Brian F. Mandell, MD, PhD

In the past 2 decades we have come a long way in recognizing the ominous significance of osteoporosis and in being able to reduce fracture rates. However, while we know that bisphosphonates such as alendronate (Fosamax) and risedronate (Actonel) reduce fracture risk in patients with moderate or severe osteoporosis, how long patients should continue to take these drugs remains uncertain.

Dr. Susan M. Ott, in this issue of the Journal, argues that many patients on bisphosphonate therapy for more than 5 years should be offered a “drug holiday.” She proposes a simple algorithm that uses measurement of bone turnover and bone density to decide whether to continue therapy, the assumption being that having accumulated in bone, the drug effect will persist after discontinuation.

This will please many patients, who prefer taking fewer drugs. Cost and potential adverse effects are their concerns. Physicians worry about adynamic bone, and as bisphosphonates accumulate in bone with prolonged therapy, they may ultimately increase the incidence of what are now rare adverse effects, ie, jaw necrosis and linear atypical fractures of the femur. To date, we have little evidence that continued drug exposure will cause more of these severe complications, but lack of data is not so comforting.

The data that support taking a bisphosphonate holiday after 5 years (vs continuing therapy for 10 years) are scant compared with the data supporting their initial benefit. The FLEX study (J Bone Miner Res 2010; 25:976–982), as Dr. Ott notes, provides only tenuous benefit for the longer therapy option (with alendronate). Benefit of 10 vs 5 years of therapy is based on subset analysis of a relevant but small group of patients in this study (those with a femoral neck T score lower than −2.5 and no vertebral fracture at baseline). Patients in this subset suffered more nonvertebral fractures after stopping the drug at 5 years. Data with other bisphosphonates may well differ. For the other subsets, 10 years of therapy did not seem better than 5. But the numbers are small, certainly too small to offer insight on the incidence of rare side effects developing with the extra 5 years of therapy.

My personal take: on the basis of limited data, I am worried about halting these drugs in patients at highest risk for fracture—those with severe osteoporosis and many prior fractures or ongoing corticosteroid use. In patients with osteoporosis but lower risk of fracture, I have increasingly offered drug holidays. Although it is clearly not based on large interventional outcome studies, I am more inclined to utilize markers of bone turnover than repeated bone density measurements in patients who have been taking bisphosphonates. Chronic bisphosphonate therapy may alter the relationship between density and fracture risk, akin (but opposite) to the way that corticosteroids increase fracture risk above what is suggested by bone density measurements.

But don’t let this discussion about how long to treat stand in the way of initiating therapy in osteoporotic patients at significant risk of fracture.

In the past 2 decades we have come a long way in recognizing the ominous significance of osteoporosis and in being able to reduce fracture rates. However, while we know that bisphosphonates such as alendronate (Fosamax) and risedronate (Actonel) reduce fracture risk in patients with moderate or severe osteoporosis, how long patients should continue to take these drugs remains uncertain.

Dr. Susan M. Ott, in this issue of the Journal, argues that many patients on bisphosphonate therapy for more than 5 years should be offered a “drug holiday.” She proposes a simple algorithm that uses measurement of bone turnover and bone density to decide whether to continue therapy, the assumption being that having accumulated in bone, the drug effect will persist after discontinuation.

This will please many patients, who prefer taking fewer drugs. Cost and potential adverse effects are their concerns. Physicians worry about adynamic bone, and as bisphosphonates accumulate in bone with prolonged therapy, they may ultimately increase the incidence of what are now rare adverse effects, ie, jaw necrosis and linear atypical fractures of the femur. To date, we have little evidence that continued drug exposure will cause more of these severe complications, but lack of data is not so comforting.

The data that support taking a bisphosphonate holiday after 5 years (vs continuing therapy for 10 years) are scant compared with the data supporting their initial benefit. The FLEX study (J Bone Miner Res 2010; 25:976–982), as Dr. Ott notes, provides only tenuous benefit for the longer therapy option (with alendronate). Benefit of 10 vs 5 years of therapy is based on subset analysis of a relevant but small group of patients in this study (those with a femoral neck T score lower than −2.5 and no vertebral fracture at baseline). Patients in this subset suffered more nonvertebral fractures after stopping the drug at 5 years. Data with other bisphosphonates may well differ. For the other subsets, 10 years of therapy did not seem better than 5. But the numbers are small, certainly too small to offer insight on the incidence of rare side effects developing with the extra 5 years of therapy.

