Diseases 2.0

Chronic Stable Angina 2.0

August 4, 2010

By Brad Pfeffer, MD

Faculty Peer Reviewed

Case: A 75- year-old non-smoking male with a history of type II diabetes, hypertension and hyperlipidemia comes to clinic with several months of stable anginal chest pain provoked by ten blocks of exercise with no change in exercise tolerance. He has seen you several times over the past year and has been placed on aspirin, beta blockers, calcium channel blockers and long acting nitrates with some relief of symptoms. In addition, he is on atorvastatin with an LDL of 77. His blood pressure is well controlled at 122/78 and his heart rate is 62.  His BMI is 25.   An EKG shows a normal sinus rhythm at 62 with no evidence of prior myocardial infarction. A transthoracic echo shows a normal ejection fraction with no wall motion abnormalities. An adenosine nuclear stress test was performed that showed a small reversible perfusion defect in the territory of the distal circumflex with a normal ejection fraction.  The patient asks if there are any further medical options or if it isnecessary for him to have a percutaneous intervention.

Coronary artery disease continues to be a leading cause of death among both women and men. Angina pectoris is one of several syndromes that results from coronary artery disease. The symptoms of angina manifest as chest discomfort resulting from insufficient supply of oxygen to the heart with increasing demand.  In the United States, 16 million adults suffer from coronary artery disease and of those 9.1 million have angina. The total cost of coronary artery disease is 475.3 billion dollars [1]. Moreover, the number of patients suffering from and the health care cost of angina will continue to rise with a growing aging population.

The traditional medical management of chronic stable angina attempts to balance oxygen supply and demand and prevent thrombosis while minimizing cardiovascular risk factors through smoking cessation, weight loss, blood pressure, cholesterol and diabetic management.  Medical management includes the use of beta-blockers, calcium channel blockers, nitrates, statins and antiplatelet therapy including aspirin or clopidogrel in patients intolerant of aspirin [2-3]. Beta-blockers should be titrated to reduce the resting heart rate to 55-60 beats per minute. In more severe cases of angina, beta-blockers can be titrated to a heart rate less than 50 if no adverse symptoms or heart block occur.  Sublingual nitroglycerin or spray nitroglycerin can be used for immediate relief of angina or prophylaxis prior to anginal causing activities. Long acting nitrates, such as isosorbide dinitrate, mononitrates, transdermal nitroglycerin patches, and nitroglycerin ointment can be used to prevent angina. Patients must have a nitrate free period of 8 to 12 hours in order to prevent nitrate tolerance [4].  Long acting nitrates can be titrated for prevention of symptoms as long as no hypotension or side effects such as headaches develop.

There is little data to suggest that dual antiplatlet therepy is beneficial in patients with stable coronary disease. Data from the CHARSIMA trial has shown that dual antiplatelet therapy with aspirin and plavix does not reduce the rate of cardiovascular events but does increase the rate of bleeding when compared to aspirin alone [5]. However, in post hoc analysis the CHARISMA trial did show a significant reduction in cardiovascular events in patients with stable chronic angina with prior history of MI, stroke or symptomatic peripheral arterial disease [6-7]. As a result, dual antiplatelet therapy may be useful for patients at the highest risk for adverse events or who have recently undergone percutaneous coronary intervention (PCI).

Revascularization continues to be the routine treatment for refractory angina. According to the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Interventions patients continuing to have angina despite medical optimization (beta-blockers, calcium channel blockers, nitrates and antiplatelets therapy) should undergo PCI if there is a low likelihood of mortality and morbidity and high likelihood of success [8].  However, the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) sought to compare clinical endpoints in patients receiving medical management alone verse medical management plus PCI.

The COURAGE trial compared cardiovascular outcomes of PCI as an initial management for chronic stable angina to optimal medical therapy alone. In the COURAGE trial, 2287 patients with evidence of ischemia or significant coronary artery disease where randomized to receive PCI plus medical optimization therapy or medical optimization alone. All patients received ischemic therapy with beta-blockers, calcium channel blockers, long and short acting nitrates, as well as antiplatelet therapy with either aspirin or clopidogrel and aggressive lipid-lowering therapy, including administration of a statin with or without ezitimibe. In the initial follow up period, there was a statistically significant reduction in the number of anginal free patients in the PCI group, at one and three years (respectively 66% vs 58%, P< 0.001 and 72% vs 67%, P=0.02). The benefit of PCI persisted at five years. However, at five years, the number of patients that were free of angina, between the two groups, was not statistically significant (74% in the PCI group and 72% in the medical therapy group, P=0.35). It is important to note that 36.6% of all patients in the medical therapy group crossed over to the PCI group by five years. The study did not find any statistical difference between the PCI and medical therapy group in composite death, myocardial infarction and stroke (respectively 20% and 19.5%, P=0.62). [9]. This study supports the idea that PCI is not superior to optimal medical management in terms of death, myocardial infarction and stroke in patients with stable coronary artery disease. However, PCI continues to be beneficial for anginal symptom relief, but can be safely deferred in patients with stable coronary artery disease who are optimally medically managed.

How should you treat patients that continue to have anginal symptoms despite lifestyle and dietary modifications and the addition of anginal medications such as beta-blockers, calcium channel blockers, nitrates and antiplatelet therapy? Or how do you treat patients that have undergone catheterization with no known lesion or are not candidates for catheterization? Is there any medical therapy beyond the current guidelines?

Ranolazine (Ranexa) was approved by the Food and Drug Administration for chronic stable angina in 2006. The use of ranolazine has been shown to be effective to improve anginal symptoms in several studies [9-10]. Ranolazine is a piperazine derivative that works through the inhibition of the late inward sodium current in cardiac cells.  Inhibition of late inward sodium current in cardiac cells leads to a decrease in intracellular calcium, increased myocardial relaxation during diastole and inhibits the rapidly activating component of the delayed rectifier potassium current (IKr). Although ranolazine inhibits the delayed rectifier potassium current and causes a modest increase in QTc, it is not associated with proarrhythmic activity [11]. However, given the possibility of prolongation of the QTc, a baseline EKG and EKG after initiation should be obtained. In clinical study, ranolazine does not statistically affect heart rate or blood pressure [12].

The Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) trial, a multi-national, randomized, double-blind, placebo-controlled study, was the first trial of ranolazine SR 500, 1000 and 1500 mg BID  monotherapy in patients with chronic angina. The study population consisted of patients older than 21 years of age with well-documented coronary artery disease, angina pain for at least three months that responded to beta-blockers, calcium channel blockers and/or long acting nitrates. During the study, all patients discontinued their anti-anginal treatment.  Comparison of exercise stress testing before and after treatment showed that exercise duration increased with ranolazine 500, 1,000, and 1,500 mg twice daily by, respectively, 94, 103, and 116 seconds (P< 0.005).  The increase in exercise performance from monotherapy ranolazine is similar to those reported for maximal doses of nitrates, beta-blockers and calcium channel blockers. [12]

The Combination Assessment of Ranolazine In Stable Angina (CARISA) trial examined the exercise tolerance, angina attacks and nitroglycerin use of 823 patients with symptomatic chronic angina taking standard doses of atenolol (50 mg), amlodipine (5 mg), or diltiazem (180 mg once daily) before and 12 weeks after being randomized to receive 750 mg or 1000 mg twice daily of ranolazine or placebo.  Ranolazine reduced the mean number of angina attacks per week from 3.3 ± 0.3 for placebo to 2.5 ± 0.2 for 750 mg (p = 0.006) to 2.1 ± 0.2 for 1000 mg (p < 0.001) ranolazine. It also significantly reduced nitroglycerin consumption (p < 0.02). Exercise duration increased significantly with ranolazine by 115.6 seconds from baseline in both ranolazine groups vs 91.7 seconds in the placebo group (P = .01).  The time to onset of anginal symptoms increased significantly in both the 750 mg and 1000 mg group (respectively 144 seconds, P=0.01 and 140.3 seconds, P=0.03).  There were no clinically significant changes in blood pressure or heart rate. These finding were independent of background therapy, and persisted for 12 weeks [10]. Similar reduction in angina symptoms were reported in the Efficacy of Ranolazine In Chronic Angina (ERICA) trial that examined the use of amlodipine (10 mg) and ranolazine (1000 mg twice daily) [13]. Post hoc analysis of diabetics in the CARISA trial showed a significant reduction in HbA1C levels [14].

