For thousands of years, our knowledge of medications has largely been based on trial and error: we haphazardly used substances and learned from the effects. Within the last half a century, however, rational drug design slowly took to the forefront as scientific discoveries improved our understanding of the underlying pathogenesis of diseases. While there have not been many victories for rational drug design so far, dupilumab is a key one on a small but growing list. As a monoclonal antibody that targets cytokines involved in type 2 helper T cell (Th2) activation, dupilumab has already demonstrated preliminary efficacy for asthma, a disease which is known to be driven, at least in part, by Th2 activation. Furthermore, Th2 activation has also been implicated in the pathogenesis of atopic dermatitis, a disease characterized by skin barrier abnormalities, Th2 immune responses, and pruritis.

To evaluate the importance of Th2 activation in the pathogenesis of atopic dermatitis and the efficacy of dupilumab as a treatment, Beck and colleagues conducted four randomized, double-blinded, placebo-controlled clinical trials and reported their results in this week’s NEJM. Two of the trials (studies M4A and M4B) were originally designed primarily for safety analysis but the clinical effects were striking. The patients were randomly assigned to four weeks of treatment with either dupilumab or placebo. Another trial (study M12) followed 109 patients for 12 weeks after initiating monotherapy with either dupilumab or placebo. The primary objective was to assess clinical efficacy. Finally, a fourth trial (study C4) compared dupilumab in combination with topical glucocorticosteroids to placebo with topical glucocorticosteroids. The primary endpoints after four weeks of combination therapy were the incidence and severity of adverse events.

In studies M4A and M4B, patients treated with dupilumab showed rapid and dose dependent improvements in all clinical outcomes that were tested, such as pruritis scale rating and improvement in eczema area. This improvement was also seen in patients treated with dupilumab at the four-week point in study M12, and this treatment group continued to improve throughout the entire 12-week course. Similarly, in study C4, patients treated with dupilumab in combination with topical glucocorticosteroids had better improvements in clinical outcomes than those treated with placebo and topical glucocorticosteroids. Finally, in terms of safety measures, there were more mild to moderate adverse events in the patients treated with dupilumab (i.e. nasopharyngitis and headache), but there were more serious adverse events in the placebo group, mostly due to skin infections and atopic dermatitis.

Overall, the data provide solid evidence for the key role of Th2 activation in the pathogenesis of the disease; these trials cannot address the clinical utility of the treatment. This advance reflects the importance of studying the molecular underpinning of diseases, because if we can truly understand the biology, we will find effective therapies for even the most stubborn illnesses.

Acute Kidney Injury and Chronic Kidney Disease

Posted by Sara Fazio • July 4th, 2014

This new review article considers evidence that acute and chronic kidney diseases are not distinct entities but rather are closely interconnected.  The implications of this insight are discussed in terms of the approach to patients with kidney disease.

During the past decade, separate conceptual models for chronic kidney disease and acute kidney injury were developed to facilitate organized approaches to clinical research and trials. Recent epidemiologic and mechanistic studies suggest that the two syndromes are not distinct entities but rather are closely interconnected — chronic kidney disease is a risk factor for acute kidney injury, acute kidney injury is a risk factor for the development of chronic kidney disease, and both acute kidney injury and chronic kidney disease are risk factors for cardiovascular disease.

Clinical Pearls

What is considered to be the most important risk factor for acute kidney injury?

Multiple risk factors for acute kidney injury are now known to include advanced age, diabetes mellitus, and black race. Similar risk factors have been identified for chronic kidney disease. However, the most important risk factor for acute kidney injury is preexisting chronic kidney disease, which increases risk by as much as 10 times, as compared with the absence of chronic kidney disease.

Figure 1. Acute Kidney Injury and Chronic Kidney Disease as an Interconnected Syndrome.

How does acute kidney injury impact the risk of developing chronic kidney disease?

Several findings suggest that acute kidney injury not only is directly linked to the progression of chronic kidney disease but causes chronic kidney disease as well. First, the increased severity of acute kidney injury is associated with the development of chronic kidney disease. Second, multiple episodes of acute kidney injury predict the development of chronic kidney disease.