My personal take: on the basis of limited data, I am worried about halting these drugs in patients at highest risk for fracture—those with severe osteoporosis and many prior fractures or ongoing corticosteroid use. In patients with osteoporosis but lower risk of fracture, I have increasingly offered drug holidays. Although it is clearly not based on large interventional outcome studies, I am more inclined to utilize markers of bone turnover than repeated bone density measurements in patients who have been taking bisphosphonates. Chronic bisphosphonate therapy may alter the relationship between density and fracture risk, akin (but opposite) to the way that corticosteroids increase fracture risk above what is suggested by bone density measurements.

But don’t let this discussion about how long to treat stand in the way of initiating therapy in osteoporotic patients at significant risk of fracture.

In the past 2 decades we have come a long way in recognizing the ominous significance of osteoporosis and in being able to reduce fracture rates. However, while we know that bisphosphonates such as alendronate (Fosamax) and risedronate (Actonel) reduce fracture risk in patients with moderate or severe osteoporosis, how long patients should continue to take these drugs remains uncertain.

Dr. Susan M. Ott, in this issue of the Journal, argues that many patients on bisphosphonate therapy for more than 5 years should be offered a “drug holiday.” She proposes a simple algorithm that uses measurement of bone turnover and bone density to decide whether to continue therapy, the assumption being that having accumulated in bone, the drug effect will persist after discontinuation.

This will please many patients, who prefer taking fewer drugs. Cost and potential adverse effects are their concerns. Physicians worry about adynamic bone, and as bisphosphonates accumulate in bone with prolonged therapy, they may ultimately increase the incidence of what are now rare adverse effects, ie, jaw necrosis and linear atypical fractures of the femur. To date, we have little evidence that continued drug exposure will cause more of these severe complications, but lack of data is not so comforting.

The data that support taking a bisphosphonate holiday after 5 years (vs continuing therapy for 10 years) are scant compared with the data supporting their initial benefit. The FLEX study (J Bone Miner Res 2010; 25:976–982), as Dr. Ott notes, provides only tenuous benefit for the longer therapy option (with alendronate). Benefit of 10 vs 5 years of therapy is based on subset analysis of a relevant but small group of patients in this study (those with a femoral neck T score lower than −2.5 and no vertebral fracture at baseline). Patients in this subset suffered more nonvertebral fractures after stopping the drug at 5 years. Data with other bisphosphonates may well differ. For the other subsets, 10 years of therapy did not seem better than 5. But the numbers are small, certainly too small to offer insight on the incidence of rare side effects developing with the extra 5 years of therapy.

My personal take: on the basis of limited data, I am worried about halting these drugs in patients at highest risk for fracture—those with severe osteoporosis and many prior fractures or ongoing corticosteroid use. In patients with osteoporosis but lower risk of fracture, I have increasingly offered drug holidays. Although it is clearly not based on large interventional outcome studies, I am more inclined to utilize markers of bone turnover than repeated bone density measurements in patients who have been taking bisphosphonates. Chronic bisphosphonate therapy may alter the relationship between density and fracture risk, akin (but opposite) to the way that corticosteroids increase fracture risk above what is suggested by bone density measurements.

But don’t let this discussion about how long to treat stand in the way of initiating therapy in osteoporotic patients at significant risk of fracture.

“Poor sleep causes diabetes.” It almost reads like a grocery store tabloid headline. Yet Drs. Carol Touma and Silvana Pannain, in this issue of the Journal, review several studies and some underlying physiologic concepts that strongly link disturbed sleep with type 2 diabetes.

Much of the data are cross-sectional and epidemiologic, so the direction of causation (if causation exists) cannot be established with certainty. There is a host of interwoven confounders, and many of these intersect around the patient’s weight and the presence of sleep apnea. Nevertheless, the authors explore some provocative associations.

Over the years, clinicians have increasingly recognized the myriad of comorbidities that accompany sleep apnea. We have discussed this in the Journal on several occasions since 2005. Naïvely, I have attributed many of these, particularly the cardiac complications, to downstream effects of repetitive hypoxic and hypercarbic insults, but there may be more fundamental physiologic principles in play, some linked to the affected sleep cycle and not to the apnea.