Chronic angina is a debilitating disease that impacts millions of Americans. The mainstay of treatment involves dietary and lifestyle modifications along with beta-blockers, calcium channel blockers, nitrates, statins and antiplatelet therapy. Current guidelines reflect these mainstays of treatment. Ranolazine should be used as second line treatment when beta-blockers, nitrates and calcium channel blockers have failed to relieve symptoms. Unlike other anti-anginal medications ranolazine does not affect hemodynamics. As a result, ranolazine should be used in addition or alone when the titration or use of beta-blockers, calcium channel blockers or nitrates is limited by blood pressure or heart rate.  The most common side effects of ranolazine include dizziness (11.8%) and constipation (10.9 %). These symptoms led to discontinuation of ranolazine in 0.9% and 0.5% of patients, respectively [15].  Syncope and orthostatic hypotension has been seen in a minority of patients receiving 1000 mg twice daily. This may be due to alpha blockade with higher doses of ranolazine and possible drug interaction between higher doses of ranolazine and diltiazem [10]. As a result, it is recommended that clinicians start at the lowest possible dose of ranolazine and titrate up to effectiveness and tolerability. Ranolazine is contraindicated in patients with preexisting long QT prolongation intervals and should be used with caution with other medications that prolong QT intervals. It is also contraindicated in clinically significant liver disease. It should be used with caution in patients with Childs-Pugh class A or B liver impairment.  Ranolazine is a potent inhibitor of CYP3A4, thus it should be used with caution in combination with other drugs that utilize CYP3A4 such as diltiazem and verpamil. When used with medications that use CYP3A4 the dose of ranolazine should not exceed 500 mg twice daily.  Ranolazine also interferes with the metabolism of digoxin and simvastatin, thus dose reduction of these drugs may be necessary.

In conclusion, the addition of ranolazine to current guidelines may defer the decision for patients with chronic angina to go for PCI. It is likely that ranolazine may be part of future chronic angina management guidelines and should be considered in patients with chronic stable angina.

Commentary by Sohah Iqbal, MD, Division of Cardiology

As the above thoughtful review has highlighted, medical therapy for coronary disease and chronic stable angina continues to evolve. Ranolazine, anecdotally and in clinical trials, has been shown to improve exercise capacity in those with activity limiting angina. There are 2 key criteria that need to be met before adding ranolazine: (1) Identifying patients with chronic stable angina and (2) Ensuring that these patients are on optimal medical management.

Angina that progressively limits patient in their basic activities of daily living or angina changing in character and pattern need to be identified as unstable in nature and should be treated via a different algorithm. Also, before adding ranolazine, patients with coronary artery disease and chronic stable angina must be on medications that have been shown to reduce clinical end points such as aspirin, beta blockers, statins, and in certain subgroups, ace-inhibitors.  Once these two criteria have been met, ranolazine is an excellent additional agent to manage chronic stable angina.

Dr. Pfeffer is Chief Resident at NYU Langone Medical Center

Peer reviewed by Sohah Iqbal, MD, Division of Cardiology, NYU Langone Medical Center


1.         Rosamond, W., et al., Heart disease and stroke statistics–2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation, 2008. 117(4): p. e25-146.

2.         Trujillo, T.C. and P.P. Dobesh, Traditional management of chronic stable angina. Pharmacotherapy, 2007. 27(12): p. 1677-92.

3.         Fraker, T.D., Jr., et al., 2007 chronic angina focused update of the ACC/AHA 2002 Guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 Guidelines for the management of patients with chronic stable angina. Circulation, 2007. 116(23): p. 2762-72.

4.         Gibbons, R., Abrams, J, Chatterjee, K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina.   [cited 2009 September 13]; Available from: http://www.acc.org/qualityandscience/clinical/guidelines/stable/stable_clean.pdf.

5.         Bhatt, D.L., et al., Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med, 2006. 354(16): p. 1706-17.

6.         Bhatt, D.L., et al., Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol, 2007. 49(19): p. 1982-8.

7.         Bakhru, M.R. and D.L. Bhatt, Interpreting the CHARISMA study. What is the role of dual antiplatelet therapy with clopidogrel and aspirin? Cleve Clin J Med, 2008. 75(4): p. 289-95.

8.         Smith, S.C., Jr., et al., ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention). Circulation, 2006. 113(7): p. e166-286.

9.         Wilson, S.R., et al., Efficacy of ranolazine in patients with chronic angina observations from the randomized, double-blind, placebo-controlled MERLIN-TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Segment Elevation Acute Coronary Syndromes) 36 Trial. J Am Coll Cardiol, 2009. 53(17): p. 1510-6.

10.       Chaitman, B.R., et al., Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA, 2004. 291(3): p. 309-16.

11.       Keating, G.M., Ranolazine: a review of its use in chronic stable angina pectoris. Drugs, 2008. 68(17): p. 2483-503.

12.       Chaitman, B.R., et al., Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol, 2004. 43(8): p. 1375-82.

13.       Stone, P.H., et al., Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J Am Coll Cardiol, 2006. 48(3): p. 566-75.

14.       Timmis, A.D., B.R. Chaitman, and M. Crager, Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur Heart J, 2006. 27(1): p. 42-8.

15.       Koren, M.J., M.R. Crager, and M. Sweeney, Long-term safety of a novel antianginal agent in patients with severe chronic stable angina: the Ranolazine Open Label Experience (ROLE). J Am Coll Cardiol, 2007. 49(10): p. 1027-34.

Alzheimer’s Disease 2.0

May 12, 2010

Jeffrey Mayne MD

Faculty peer reviewed

Dr. Okonkwo’s post this past summer to PrimeCuts summarized ongoing research in Alzheimer’s Disease (AD), the most common cause of dementia affecting 15 million individuals worldwide and more than 5 million in the United States. It is a disease marked by cognitive deterioration that slowly breaks down one’s ability to perform activities of daily living and leaves individuals unable to care for themselves.

Briefly, the diagnosis of AD is based on clinical criteria and histologic confirmation at death. Based on these findings, the disease is broken into three categories: definite, probable, and possible. Classic clinical features include an amnestic type memory impairment (a partial or total loss of antegrade memory and impaired learning with preserved general cognition), deterioration of language, and visuospatial deficits. Definitive diagnosis is by pathologic examination, though biopsy is not routinely performed because of the danger of the procedure, the cost, and low yield. In a patient who presents with symptoms suspicious for Alzheimer’s, brain imaging, preferably MRI, is performed.

Imaging techniques differentiate AD from other causes of dementia, including cerebrovascular disease, structural diseases (i.e. chronic subdural hematoma, cerebral neoplasm, normal pressure hydrocephalus) as well as regional brain atrophy such as frontotemporal dementia. In AD there is nonspecific focal and diffuse atrophy, as well as white matter lesions, though some investigators have associated reduced hippocampal volumes with the disease. There are no laboratory tests to diagnose AD.

The Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) defines the clinical criteria for diagnosis as: (1) a standardized brief mental status exam; (2) deficits in two or more areas of cognition; (3) progressive worsening of memory; (4) no disturbance of consciousness; and (5) onset between ages 40 and 90. The pathological hallmarks include neuronal intracellular neurofibrillary tangles of hyperphosphorylated tau proteins and extracellular deposits of synaptotoxic ß-amyloid (Aß) peptides in fibril structures. Read more »

Alzheimer’s Disease 2.0

April 21, 2010

Jeffery Mayne MD

Faculty peer reviewed

Dr. Okonkwo’s post this past summer to PrimeCuts summarized ongoing research in Alzheimer’s Disease (AD), the most common cause of dementia affecting 15 million individuals worldwide and more than 5 million in the United States. It is a disease marked by cognitive deterioration that slowly breaks down one’s ability to perform activities of daily living and leaves individuals unable to care for themselves.

Briefly, the diagnosis of AD is based on clinical criteria and histologic confirmation at death. Based on these findings, the disease is broken into three categories: definite, probable, and possible. Classic clinical features include an amnestic type memory impairment (a partial or total loss of antegrade memory and impaired learning with preserved general cognition), deterioration of language, and visuospatial deficits. Definitive diagnosis is by pathologic examination, though biopsy is not routinely performed because of the danger of the procedure, the cost, and low yield. In a patient who presents with symptoms suspicious for Alzheimer’s, brain imaging, preferably MRI, is performed.

Imaging techniques differentiate AD from other causes of dementia, including cerebrovascular disease, structural diseases (i.e. chronic subdural hematoma, cerebral neoplasm, normal pressure hydrocephalus) as well as regional brain atrophy such as frontotemporal dementia. In AD there is nonspecific focal and diffuse atrophy, as well as white matter lesions, though some investigators have associated reduced hippocampal volumes with the disease. There are no laboratory tests to diagnose AD.

The Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) defines the clinical criteria for diagnosis as: (1) a standardized brief mental status exam; (2) deficits in two or more areas of cognition; (3) progressive worsening of memory; (4) no disturbance of consciousness; and (5) onset between ages 40 and 90. The pathological hallmarks include neuronal intracellular neurofibrillary tangles of hyperphosphorylated tau proteins and extracellular deposits of synaptotoxic ß-amyloid (Aß) peptides in fibril structures.

Current research in AD is focused on identifying the onset of the pathological processes, to detect AD in its earliest stages in order to gain a better understanding of its pathogenesis. The July 2009 JAMA article Use of Alzheimer Disease Biomarkers reports on the utility of cerebrospinal fluid (CSF) markers ß-amyloid (Aß42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with mild cognitive impairment (MCI). The research concludes that CSF Aß42, T-tau, and P-tau identify incipient AD with good accuracy, that these biomarkers could be used to predict outcomes, and that they could potentially be useful in identifying patients for clinical trials and for screening tests in memory clinics.

Of critical importance is the fact that at this time no treatment exists to prevent or alter the course of the disease. A recent review by the American College of Physicians and the American Academy of Family Physicians found little evidence that drug treatments are clinically meaningful. Three of the most common medications used in practice today are donepezil, rivastigmine and galantamine. These work by reversibly and noncompetitively inhibiting centrally active acetylcholinesterase, the enzyme that hydrolyzes acetylcholine, resulting in increased concentrations of acetylcholine available for synaptic transmission in the central nervous system. Galantamine also modulates the nicotinic acetylcholine receptor to increase acetylcholine from surviving presynaptic nerve terminals.

Current FDA approved treatment for AD consists of the cholinesterase inhibitors, including donepezil. Overall, cholinesterase inhibitors such as tacrine, donepezil, and rivastigmine have shown marginal benefits, though their effects have been shown to be statistically significant. Importantly, they are generally well tolerated by patients; the adverse effects on the alimentary tract associated with the cholinesterase inhibitors are transient and occur in a small percentage of cases. Other medications either in clinical trials or for which only preliminary data exists include the antioxidant vitamin E, drugs such as selegine and memantine (an NMDA antagonist), anti-inflammatory agents (such as prednisone, diclofenac, rofecoxib, and naproxen), as well as hormone-replacement therapies. A trial by Aisen, Scheider, Sano, et al. reported in JAMA determined that treatment with high-dose vitamin B supplements for 18 months did not slow cognitive decline in individuals with mild to moderate AD.

Ongoing research is aimed at identifying AD in its earliest stages and preventing its progression. Chelators, which may help in promoting the degradation of amyloid beta plaques have been studied in phase II randomized controlled trials, with treatment associated with a dose-dependent reduction in amyloid beta-42 levels in the cerebrospinal fluid. In other research the inhibition of beta-secretase has been shown to have a dose-related effect on activities of daily living and global function.

Researchers are also investigating the possibility of vaccination. Early studies in mice have shown that immunization with amyloid beta peptide reduced amyloid cerebral angiopathy (the accumulation ofAß in the wall of vascular vessels). A study published in the Lancet in July 2008 showed a decrease in post-mortem amyloid cerebral angiopathy in eight immunized patients compared to non-immunized controls. Despite the results, seven of eight patients had severe end-stage dementia at the time of death. Additionally,, immunized patients had a greater amyloid beta plaque burden in cortical blood vessels compared to non-immunized patients. Although in this study, vaccinated patients experienced a progression of disease to the final stage, there are a number of studies indicating beneficial effects of the treatment on the disease course, even though these trials were prematurely halted.

Finally, the use of CSF biomarkers is being explored, with the hope of identifying the disease in its earliest stages before the cognitive effects are apparent. Future research will utilize neuroimaging techniques, including positron emission tomography (PET), FDG-PET or SPECT scans, which reveal distinct regions of low metabolism and hypoperfusion in AD. In addition. PiB (Pittsburg Compound B) PET will be integrated with biomarker data to identify the optimal panel to use for predictive testing for AD, AD diagnosis and clinical trial monitoring.

Dr. Mayne is a first year resident in internal medicine at NYU Medical Center.


1.) Blennow K, deLeon MJ, Zetterberg H. Alzheimer’s disease. Lancet. 2006;368(9533):387-403.

2.) Cummings J. Alzheimer’s Disease. N Engl J Med. 2004; 351:56-67.

3.) Knopman, DS, DeKosky, ST, Cummings, JL, et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001; 56:1143.

4.) Silverman, DH, Small, GW, Chang, CY, et al. Positron emission tomography in evaluation of dementia: Regional brain metabolism and long-term outcome. JAMA 2001; 286:2120.

5.) McKhann G, Drachman D, Folstein M, et al. Clinical Diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health ad Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34:939.

6.) Mattsson N, Zetterberg H, Hansson O, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA. 2009;302(4):385-393.

7.) Savva G, Wharton S, Forster G, et al. Age, Neuropathy, and Dementia. N Eng J Med. 2009;360(22)2302-2309.

8.) Voelker R. Guideline: dementia drugs’ benefit uncertain. JAMA. 2008;299(15):1763.

9.) Aisen PS, Scheider LS, Sano M, et al. High-dose vitamin B supplementation and cognitive decline in Alzheimer disease. JAMA. 2008;300(15):1774-1783.

10.) Friedrich MJ. Therapeutic Environmental Design Aims to Help Patients with Alzheimer Disease. JAMA. 2009;301(23):2430-2433.

11.) Holmes C, Boche D, Wilkinson D, et al. Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomized, placebo-controlled phase I trial. Lancet. 2008; 372(9634):216-23.

Diseases 2.0: Rheumatoid Arthritis

September 18, 2009

raDiseases 2.0 – Bringing you the latest updates on disease pathophysiology and treatment

Rachana Jani MD

Faculty peer reviewed

Rheumatoid arthritis is a well-recognized but enigmatic disease afflicting the lives of thousands of individuals each year. The mysterious nature of RA has become increasingly uncovered as research has mapped various pathways of cytokine production and interleukin activation. However, in practice, we use clinical criteria to diagnose RA and evaluate the effectiveness of these new therapies.Though soon to be updated, the American College of Rheumatology (ACR) currently uses the following classification criteria to diagnose rheumatoid arthritis: morning stiffness greater than 1 hour, arthritis of three or more joints (PIP, MCP, wrist, elbow, knee, ankle, and MTP joints), involvement of wrist, MCP, or PIP joint, symmetric involvement, rheumatoid nodules, positive RF, radiographic changes of said joints. With the advent of multiple treatments for rheumatoid arthritis, ACR criteria have become the standard with which to compare trials and effectiveness of medications. ACR criteria measures improvement in at least three of the following five parameters: acute phase reactants, patient assessment, physician assessment, pain scale, disability/functional questionnaire. Often quoted are ACR 20,50 and 70 which indicates the percentage of patients who receive either 20, 50, or 70 percent improvement in tender and swollen joints as well as that percent improvement in three out of the above five criteria.

Early additions to the RA biologic arsenal include infliximab and etanercept – TNF antagonists, and anakinra – a recombinant IL-1 receptor antagonist. TNF-a is one of the cytokines that initiates and sustains the inflammatory pathway. IL-1 stimulates bone resorption and cartilage degradation. Though promising, these treatments are effective for only a subset of patients in this population. More recently in 2006, abatacept and rituximab were introduced. Abatacept interferes with signal transduction between the antigen presenting cell and the naïve T-cell via a fusion protein that competes with CD28 binding to CD80 and CD86. Without the binding of these co-stimulatory molecules, the pro-inflammatory T-cells cannot be fully activated. Largely used for people who have failed MTX and TNF inhibitors, abatacept has shown significant slowing of joint damage compared to placebo by ACR 20, 50 and 70 criteria at 1 year with sustained results into the second year [1]. Rituximab, known for its role in the treatment of B-cell lymphoma, is a CD20 antibody, expressed by both B-cell precursors and mature B-cells. B-cells, via CD40/CD40 ligand, are stimulated to induce the production of auto-antibodies to RF, citrullainated peptides, and rheumatoid arthritis antigen, which form immune complexes furthering joint damage [2]. Like abatacept, rituximab is indicated for patients who have failed prior biologic and/or MTX, or have a contraindication to other therapies. The DANCER and REFLEX trials , have shown significant ACR 20, 50 and 70 responses [3].