Morning Report Questions

Q: What is the association between acute kidney injury or chronic kidney disease and cardiovascular disease?

A: In addition to being associated with chronic kidney disease, acute kidney injury is linked to the development and treatment of cardiovascular disease. A strong association between chronic kidney disease and an increased risk of cardiovascular events is well documented. Patients who survive an episode of acute kidney injury are also at risk for major adverse cardiovascular events, as well as for progression to chronic kidney disease, regardless of whether there is underlying cardiovascular disease. Patients with acute kidney injury after coronary angiography are at risk for hospitalization for cardiovascular causes, myocardial infarction, and vessel reocclusion; the severity of acute kidney injury has been associated with hospitalization for heart failure. Acute kidney injury is associated with higher rates of death or subsequent hospitalization for stroke, heart failure, or myocardial infarction than the rates associated with previous myocardial infarction.

Figure 1. Acute Kidney Injury and Chronic Kidney Disease as an Interconnected Syndrome.

Q: What are strategies for management after an episode of acute kidney injury?

A: Patients with acute kidney injury should have periodic assessment of renal function and the urinary albumin-to-creatinine ratio to assess prognosis and outcome after discharge. The appropriate treatment for patients who survive an episode of acute kidney injury, regardless of whether they have chronic kidney disease, is unclear. Reasonable therapeutic approaches to patients who do not have preexisting kidney disease but do have evidence of renal injury include, first, “do no harm,” by avoiding nephrotoxic medications, including nonsteroidal antiinflammatory drugs and radiocontrast agents. In addition, one needs to determine the appropriate treatment for important risk factors for chronic kidney disease such as diabetes and hypertension. The preventive use of inhibitors of the renin-angiotensin-aldosterone system, low-sodium diets, or both should be evaluated in such patients. The authors note that it is not known whether these therapeutic approaches ameliorate or worsen outcomes in patients with acute kidney injury or in those with combinations of acute kidney injury and chronic kidney disease. Patients who have had acute-on-chronic episodes of acute kidney injury and chronic kidney disease should be followed by primary care physicians as well as nephrologists to ensure the highest standards of care.

Giant-Cell Arteritis and Polymyalgia Rheumatica

Posted by Sara Fazio • July 4th, 2014

Both giant-cell arteritis and polymyalgia rheumatica are immune-mediated diseases that are treated with glucocorticoids, with higher doses used for giant-cell arteritis. In our latest Clinical Practice article, prompt initiation of high doses and a biopsy are recommended when ischemic optic neuropathy is suspected.

Giant-cell arteritis is an inflammatory vasculopathy that typically occurs in medium and large arteries with well-developed wall layers and adventitial vasa vasorum. The vascular beds that are usually affected include the external carotid branches (e.g., temporal and occipital arteries), the ophthalmic, vertebral, distal subclavian, and axillary arteries, and the thoracic aorta. Polymyalgia rheumatica causes aching and stiffness in selected muscle groups, predominantly in the neck, shoulders, upper arms, and pelvic girdle. Symptoms are most pronounced in the morning.

Clinical Pearls

What is the epidemiology of giant-cell arteritis and polymyalgia rheumatica, and how often do the diagnoses overlap?

Giant-cell arteritis and polymyalgia rheumatica have multiple risk factors and pathogenic abnormalities in common. Approximately 50% of patients with giant-cell arteritis present with polymyalgia rheumatica before, at the time of, or after the diagnosis of vasculitis. Symptoms of polymyalgia rheumatica often appear when the therapy for giant-cell arteritis is being tapered. Both giant-cell arteritis and polymyalgia rheumatica are diseases that affect the elderly, with a peak incidence at the age of 70 to 80 years; age (50 years or older) is considered a criterion for the diagnosis. Women account for 65 to 75% of patients. Polymyalgia rheumatica occurs at a frequency that is 3 to 10 times that of giant-cell arteritis.