Drs. Touma and Pannain discuss some of the physiologic consequences of altered or decreased sleep cycles. Some of these are a result of disrupting the circadian release of hormones such as glucocorticoids and growth hormone, both of which can influence the body’s sensitivity to insulin’s hypoglycemic effects. The same can be said for disruption of normal sympathetic-parasympathetic nerve flow. In addition, sleep disruption affects appetite. Thinking back to residency, I recall the need to follow the admonition of one of my peers: in order to survive nights on call, never miss a meal. I still remember the (leptin-linked?) cravings after being up all night for a heavy carbohydrate-laden breakfast. Given these effects, coupled with the fatigue of sleep deprivation resulting in decreased exercise, it is easy to construct innumerable positive feedback loops contributing to the development of insulin resistance and type 2 diabetes.

So while it is a truism that sleep is good and that we all need to “recharge our batteries,” we still lack a full understanding of the complex physiology of sleep and the effects of sleep deprivation on a number of clinical conditions, from diabetes to fibromyalgia.

Recognizing the associations is a beginning. Knowing what to do about defective sleep in terms of preventing or ameliorating disease awaits appropriately controlled interventional trials—and the definition of appropriate interventions to evaluate.

“Poor sleep causes diabetes.” It almost reads like a grocery store tabloid headline. Yet Drs. Carol Touma and Silvana Pannain, in this issue of the Journal, review several studies and some underlying physiologic concepts that strongly link disturbed sleep with type 2 diabetes.

Much of the data are cross-sectional and epidemiologic, so the direction of causation (if causation exists) cannot be established with certainty. There is a host of interwoven confounders, and many of these intersect around the patient’s weight and the presence of sleep apnea. Nevertheless, the authors explore some provocative associations.

Over the years, clinicians have increasingly recognized the myriad of comorbidities that accompany sleep apnea. We have discussed this in the Journal on several occasions since 2005. Naïvely, I have attributed many of these, particularly the cardiac complications, to downstream effects of repetitive hypoxic and hypercarbic insults, but there may be more fundamental physiologic principles in play, some linked to the affected sleep cycle and not to the apnea.

Drs. Touma and Pannain discuss some of the physiologic consequences of altered or decreased sleep cycles. Some of these are a result of disrupting the circadian release of hormones such as glucocorticoids and growth hormone, both of which can influence the body’s sensitivity to insulin’s hypoglycemic effects. The same can be said for disruption of normal sympathetic-parasympathetic nerve flow. In addition, sleep disruption affects appetite. Thinking back to residency, I recall the need to follow the admonition of one of my peers: in order to survive nights on call, never miss a meal. I still remember the (leptin-linked?) cravings after being up all night for a heavy carbohydrate-laden breakfast. Given these effects, coupled with the fatigue of sleep deprivation resulting in decreased exercise, it is easy to construct innumerable positive feedback loops contributing to the development of insulin resistance and type 2 diabetes.

So while it is a truism that sleep is good and that we all need to “recharge our batteries,” we still lack a full understanding of the complex physiology of sleep and the effects of sleep deprivation on a number of clinical conditions, from diabetes to fibromyalgia.

Recognizing the associations is a beginning. Knowing what to do about defective sleep in terms of preventing or ameliorating disease awaits appropriately controlled interventional trials—and the definition of appropriate interventions to evaluate.

“Poor sleep causes diabetes.” It almost reads like a grocery store tabloid headline. Yet Drs. Carol Touma and Silvana Pannain, in this issue of the Journal, review several studies and some underlying physiologic concepts that strongly link disturbed sleep with type 2 diabetes.

Much of the data are cross-sectional and epidemiologic, so the direction of causation (if causation exists) cannot be established with certainty. There is a host of interwoven confounders, and many of these intersect around the patient’s weight and the presence of sleep apnea. Nevertheless, the authors explore some provocative associations.

Over the years, clinicians have increasingly recognized the myriad of comorbidities that accompany sleep apnea. We have discussed this in the Journal on several occasions since 2005. Naïvely, I have attributed many of these, particularly the cardiac complications, to downstream effects of repetitive hypoxic and hypercarbic insults, but there may be more fundamental physiologic principles in play, some linked to the affected sleep cycle and not to the apnea.