Tocilizimab, available since this September, targets the pro-inflammatory IL-6 that has been implicated in causing synovial fibroblast proliferation, and which functions as an agent for perpetuating joint damage by activating T- and B- cells in an autocrine fashion [4]. Activated synovial fibroblasts are implicated in joint damage. They produce matrix metalloproteinases, as well as inflammatory mediators including TNF-a, cytokines and prostaglandins,.. In this way, or by direct invasion, the synoviocytes destroy cartilage and bone. The CHARISMA trial showed a 61 and 63% ACR 20 response, compared to MTX with 41% response [5]. Most recently, the OPTION trial showed significant ACR 20, 50 and 70 responses versus placebo in addition to a 27% remission rate (8mg/kg) versus 0.8% with placebo at 24 weeks.

Anti-RANKL antibody, denosumab, more famous for treatment of osteoporosis, has also shown promising results to arrest bone erosion by osteoclast activation in a small study population with rheumatoid arthritis [6]. Osteoclasts, derived from monocytic cells, function via the RANKL-RANK-receptor system and are formed from the expression of MCSF and receptor activator of NF-kB ligand (RANKL). Both MCSF and RANKL are expressed by fibroblasts and activated T-cells, which bind to the surface of monocytes driving them to osteoclast formation and activation to resorb bone [7].

Other treatments on the forefront include targets for B-cells, more recently elucidated cytokines, and newer TNF antagonists. New B-cell inhibitors are belimumab and atacicept. These two therapies target B-cell activation factor (BAFF) also recognized as B-lymphocyte stimulator (BlyS), a key component in the production of auto-antibodies and perpetuation of aberrant B-cell hyperactivity [14]. Cytokines such as IL-15 and IL-17 are also under investigation. IL-15 inhibitors slowed the progression of active disease and resulted in reduced cartilage and bone destruction, with ACR 20, 50, and 70 responses showing 63%, 38%, and 25%. IL-17 is induced by many factors that result in synovial inflammation and cartilage and bone destruction. Animal models have shown a reduction in clinical disease severity with the inhibition of IL-17. Multiple other cytokines are under investigation as therapeutic targets such as IL-23, in addition to an inhibitor of Jak3, which has been implicated in signal transduction of IL-2, 4,7, 9, 15, and 21 [8,9].

The list of investigational therapeutics does not end there – in addition to newer pegylated and human anti-TNF agents, certolizumab and golimumab, other mediators such as leukotrienes (a,B) and chemokines (CXCL13 and CCL21) have also been evaluated as targets for therapy [10].

It may seem overwhelming to explore several targets for one disease. However, it is the redundancy in the immune system and the multiple inflammatory pathways that are triggered that do not allow for one effective therapy. Moreover, the precarious nature of immunomodulatory agents makes the therapeutic treatment range quite narrow, where clinical remission is limited by infection and toxicity, thus further demanding an aggressive search for the rheumatoid panacea.

Dr. Jani is a 3rd year internal medicine resident at NYU Medical Center

Peer reviewed and commentary by Pamela Rosenthal MD, Assistant Professor, NYU Division of Rheumatology

Per the above thoughtful review, patients who suffer from Rheumatoid Arthritis are benefitting from an explosion of targeted therapies. For our patients, our goal is to prevent joint damage and control the inflammation that is the hallmark of the disease. The new therapies have given patients and physicians alike a whole new and fascinating toolbox. However, it is important to keep in mind that Methotrexate, remains the mainstay of Rheumatoid Arthritis therapy. Methotrexate is both the first line drug of choice, and is often adjunctive therapy in the background of biologic therapy.

Nonetheless the explosion of targeted biologic therapies has taught us some very interesting lessons about the immune system. Somehow we can interfere with the functioning of apparently key immune regulatory players, yet continue to enjoy the protection of a broadly still functional immune response. However we have also learned that judicious and selective use of targeted biologic therapy is prudent. Poly-biologic therapy greatly increases the risk of infection. Equally the inhibition of different targets leaves us vulnerable to selective spectrum of pathogens and side effects, TNF inhibition and reactivation TB being the most well known example.

As we enter the second phase of the biologic pharmacology era we look forward to improved patient outcomes as well as the learning how to best use these and other therapies. Equally we look forward to the day when we better understand the etiology of Rheumatoid Arthritis and hence might even develop a chance for cure.

1. Kremer JM et al. Effects of abatacept in patients with methotrexate-resistent active rheumatoid arthritis. Ann Intern Med 2006: 144: 865-76.
2. Emery JC et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIb randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 2006:54:1390-400.
3. Van Snick J. Interleukin-6: an overview. Annual Rev of Immun 1990: 8:253-278.
4. Maini RN et al. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum 2006: 54:2817-29.
5. Cohen SB et al. RANKL inhibition with denosumab reduces progression of bone erosions in patients with rheumatoid arthritis: month 6 MRI results. Arthritis Rheum 2006: 54: S831
6. Schett G. Cells of the synovium in rheumatoid arthritis. Osteoclasts. Arth Res and Ther. 2007: 9: 203.
7. Seyler TM et al. BlyS and APRIL in rheumatoid arthritis. J Clin Invest 2005: 115: 3083-92.
8. Kim HR et al. Up-regulation of IL-23p19 expression in rheumatoid arthritis synovial fibroblasts by IL-17 through PI3-kinase, NF-kB and p38 MAPK-dependent signaling pathways. Rheum 2007: 46:57-64.
9. Comparison of six CP-690,550 doses versus placeboe each combined with methotrexate, for the treatment of rheumatoid arthritis. www.clinicaltrials.gov/ct/show/NCT00413660?order=2. 2007.
10. Gerlag DM et al. Novel approaches for the treatment of rheumatoid arthritis: lessons from the evaluation of synovial biomarkers in clinical trials. Best Prac and Res Clin Rheum 2008: 22: 311-23.

Diseases 2.0: Calcific Uremic Arteriolopathy (CUA)

August 26, 2009

calciphylaxisRebecca Hall MD

Faculty Peer Reviewed

Diseases 2.0 – Bringing you the latest updates on disease pathophysiology and treatment

Patient S.J. is a 36 year old female with a 20 year history of lupus and lupus nephritis now with end stage renal disease (ESRD) on hemodialysis. She presented with indurated, violaceous skin lesions with ulceration on both thighs. The lesions worsened and became increasingly painful over the last 6 months. Her extensive four month hospital course has been complicated by numerous episodes of superinfection and sepsis with methicillin resistant Staph aureus treated by intravenous antibiotics and wound debridement and negative pressure wound dressings. Over the last several weeks, her exquisitely painful skin ulcerations continue to worsen and have expanded to involve her trunk.

Calcific uremic arteriolopathy, also called by the older term calciphylaxis, is a rare and devastating disorder which most often occurs in patients with severe renal disease.(1,3) In humans, the term calciphylaxis is used to describe a disorder of the soft tissue characterized by arterial calcification.(1) CUA occurs in up to 5% of patients on hemodialysis.(2) Other risk factors for its development include female gender(2,4), obesity(2,3), diabetes(2), systemic steroid use(3,4), warfarin use (2,3), liver disease(3,4), and calcium-phosphate product of greater than 70 mg2/dL.(2.3,4)   Some believe that the disorder is much more frequent in an era in which calcium is used as a first-line phosphate binder, contributing to an increased calcium-phosphate product. The survival rate at one year is just 45.8%.(3)

CUA presents as painful necrotic skin ulcerations. Tissue biopsy, showing characteristic histopathological findings, remains the gold standard for diagnosis.(2) The pathophysiology of this disorder remains unclear, but recent research suggests that multiple factors may ultimately converge to activate the NFκB pathway, leading to bone pathology and vascular calcification.(5) It is thought that the cutaneous necrosis of CUA is ischemic in nature, resulting from thrombotic vascular occlusion of vessels with narrowed lumens secondary to medial arteriolar calcium deposition and subintimal fibrosis with fibrin thrombi. (5)