What are laboratory results in patients with giant-cell arteritis and polymyalgia rheumatica?

Marked elevations in the erythrocyte sedimentation rate (ESR) and the level of C-reactive protein (CRP) are common in giant-cell arteritis and polymyalgia rheumatica, as are the presence of thrombocytosis and anemia. In a cohort of 764 patients with suspected giant-cell arteritis who underwent biopsy, with the diagnosis confirmed in 177 patients, the sensitivity of an elevated ESR was 84% and that of an elevated CRP level was 86%; the specificity of these markers was low, however, at 30%. Only 4% of patients with confirmed giant-cell arteritis had both a normal ESR and a normal CRP level at the time of diagnosis. Assessment of inflammatory markers is helpful during diagnostic evaluation and long-term monitoring, but elevated levels of these markers should not be the only indication for immunosuppressive therapy. No highly specific biomarkers for giant-cell arteritis and polymyalgia rheumatica have been validated.

Morning Report Questions

Q: What is the standard for diagnosis of suspected giant-cell arteritis?

A: In cases of suspected giant-cell arteritis, histologic verification of vasculitis should be sought by means of a temporal-artery biopsy with assessment of a vascular segment that is 1.5 to 2.0 cm in length. Histologic analysis is the standard for diagnosis; it can detect small inflammatory infiltrates and can also distinguish giant-cell arteritis from non-giant-cell arteritis arteritides (e.g., ANCA-associated vasculitis). High-field-strength MRI may emerge as a method that is sensitive to the detection of temporal-artery inflammation, but neither ultrasonography nor MRI has yet replaced temporal-artery biopsy, which is highly sensitive for even minor inflammatory changes.

Q: What is the optimal treatment for giant-cell arteritis and polymyalgia rheumatica?

A: Giant-cell arteritis and polymyalgia rheumatica are responsive to glucocorticoids. Most treatment recommendations are based on clinical experience rather than the results of randomized, controlled trials. Therapy for giant-cell arteritis is initiated with prednisone at a dose of 1 mg per kilogram of body weight per day. Given the risk of irreversible ischemic complications, new-onset clinical manifestations of disease indicating an unstable supply of blood to the eyes or the central nervous system (e.g., arteritic optic neuropathy) are typically managed with intravenous pulse therapy (e.g., 1000 mg of methylprednisolone per day for 3 consecutive days) to optimize immunosuppression and suppress tissue edema. The doses of glucocorticoids used to treat polymyalgia rheumatica are much lower than those used for the treatment of giant-cell arteritis. In the majority of patients, a dose of 15 to 20 mg of prednisone per day is sufficient to control myalgia. No glucocorticoid-sparing agents have been approved for the treatment of giant-cell arteritis or polymyalgia rheumatica.

Glucocorticoid Injections for Spinal Stenosis

Posted by Daniela Lamas • July 2nd, 2014

Spinal stenosis is a pain – both for those who suffer it, and the doctors who treat it.

As surgery is a potentially risky option with uncertain benefit, many doctors turn to glucocorticoid injections for their patients, to decrease pain and increase mobility.  An estimated ten to eleven million such injections are performed in the US annually, numbers that have grown rapidly in recent years.

But do glucocorticoid injections actually help? A recent review from the North American Spine Society highlighted the paucity of data, concluding that there is insufficient evidence to make a recommendation either for or against. And this therapy isn’t always benign. While serious complications are rare, complications including paralysis and nerve damage have been reported.

With this background, Janna Friedly and colleagues set out to determine whether glucocorticoid injections actually benefit patients with spinal stenosis. Their results, published in this week’s issue of NEJM, suggest that the increasingly popular treatment is no better than their comparator, an injection of lidocaine alone.

The study investigators enrolled 400 patients with lumbar spinal stenosis, whose disease caused them moderate-to-severe leg pain and disability and who had been referred for steroid injections. All study participants were older than 50 and hadn’t ever undergone lumbar surgery, or received epidural steroid injections in the previous six months. Patients were randomly assigned to either epidural glucocorticoid injection with lidocaine, or lidocaine injection alone. The participants could receive a second injection three weeks later, at the patient’s discretion.