Drs. Touma and Pannain discuss some of the physiologic consequences of altered or decreased sleep cycles. Some of these are a result of disrupting the circadian release of hormones such as glucocorticoids and growth hormone, both of which can influence the body’s sensitivity to insulin’s hypoglycemic effects. The same can be said for disruption of normal sympathetic-parasympathetic nerve flow. In addition, sleep disruption affects appetite. Thinking back to residency, I recall the need to follow the admonition of one of my peers: in order to survive nights on call, never miss a meal. I still remember the (leptin-linked?) cravings after being up all night for a heavy carbohydrate-laden breakfast. Given these effects, coupled with the fatigue of sleep deprivation resulting in decreased exercise, it is easy to construct innumerable positive feedback loops contributing to the development of insulin resistance and type 2 diabetes.

So while it is a truism that sleep is good and that we all need to “recharge our batteries,” we still lack a full understanding of the complex physiology of sleep and the effects of sleep deprivation on a number of clinical conditions, from diabetes to fibromyalgia.

Recognizing the associations is a beginning. Knowing what to do about defective sleep in terms of preventing or ameliorating disease awaits appropriately controlled interventional trials—and the definition of appropriate interventions to evaluate.

More and more patients are receiving highly specific anti-inflammatory and immunosuppressive medications. As Drs. Derek Tang and Lawrence Ward emphasize in this issue of the Journal, these drugs have side effects, some predictable and some surprising. Because they blunt the immune response (which is why we give them), our concern about opportunistic infection is naturally high, but we must also recognize some seemingly paradoxical reactions.

Many of the adverse effects of the small-molecule drugs such as azathioprine (Imuran) and methotrexate are those expected from chemical toxicity or inhibition of proliferation, eg, aminotransferase elevation, leukopenia, and alopecia. Mycophenolate mofetil (CellCept) uniquely can cause profound anemia, cyclophosphamide (Cytoxan) elicits cystitis, and many of these drugs trigger virus-associated malignancies. In perhaps 8% of patients, azathioprine causes a systemic hypersensitivity reaction with high fevers, variable rash, leukocytosis, and elevated aminotransferase levels shortly after it is started. Yet we are often slow to recognize this syndrome, as we tend to search for an infection and forget that even immunosuppressive drugs can cause systemic allergic-type reactions. A similar syndrome following initiation of phenytoin (Dilantin) would be recognized far more rapidly.

But the biologic agents, which target specific components of the immune system, resulting in focal immunosuppression and a disturbance in the homeostatic balance of the immune system, elicit some of the more challenging and sometimes paradoxical side effects. Interferon alfa, which has antiviral effects, is also used as an immunomodulator to treat Behçet disease and as part of regimens that treat specific malignancies. Perhaps because it up-regulates the expression of major histocompatibility complex class II molecules on antigen-presenting cells, interferon therapy also triggers several organ-specific autoimmune syndromes, including autoimmune thrombocytopenia, hypothyroidism, hemolytic anemia, hepatitis, and psoriasis.

Even more challenging to understand and sometimes to treat are the inflammatory effects of anti-tumor necrosis factor agents. Drugs of this class can evoke a demyelinating syndrome similar to multiple sclerosis. Further, even though they are used to treat psoriasis, they can also provoke a psoriasiform, often palmar and pustular, reaction.

So as we continue to adopt targeted immunologic therapies and revel in their efficacy, we need to remain humbled by what we don’t yet fully understand about the complexity of what the 19th century physiologist Claude Bernard termed the milieu intérieur (homeostasis) and keep in mind that even the most specific of drugs can have untoward biologic effects by weirdly disrupting our finely balanced immune system.

More and more patients are receiving highly specific anti-inflammatory and immunosuppressive medications. As Drs. Derek Tang and Lawrence Ward emphasize in this issue of the Journal, these drugs have side effects, some predictable and some surprising. Because they blunt the immune response (which is why we give them), our concern about opportunistic infection is naturally high, but we must also recognize some seemingly paradoxical reactions.