The best approach to preventing CUA is to employ strategies that limit the development of vascular calcifications in all patients at high risk, which includes ESRD patients. These strategies should include agents that directly or indirectly inhibit the NFκB cascade such as bisphosphonates, recombinant OPG (osteoprotegerin), anti-RANKL antibodies, and BMP.(7, 2, 5)  Bisphosphonates are the only option among these that is currently available. The NFκB pathway is integral to the mineral deposition and resorption of bone and plays a role in the regulation of extraosseous mineralization.(3)  Bisphosphonates are thought to increase OPG production and thereby inhibit NFκB or RANKL activity,(2) whereas PTH, corticosteroids, aluminum, liver disease, and other forms of inflammation increase RANKL expression, decrease OPG, and activate NFκB.(3)

Once CUA has developed, therapeutic options remain controversial and minimally to moderately effective at best. Few case-control studies exist comparing various treatment options for this disease. One goal of traditional therapy is decreasing the calcium-phosphate product.  Agents used for this purpose include phosphate binders like sevelamer, bisphosphonates, and cinacalcet.(1,2)  As secondary hyperparathyroidism has been implicated as a contributor to CUA, suppression of PTH has been an unproven goal of therapy. Surgical resection of the parathyroid glands has been used with variable success to improve calcium, phosphate, and parathyroid hormone levels. One small retrospective study in the journal Surgery showed an increase in median overall survival in patients after parathyroidectomy (80 months) compared to patients who had not had a parathyroidectomy (35 months).(6) However, this benefit remains controversial and most authors suggest that parathyroidectomy be reserved for patients with severe hyperparathyroidism that is not responsive to medical correction.(4)  Medical suppression of PTH involves the use of the calcimimetic agent cinacalcet. Although case reports include patients in whom cinacalcet was one of several therapies utilized successfully, its relative importance in therapy is not established. Therapies must also focus on restoring tissue perfusion and improving cutaneous oxygenation.(5) Hyperbaric oxygen, antithrombolytic therapy with tPA, and anticoagulation to maintain vascular patency are used to this effect.(2,4)

Aggressive wound care measures must be implemented. Larval and surgical wound debridement have shown promise in promoting healing and decreasing the incidence of wound infection and sepsis.(4) Larval debridement shows promise as a low-pain, microbe-reducing, adjunctive therapy that spares viable tissue. Surgical debridement appears to improve outcomes with 6.2% one-year survival in patients who had had surgical debridement compared to 37.4% one- year survival in patients who did not undergo debridement.(3) Wound healing may be promoted through the use of sodium thiosulphate. Sodium thiosulphate is a chelator of cations including calcium and helps to convert calcified deposits into a more soluble form.(1,2) It is also an antioxidant which may help reverse endothelial dysfunction.

Other novel therapies including hematopoietic stem cell transplantation (HSCT) have resulted in resolution of calciphylaxis in case reports. (1)  However, the fact that such benefit was achieved from HSCT suggests that immunosuppressive therapies may hold promise for targeting the inflammation which appears to be a component of the pathogenesis of this devastating and deadly disease.

Regrettably, despite multiple debridements, broad spectrum antibiotics, anti-thrombolytic therapy, and sevelemar, our patient S.J. eventually succumbed to her CUA, likely secondary to sepsis as a result of wound superinfection. Unfortunately, none of the therapies for CUA offer a definitive cure or are consistently successful. The number of randomized controlled trials looking at outcomes also continues to be very limited. One hopes that some of the recent discoveries related to the pathogenesis of CUA will lead to the development of new strategies to help improve outcomes.

Reviewed by David Goldfarb, MD, Professor of Medicine, NYU Medical Center, Chief Nephrology Section VA New York Harbor


1. Mandelbrot DA, Santos PW, Burt RK et al. Resolution of SLE-related soft-tissue calcification following haematopoietic stem cell transplantation. NDT Advance Access published on August 1, 2008, DOI 10.1093/ndt/gfn036. Nephrol. Dial. Transplant. 23: 2679-2684. http://ndt.oxfordjournals.org/cgi/content/full/23/8/2679

2. Rogers NM. Coates PT. Calcific uraemic arteriolopathy: an update. [Review] [60 refs] [Journal Article. Review] Current Opinion in Nephrology & Hypertension. 17(6):629-34, 2008 Nov.

3. Weenig R, Sewell L, Davis M, et al. Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol 2007; 56:569-579.

4. Weenig RH. Gibson LE. el-Azhary R. The role of the hospital dermatologist in the diagnosis and treatment of calciphylaxis and nephrogenic systemic fibrosis. [Review] [20 refs] [Case Reports. Journal Article. Review] Seminars in Cutaneous Medicine & Surgery. 26(3):163-7, 2007 Sep.

5. Weenig RH. Pathogenesis of calciphylaxis: Hans Selye to nuclear factor kappa-B. [Review] [149 refs] [Biography. Historical Article. Journal Article. Review] Journal of the American Academy of Dermatology. 58(3):458-71, 2008 Mar.

6. Arch-Ferrer JE, Beenken SW, Rue LW et al. Therapy for calciphylaxis: An outcome analysis. Surgery – December 2003 (Vol. 134, Issue 6, Pages 941-944.

Diseases 2.0: Sepsis

February 5, 2009

fluid11.jpgDiseases 2.0 – Bringing you the latest updates on disease pathophysiology and treatment

Commentary by Andrew McKinstry MD PGY-1

Faculty Peer Reviewed

For anyone who has stepped into an ICU, the septic patient is a familiar sight. Despite advances in research and management, including goal directed therapy and recombinant human activated protein C (Xigris), sepsis continues to be a major cause of mortality in the critical care setting, with an estimated 215,000 deaths annually, and costing roughly 16.7 billion dollars per year. Despite these staggering human and monetary costs, the nature of and mechanisms involved in sepsis remain either unknown or hotly contested. The continuing research into this problem is on the verge of producing a number of promising insights and interventions, from insights into the nature of the syndrome to new pharmaceutical solutions and systems-based interventions.

While sepsis is a well-documented syndrome, there is debate among sepsis researchers whether sepsis is actually a number of different processes with a common late-stage presentation. While this could seem a largely academic debate, a mechanistic understanding of sepsis would be important in determining biomarkers for use in early detection of the syndrome. Recently, procalcitonin emerged as a possible candidate for a sepsis biomarker. Studies as early as 1993 described procalcitonin as an infection variable, and a few studies early this decade showed higher levels of procalcitonin in septic states than other inflammatory states. Further investigation found that while is was another good indicator of systemic inflammation, calcitonin was not specific for sepsis to be useful as a diagnostic test. Research groups at Duke University and Henry Ford Hospital, at the University of Zurich and members of the SPEEDI trial in Copenhagen are now in the process of throwing a wide net in search of sepsis biomarkers using high-throughput protein screening.
The available armamentarium against sepsis is limited to recombinant human activated protein C (APC) which targets one of the dysregulated systems in sepsis, coagulation, and likely affects what is the major dysregulation of sepsis, inflammation. APC has been shown to improve all-cause mortality in severe sepsis, though is ineffective and potentially harmful in less severe sepsis due to a high complication risk. Looking down the pipeline, at least two other drugs that target the hypercoaguable state in sepsis are in late phase trials. Recombinant human soluble thrombomodulin and recombinant anti-thrombin are in trials for treatment of DIC in sepsis, with the hope that they might provide a similar improvement in mortality with fewer hemorrhagic complications associated with APC.

Current drug research in sepsis is primarily focused on correction of inflammatory dysfunction, and coagulation dysfunction. Earlier theories of sepsis categorized it as a purely hyperinflammatory state, and unsuccessful experimental therapies focused on broad reduction of inflammation systemically. Coritcosteroid treatment has been shown to be ineffective, and there was a mixed picture for the efficacy of monoclonal anti-TNF antibodies in sepsis. While there was a meta-analysis of trials using monoclonal anti-TNF antibodies in severe sepsis suggests some efficacy, none of the individual trials showed any significant improvement in outcome.

Current theories on mechanisms of sepsis postulate a complex, heterogenous dysfunction of inflammatory processes- a cytokine storm that can lead to a mixed hyper- and hypoinflammatory state. In animal models of bacterial sepsis, blockade of IL-22 resulted in improved bacterial clearance in the liver and kidneys with reduced kidney damage, a possible future therapy aimed at prevention of end-organ damage in sepsis. Similarly, in translational studies blocking function of IL-27, subjects showed an increase in survival- another potential target for future therapies. Hemodiafiltration using a membrane that filters cytokines shows some promise in treating the cytokine storm of sepsis- human trials have shown decreased markers of end-organ damage, though no survival benefit has yet been demonstrated. Statins, the wonder drugs that seem to have no end of new uses, also show some potential in treatment of sepsis. Prior statin use has been shown to decrease the rate of severe sepsis in hospitalized patients, and statin use in patients with multi-organ dysfunction have been shown to have improved survival.