After six weeks, patients in both groups were asked to rate their average buttock, hip and leg pain in the previous week and to fill out a questionnaire that quantifies degree of pain and associated disability. They were also asked to respond to surveys of depression, anxiety and quality of life.

The results? Both groups of patients reported improvement in their pain and physical function at three and six weeks, whether or not their injections included glucocorticoids. At six weeks, there were no significant differences in pain or function ratings between the two groups. Of note, the patients randomly assigned to the glucocorticoid injections were more likely to have improvement in depressive symptoms. Those receiving glucocorticoid injections had a higher rate of adverse events, although the complications were generally mild.

In an accompanying editorial discussing these results, orthopedic surgeon Gunnar Anderson notes the difficulties inherent in trials of treatments for spinal stenosis. For one, spinal stenosis is a heterogeneous disease both in terms of cause – congenital versus degenerative – location, and extent. Additionally, Friedly’s trial did not include a control group that received sham injections, leaving open the question of whether the benefit seen in both groups could be due to the lidocaine injection itself, although this would be unlikely.

Despite these questions, Anderson concludes that the study “raises serious questions about benefits from epidural corticosteroid injections for spinal stenosis…Patients should be informed that currently best available data have not supported a significant long term clinical benefit overall, and that complications are possible.”

Dying with Dignity in the Intensive Care Unit

Posted by Sara Fazio • June 27th, 2014

It is common for patients to have an expected death in an ICU. The final review in the Critical Care series covers issues related to the end of life in the absence of discordance between the patient’s family and caregivers.

The traditional goals of intensive care are to reduce the morbidity and mortality associated with critical illness, maintain organ function, and restore health. Despite technological advances, death in the intensive care unit (ICU) remains commonplace.

Clinical Pearls

According to the authors, what are the principles of “dying with dignity?”

The definition of “dying with dignity” recognizes the intrinsic,unconditional quality of human worth but also external qualities of physical comfort, autonomy, meaningfulness, preparedness, and interpersonal connection. Respect should be fostered by being mindful of the “ABCDs” of dignity-conserving care (attitudes, behaviors, compassion, and dialogue).

Table 1. Examples of the ABCDs of Dignity-Conserving Care.

How is palliative care defined by the World Health Organization?

The World Health Organization defines palliative care as “an approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual.” Palliative care, which is essential regardless of whether a medical condition is acute or chronic and whether it is in an early or late stage, can also extend beyond the patient’s death to bereaved family members.

Figure 1. Curative and Palliative Approaches to Care throughout a Critical Illness.

Morning Report Questions

Q: How is family satisfaction in the ICU setting impacted by communication with clinicians?

A: Clear, candid communication is a determinant of family satisfaction with end-of-life care. Notably, measures of family satisfaction with respect to communication are higher among family members of patients who die in the ICU than among those of ICU patients who survive, perhaps reflecting the intensity of communication and the accompanying respect and compassion shown by clinicians for the families of dying patients. The power of effective communication also includes the power of silence. Family satisfaction with meetings about end-of-life care in the ICU is greater when physicians talk less and listen more.

Q: How many physicians in the ICU feel comfortable making recommendations to forgo the use of life-supporting technology, and how many report consistently doing so?

A: Physicians in the ICU sometimes make recommendations to forgo the use of life-support technology. In one study involving surrogates of 169 critically ill patients, 56% preferred to receive a physician’s recommendation on the use of life support, 42% preferred not to receive such a recommendation, and 2% stated that either approach was acceptable. A recent survey of ICU physicians showed that although more than 90% were comfortable making such recommendations and viewed them as appropriate, only 20% reported always providing recommendations to surrogates, and 10% reported rarely or never doing so. In this study, delivering such recommendations was associated with perceptions about the surrogate’s desire for, and agreement with, the physician’s recommendations. Other potential influences are uncertainty, personal values, and litigation concerns.