The ability of relatively small amounts of lipopolysaccharide (LPS) from gram-negative bacteria to induce a septic-shock-like condition has long been known, but the discovery in the last decade of the receptor through which LPS induces a vasodilatory state, Toll-like Receptor 4 (TLR4), presented a promising drug-target. Eritorian is a TLR4 antagonist currently in Phase III trials for treatment of severe sepsis, and TAK-242, a small molecule cytokine inhibitor of TLR4 signaling, is also in late phase trials.

Last but not least, some of the most significant advances in treatment of sepsis have not come from new pharmaceutical interventions, but in improved delivery of care. Early goal-directed therapy was hugely successful in improving sepsis outcomes, but now researchers at the University of Pittsburgh are performing a head-to-head comparison between goal directed therapy (which requires a central venous line with all of its associated complications) to protocolized care (which does not require a central line) in the treatment of septic patients. Who knows, depending on the results of that study, maybe next year in the ICU, not every sepsis patient will need that central line that they have now.

Given the variety of research and the number of late-phase trials currently underway, the clinical approach to sepsis will likely have a number of significant changes in the next five years. Improved diagnostic tests will help ensure earlier interventions, improved protocols will improve the quality of interventions, and new pharmaceuticals will be available for treatment of both complications of sepsis and the dysfunctional inflammatory state of sepsis itself. Continued success in sepsis research may mean that at some point in the no-so-distant future, a sepsis diagnosis will be as simple as a blood test, and pharmaceutical treatment will be as straight forward as antibiotics and an inflammatory modulator. In the mean time, though, make sure those fluids are hanging.

Reviewed by Laura Evans MD, NYU Division of Pulmonary and Critical Care Medicine



Leaver, S. et al. Sepsis since the discovery of Toll-like receptors: Disease concepts and therapeutic opportunities. Critical Care Medicine. Vol 35, No. 5 2007. p1404-10

Leon, C et al. Discovery and Development of Toll-Like Receptor 4 (TLR4) Antagonists:
A New Paradigm for Treating Sepsis and Other Diseases. Pharmaceutical Research. Vol 25, No 8, August 2008. p1751-61.

Nakada, T et al. Continuous Hemodiafiltration with PMMA Hemofilter in theTreatment of Patients with Septic Shock. Molecular Medicine. 14(5-6) p 257-63.

Remick, D. Pathophysiology of Sepsis. The American Journal of Pathology, Vol. 170, No. 5, May 2007, p 1435-44.

Weber, G et al. Inhibition of Interleukin-22 Attenuates Bacterial Load and Organ
Failure during Acute Polymicrobial Sepsis. Infection and Immunity, Apr. 2007, p. 1690–97

Wirtz, S et al. Protection from lethal septic peritonitis by neutralizing the biological function
of interleukin 27. The Journal of Experimental Medicine. Voll 203, No 8, August 7, 2006. p 1875-81.

Addiction 2.0 Part 2

September 4, 2008

alcohol.jpgCommentary by Joshua Lee MD, Ellie Grossman MD and Marc Gourevitch MD, NYU Division of General Internal Medicine

Please also see Part 1 of this series, posted last week

Alcohol treatment in primary care: evidence for effectiveness and neharmacotherapies

Brief interventions by primary care physicians to address unhealthy alcohol use have been shown in multiple studies and settings to promote reduced drinking and engagement in other treatment, although long-term impact on alcohol-related morbidity and mortality is not clear.(Saitz 2005) Standard brief intervention techniques are based on the 4 A’s: Ask (about drinking using validated screens); Advise (regarding a diagnosis of hazardous drinking, alcohol abuse, or alcohol dependence); Assist (with the patient’s motivation for change), and Arrange (follow-up with the physician or refer to a treatment program). Brief intervention is indeed intended to be brief – only 5-10 minutes of discussion with a patient per session has been shown to be an effective intervention (http:/niaaa.gov/cliniciansguide2008/).

Pharmacotherapies for Alcohol. With the 2006 FDA approval of extended-release naltrexone (XR-NTX, Vivitrol), the physician has four FDA-labeled agents available for the treatment of alcohol dependence: disulfiram (Antabuse), oral naltrexone (ReVia, 1994), acamprosate (Campral, 2004), and extended-release naltrexone. The recent COMBINE study employed a complex 3×3 randomized factorial design to study oral naltrexone and acamprosate on their own and combined, with or without other treatment modalities.(Anton 2006) These researchers found that alcohol treatment delivered by a physician (medical management) on its own was as effective as cognitive behavioral therapy or motivation enhancement delivered as additional individual therapy. In addition, oral naltrexone pharmacotherapy in addition to medical management was more effective at reducing alcohol use than acamprosate or placebo. Separate efficacy trials have shown disulfiram, XR-NTX, and acamprosate are beneficial when compared to placebo (Kiefer F et al. 2003.; Garbutt 2005).

XR-NTX is the newest addition to the alcohol-dependence pharmacotherapy armamentarium.(Garbutt 2005) Its development was grounded in the experience that oral naltrexone is effective at reducing alcohol use, but only for patients who actually took the drug – a significant barrier for a disease rooted in daily behavior like alcohol dependence. XR-NTX is a depot formulation that is injected monthly into the gluteal region – thereby overcoming issues of daily medication adherence. However, use of this medication remains lower than anticipated due to its high cost (and incomplete coverage by public insurers) and its injection format. Unlike primary care practices, most office-based addiction psychiatrists may not be equipped to perform injections or comfortable with such an invasive procedure. XR-NTX prescribing has to date mostly occurred in specialty addiction centers and internal medicine and family practice office-based settings. To date in an on-going single-arm study of primary care-based pharmacotherapy of alcohol dependence at Bellevue Hospital, we have shown that offering XR-NTX to low-income and uninsured patients is feasible: interest and acceptance of XR-NTX therapy is high among eligible patients, and retention through a 3 month treatment phase is roughly 75% per month (25% per month discontinue treatment). This compares favorably to other outpatient medical or psychosocial alcohol treatment, the literature for which reports generally lower rates of short-term treatment retention. Self-reported alcohol use in those remaining in XR-NTX treatment has been substantially lower than at baseline, as expected.

Limitations and referrals
The primary care or office-based specialty physician ready and willing to offer frontline addiction treatment can look forward to many rewarding cases, as patients are often younger and in otherwise good health excepting problematic substance use. However, psychiatric comorbidities, polysubstance dependencies, and chaotic social circumstances including homelessness, unemployment, and insurance difficulties often appear as complications to straight-forward treatment and recovery. Even in the simplest cases, chronic difficulties with cravings and relapse are the rule. The office—based practitioner always needs to keep these realities and limitations in mind, with other referral sources and backup resources available when more help is required. Linkages to general psychiatric care and specialty addiction treatment resources are practical next steps when a case requires that primary psychiatric diagnoses be addressed, or more comprehensive addiction care, including inpatient detoxification, residential rehabilitation, or intensive outpatient care involving individual counseling and frequent structured group therapy, be considered.


Center for Substance Abuse Treatment. Clinical guidelines for the use of buprenorphine in the treatment of opioid addiction: A Treatment Improvement Protocol (TIP) Series 40. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2004

Lee JD, Grossman E, DiRocco D, Gourevitch M. At-Home Buprenorphine/Naloxone Induction in Urban Primary Care. Association for Medical Education and Research in Substance Abuse (AMERSA) National Meeting (podium) Washington DC, Nov. 10, 2007; Society of General Internal Medicine Annual Meeting (poster) Pittsburgh PA, April 10, 2008; American Society of Addiction Medicine Annual Scientific and Medical Meeting (poster) Toronto, ON, April 11, 2008.

Anton RF et al, Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA, 295(17), 2006:2003-17.

Garbutt JC et al. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. JAMA, 293(13), 2005:1617-25.

Lee JD, Grossman E, DiRocco D, Truncali A, Rotrosen J, Hanley K, Stevens D, Gourevitch MN. Extended-release Naltrexone Injectable Suspension for Treatment of Alcohol Dependence in Urban Primary Care – A Feasibility Study: Preliminary Analysis. Society of General Internal Medicine Annual Meeting (poster) Pittsburgh PA, April 10, 2008; American Society of Addiction Medicine Annual Scientific and Medical Meeting (poster) Toronto, ON, April 11, 2008; College of Problems on Drug Dependence (poster) San Juan PR, June 18, 2008; Research Studies on Alcoholism (poster) Washington DC, July 2, 2008.

Kiefer F. et al. Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind ,placebo-controlled study. Arch Gen Psychiatry 2003 Jan;60(1):92-9.Saitz R. Unhealthy alcohol use. N Engl J Med 2005;352:596-607.

Addiction 2.0 Part 1

August 27, 2008

bottles.jpgCommentary by Joshua Lee MD, Ellie Grossman MD and Marc Gourevitch MD, NYU Division of General Internal Medicine

Substance abuse remains a leading cause of disease and mortality in the US, yet it is rarely addressed in general practice settings. In the past, clinicians could point to a relative paucity of effective interventions by way of explaining their disengagement in the care of these medical disorders. In recent years, however, effective pharmacotherapies have emerged for two classes of substances that are particularly destructive when abused, as they commonly are: opioids (heroin and prescription narcotics) and alcohol. In this two-part entry, we will review the current state-of-the-art in strategies for addressing these conditions in the office-based practice setting. The great majority of affected patients do not seek dedicated substance abuse treatment programs yet do interact with physicians for other reasons. With the new tools available to them, office-based physicians now therefore have the opportunity to substantially increase access to effective treatment of opioid and alcohol abuse and dependence. Part 1 follows below. Part 2 will be posted next week.

I. Office-based opioid treatment.

Buprenorphine, a partial mu opioid receptor agonist, was approved by the FDA in 2002 for the treatment of opioid dependence in office-based settings.(CSAT 2004) This development has ushered in a new treatment paradigm for opioid disorders – that of treating them pharmacologically in primary care practices, as distinct from traditional methadone maintenance treatment programs. Due to its ‘ceiling effect,’ it is virtually impossible to overdose on buprenorphine, making it safer than methadone, and resulting in the DEA classifying it as a Schedule III compound. In its most widely available form, buprenorphine is marketed as a compound mixture with naloxone (brand name ‘Suboxone’), to deter its misuse by injection. A physician need only complete a relatively brief training course in order to obtain a DEA waiver authorizing prescribing. Thereafter, physicians can now incorporate treatment of heroin or prescription opioid dependence into everyday practice. Buprenorphine can be used as a long-term maintenance medication (much like methadone maintenance), or in tapering doses to prevent and treat withdrawal symptoms when the opioid drug of abuse is discontinued.

Buprenorphine prescribing has grown slower than expected in New York City, in part because of concerns that actually beginning patients on the medication (“induction”) might be complicated medically and problematic in terms of office logistics. Because of its high affinity for the mu opioid receptor and its partial agonist activity, buprenorphine can actually precipitate withdrawal symptoms in patients under the influence of other opiates. Published prescribing guidelines therefore suggest that the first few doses of buprenorphine be taken by the patient in the physician’s office, with monitoring of the patient for several hours afterward to minimize the risk of buprenorphine-associated precipitated withdrawal on induction.(CSAT 2004) However, as one might imagine, such a process might pose a significant burden on the average primary-care office practice. Locally, the Bellevue Hospital Center Primary Care Buprenorphine Initiative has recently documented what many experienced buprenorphine providers already knew: that an at-home induction protocol, which minimizes clinic visit times by having the patient administer the first buprenorphine dose at home, is safe and feasible.(Lee 2008) Such induction approaches may shrink logistical barriers and encourage prescribing.

A second potential barrier to buprenorphine usage in New York City is the high out-of-pocket cost of the drug (roughly $15/day for an average 16mg maintenance dose). However, in New York State we are fortunate that Medicaid covers the cost of buprenorphine/naloxone (Suboxone) and buprenorphine (Subutex), making it more accessible to our public-hospital population.

Buprenorphine is not the ideal medication for every opioid-dependent patient. Patients who require very high doses of methadone to avoid withdrawal symptoms may not achieve comfort on buprenorphine. Some patients benefit from the daily structure of methadone maintenance, and the group meetings and other counseling that can occur on-site at these programs. Patients who are unable to reduce their illicit opioid use while on buprenorphine may be better served in the more treatment-intensive environment of methadone maintenance or other programs. Physicians prescribing buprenorphine should be aware of local methadone programs and other treatment resources (as well as Narcotics Anonymous) where patients can receive counseling and related psychosocial services. Directories of such resources locally are available from the authors.



Center for Substance Abuse Treatment. Clinical guidelines for the use of buprenorphine in the treatment of opioid addiction: A Treatment Improvement Protocol (TIP) Series 40. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2004

Lee JD, Grossman E, DiRocco D, Gourevitch M. At-Home Buprenorphine/Naloxone Induction in Urban Primary Care. Association for Medical Education and Research in Substance Abuse (AMERSA) National Meeting (podium) Washington DC, Nov. 10, 2007; Society of General Internal Medicine Annual Meeting (poster) Pittsburgh PA, April 10, 2008; American Society of Addiction Medicine Annual Scientific and Medical Meeting (poster) Toronto, ON, April 11, 2008.

Class Act: Polycystic Ovarian Syndrome 2.0

August 1, 2008

metformin.jpgClass act is a feature of Clinical Correlations written by NYU 3rd and 4th year medical students. These posts focus on evidenced based answers to clinical questions related to patients seen by our students in the clinics or on the wards. Prior to publication, each commentary is thoroughly reviewed for content by a faculty member.

Commentary by Marty Wolff MS-4, and Susan Zweig MD, Clinical Instructor, NYU Division of Endocrinology

NH is a 32 year-old obese Hispanic female with a history of hypertension, chronic cold urticaria, focal segmental glomerulosclerosis, and polycystic ovarian syndrome who presented for routine follow-up in primary care clinic. The patient was diagnosed with polycystic ovarian syndrome in November 2007. At that time, she presented with irregular menses and dysmenorrhea, at which point pelvic ultrasound revealed polycystic ovaries. The patient was prescribed daily oral contraceptive medication, but was recently advised to discontinue this medication secondary to persistence of irregular menses. Her last menstrual period was 1/3/2008 – 1/10/2008. Her BMI is 30.7 and she had a normal oral glucose tolerance test. The clinical question of whether or not to begin treatment with metformin warranted further discussion:

Polycystic ovarian syndrome (PCOS) affects nearly 5-7 percent of reproductive age women and is characterized by chronic oligo-ovulation or anovulation, androgen excess, insulin resistance, obesity, hirsutism, infertility, and (in some cases) polycystic ovaries (1, 2). These patients are at a markedly increased risk for impaired glucose tolerance, type 2 diabetes, and other metabolic derangements. Metformin, a medication whose major effect is to decrease hepatic glucose production and increase insulin sensitization in peripheral tissues, plays a pivotal role in the treatment armamentarium for PCOS.

The pathophysiology of PCOS is incompletely understood, but is thought to involve multiple interactions among the gonadotropins and androgens, insulin, and the ovaries. Insulin resistance and hyperinsulinemia are central features of PCOS and appear to be responsible for the associations between PCOS and type 2 diabetes, dyslipidemia, hypertension, and other physiological and anatomical cardiovascular maladaptations (3, 4). In brief, there are four concurrent mechanisms of action:

1. Although peripheral tissues such as skeletal muscle and fat are insulin-resistant in this syndrome, insulin actually stimulates the ovarian production of androgens in PCOS.
2. Insulin also stimulates leutenizing hormone production by the anterior pituitary, further driving ovarian stimulation and increasing serum androgen levels.
3. The progressive hyperinsulinemia inhibits hepatic production of sex hormone-binding globulin, a phenomenon that augments circulating free testosterone levels.
4. Finally, insulin inhibits the ovulatory cycle by interfering with gonadotropin secretion, increasing intra-ovarian androgen levels, and directly affecting follicular development.

Inhibiting insulin release with the use of diazoxide or octreotide, improving insulin sensitivity through weight loss, metformin, or thiazolidinediones, and reducing carbohydrate absorption through the use of acarbose have all been shown to lower circulating insulin levels, increase ovulatory frequency or menses, and/or reduce serum testosterone (5). Clearly, the hyperinsulinemia that is so critical to the pathogenesis and natural history of PCOS is a major therapeutic target.

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Diseases 2.0: Uric acid stones linked to diabetes

July 3, 2008

uric_acid_apatite_stone.jpgDiseases 2.0 – Bringing you the latest updates on disease pathophysiology and treatment

Commentary By David Goldfarb, M.D. Professor of Medicine, NYU Medical Center, Chief Nephrology Section VA New York Harbor

At the recent meeting of the National Kidney Foundation in Dallas, Dr. Orson Moe reviewed the links between diabetes and uric acid stones . Uric acid stones are most often caused by low urine pH. With a low urine pH, even relatively little uric acid can precipate, as it forms the protonated form, which is poorly soluble. At higher pH values, uric acid dissociates to the urate anion and the proton is titrated by the base. This dissociated form is quite soluble. With urine pH values of 6.5, even high amounts of urinary uric acid will not be associated with stones. Hyperuricosuria is a less important risk factor. So while patients with hyperuricosuria may have stones, urinary alkalinization is usually a preferred treatment as compared with allopurinol. If uric acid excretion is reduced by this xanthine oxidase inhibitor but urine pH is not raised, uric acid stones may still form. Allopurinol is best indicated in patients who have trouble alkalinizing the urine or continue to have stones despite alkalinization. Hyperuricosuria is seen with some myeloproliferative disorders such as polycythemia vera, high animal protein intake (equivalent to high purine intake). Low pH is seen in states of chronic diarrhea (ileostomy, colitis, Crohns) and diabetes.

The links between diabetes and low pH are being studied. Higher body mass intake is associated with lower urine pH, and this might be explained by higher BMI being associated with insulin resistance. In fact, the more features of metabolic syndrome become evident in an individual patient, the lower the urine pH. Insulin is important in ammoniagenesis, and recent data from U. Texas Southwestern indicate that insulin resistance is associated with impaired ammoniagenesis. In this case, there is less urine ammonia available to accept protons and with less urine buffer, and pH is lower. Some studies suggest that patients with uric acid stones also have increased net acid excretion, suggesting a dietary component of greater acid ingestion. Although research suggests that insulin directly impairs ammoniagenesis, new data from Southwestern are exploring the possibility that the effect is mediated by renal fat. In this hypothesis, increased BMI is associated with deposition of fat in the kidney. MR spectroscopy techniques developed at UT Southwestern are measuring renal fat deposition and attempting to correlate the imaging studies with fat stained in kidney biopsies. This lipotoxicity in the kidney may correlate with impaired insulin effect and impaired ammoniagenesis.

The treatment of recurrent uric acid stones is alkalinization of the urine. This is best accomplished with potassium citrate. Sodium citrate (e.g. Shohls solution or Bicitra) should be reserved for patients with hyperkalemia or GI intolerance as the sodium load, though often tolerated, may increase urine calcium excretion. Potassium citrate (20-30 meq) can be given with liquids or food to minimize GI intolerance. It is usually given 2-3 times per day to achieve round-the-clock alkalinization for patients with stones in place. It can be given once a day (at night) or even every other day for prevention in patients who do not currently have stones.

1: Bobulescu IA, Dubree M, Zhang J, McLeroy P, Moe OW. Effect of renal lipid accumulation on proximal tubule Na+/H+ exchange andammonium secretion.Am J Physiol Renal Physiol. 2008 Apr 16; [Epub ahead of print]PMID: 18417539

2: Sakhaee K, Maalouf NM. Metabolic syndrome and uric Acid nephrolithiasis.Semin Nephrol. 2008 Mar;28(2):174-80.PMID: 18359398

3: Maalouf NM, Cameron MA, Moe OW, Adams-Huet B, Sakhaee K. Low urine pH: a novel feature of the metabolic syndrome.Clin J Am Soc Nephrol. 2007 Sep;2(5):883-8. Epub 2007 Aug 16.PMID: 17702734

4: Cameron MA, Baker LA, Maalouf NM, Moe OW, Sakhaee K. Circadian variation in urine pH and uric acid nephrolithiasis risk.Nephrol Dial Transplant. 2007 Aug;22(8):2375-8. Epub 2007 May 3. No abstractavailable.PMID: 17478488

5: Cameron MA, Maalouf NM, Adams-Huet B, Moe OW, Sakhaee K. Urine composition in type 2 diabetes: predisposition to uric acidnephrolithiasis.J Am Soc Nephrol. 2006 May;17(5):1422-8. Epub 2006 Apr 5.PMID: 16597681

Bell’s Palsy 2.0—Crocodile Dundee Tears

March 5, 2008

120px-darica_corcodile_02349.jpgDiseases 2.0 – Bringing you the latest updates on disease pathophysiology and treatment

Commentary by Aaron Lord MD, PGY-1

A 39 year-old woman awakes one morning and notices that the left side of her face is droopy. While at work, she has trouble controlling her saliva and it dribbles down the left side of her chin. At dinner, she has trouble eating and notices food stuck between her lips and teeth on the left side. The next morning she sees her primary care physician with the above complaints and also says she has noticed excessive tearing from the left eye. Neurological exam shows the following left-sided deficits: loss of the nasolabial fold, unfurrowing of the brow, inability to close eyelids (with upward deviation of the eyeball when attempting to close the eye), decreased lacrimation, corneal abrasion, and loss of taste on the anterior left 2/3rd of the tongue.

The etiology of Bell’s Palsy has remained elusive since it was first described over a hundred and fifty years ago by the Scottish surgeon Charles Bell (who interestingly wrote one of the first treatises on the anatomy of facial expressions for painters). More recent research in the mid- to late-1990’s led some observers to believe that HSV-1 may play a role, and acyclovir was added to the standard treatment protocol by many providers. New research, however, has called that practice into question, making the etiology of the disease as enigmatic and elusive as ever.

Bell’s Palsy is a peripheral-nerve palsy, usually unilateral, affecting the facial nerve (CN VII) at the level of the geniculate ganglion. It affects 15-30 out of 100,000 individuals every year and people with diabetes, pregnancy, or in their 40s tend to be more affected.

Observations by surgeons and neuroradiologists show that there is inflammation and edema of the affected facial nerve at the level of the geniculate ganglion. At this location, the facial nerve carries not only the motor fibers that innervate the muscles of facial expression and stapedius muscle in the middle ear, but also autonomic fibers that control lacrimation, salivation, and taste to the anterior 2/3 of the tongue. Patients usually present with the acute onset (hours to 1-2 days) of unilateral facial weakness which may progress to complete paralysis by the third or fourth day. There is loss of facial folds and furrows, drooping of the mouth with dribbling of saliva, inability to clear food from between the teeth and lips on the affected side, and inability to close the eyelid completely. The upward rotation of the eye when attempting to close the eyelids is known as Bell’s Phenomenon. Tear production is actually decreased due to loss of parasympathetic fibers to the lacrimal glands, but the drooping of the lower lid and spillage of tears leads to complaints of excessive tearing. The cornea often drys out and can suffer from abrasions due to exposure and dryness.

The differential diagnosis for a patient who presents with unilateral facial weakness includes both peripheral and central causes. Other peripheral causes include Lyme Disease, otitis media, Ramsay Hunt Syndrome (zoster of the 7th cranial nerve), Guillain-Barre Syndrome, and compression by a tumor of the parotid gland. Thus it is important to ask for recent tick exposure, rashes, arthralgias, ear pain or fever, appearance of vesicles in the external auditory canal, and weakness in other parts of the body. Central causes include stroke, tumor, and multiple sclerosis. Central causes will usually be associated with other neurological deficits or weakness of other body parts, mental status changes, and sparing of weakness in the forehead muscles due to bilateral innervation, so a good history and physical exam are necessary. Obtaining imaging is usually not necessary without any of these other central symptoms.

The idea that HSV-1 (and other herepes family viruses) may play a part in the etiology of Bell’s Palsy was fostered in the 1980s with a study that showed a higher prevalence of herpes simplex virus (HSV) antibodies in Bell’s Palsy patients when compared to controls. With the newly invented technique of PCR, researchers in the 90’s reported case-studies showing the detection of HSV-1 DNA in the geniculate ganglions of individual patients with Bell’s Palsy, helping to firm up HSV-1’s role. Other research has arisen, however, refuting HSV-1 significance in the etiology of Bell’s Palsy. A Swedish group recently published a series of 20 face muscle biopsies and detected HSV and VZV DNA in 1 patient each (5% of samples per virus) and no increase in serum antibody titers to HSV. Moreover, a Japanese group recently showed reactivation of HSV-1, VZV, or both viruses in only 15.3%, 14.7%, and 4.0% of patients, respectively. The most recent evidence refuting the etiological role of HSV-1 was a case-control study published this summer by Kanerva et. and showed no evidence of HSV-1 DNA (as detected by PCR) in any of the patients suffering from Bell’s Palsy (or the controls for that matter).

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