Many of the adverse effects of the small-molecule drugs such as azathioprine (Imuran) and methotrexate are those expected from chemical toxicity or inhibition of proliferation, eg, aminotransferase elevation, leukopenia, and alopecia. Mycophenolate mofetil (CellCept) uniquely can cause profound anemia, cyclophosphamide (Cytoxan) elicits cystitis, and many of these drugs trigger virus-associated malignancies. In perhaps 8% of patients, azathioprine causes a systemic hypersensitivity reaction with high fevers, variable rash, leukocytosis, and elevated aminotransferase levels shortly after it is started. Yet we are often slow to recognize this syndrome, as we tend to search for an infection and forget that even immunosuppressive drugs can cause systemic allergic-type reactions. A similar syndrome following initiation of phenytoin (Dilantin) would be recognized far more rapidly.

But the biologic agents, which target specific components of the immune system, resulting in focal immunosuppression and a disturbance in the homeostatic balance of the immune system, elicit some of the more challenging and sometimes paradoxical side effects. Interferon alfa, which has antiviral effects, is also used as an immunomodulator to treat Behçet disease and as part of regimens that treat specific malignancies. Perhaps because it up-regulates the expression of major histocompatibility complex class II molecules on antigen-presenting cells, interferon therapy also triggers several organ-specific autoimmune syndromes, including autoimmune thrombocytopenia, hypothyroidism, hemolytic anemia, hepatitis, and psoriasis.

Even more challenging to understand and sometimes to treat are the inflammatory effects of anti-tumor necrosis factor agents. Drugs of this class can evoke a demyelinating syndrome similar to multiple sclerosis. Further, even though they are used to treat psoriasis, they can also provoke a psoriasiform, often palmar and pustular, reaction.

So as we continue to adopt targeted immunologic therapies and revel in their efficacy, we need to remain humbled by what we don’t yet fully understand about the complexity of what the 19th century physiologist Claude Bernard termed the milieu intérieur (homeostasis) and keep in mind that even the most specific of drugs can have untoward biologic effects by weirdly disrupting our finely balanced immune system.

More and more patients are receiving highly specific anti-inflammatory and immunosuppressive medications. As Drs. Derek Tang and Lawrence Ward emphasize in this issue of the Journal, these drugs have side effects, some predictable and some surprising. Because they blunt the immune response (which is why we give them), our concern about opportunistic infection is naturally high, but we must also recognize some seemingly paradoxical reactions.

Many of the adverse effects of the small-molecule drugs such as azathioprine (Imuran) and methotrexate are those expected from chemical toxicity or inhibition of proliferation, eg, aminotransferase elevation, leukopenia, and alopecia. Mycophenolate mofetil (CellCept) uniquely can cause profound anemia, cyclophosphamide (Cytoxan) elicits cystitis, and many of these drugs trigger virus-associated malignancies. In perhaps 8% of patients, azathioprine causes a systemic hypersensitivity reaction with high fevers, variable rash, leukocytosis, and elevated aminotransferase levels shortly after it is started. Yet we are often slow to recognize this syndrome, as we tend to search for an infection and forget that even immunosuppressive drugs can cause systemic allergic-type reactions. A similar syndrome following initiation of phenytoin (Dilantin) would be recognized far more rapidly.

But the biologic agents, which target specific components of the immune system, resulting in focal immunosuppression and a disturbance in the homeostatic balance of the immune system, elicit some of the more challenging and sometimes paradoxical side effects. Interferon alfa, which has antiviral effects, is also used as an immunomodulator to treat Behçet disease and as part of regimens that treat specific malignancies. Perhaps because it up-regulates the expression of major histocompatibility complex class II molecules on antigen-presenting cells, interferon therapy also triggers several organ-specific autoimmune syndromes, including autoimmune thrombocytopenia, hypothyroidism, hemolytic anemia, hepatitis, and psoriasis.

Even more challenging to understand and sometimes to treat are the inflammatory effects of anti-tumor necrosis factor agents. Drugs of this class can evoke a demyelinating syndrome similar to multiple sclerosis. Further, even though they are used to treat psoriasis, they can also provoke a psoriasiform, often palmar and pustular, reaction.

So as we continue to adopt targeted immunologic therapies and revel in their efficacy, we need to remain humbled by what we don’t yet fully understand about the complexity of what the 19th century physiologist Claude Bernard termed the milieu intérieur (homeostasis) and keep in mind that even the most specific of drugs can have untoward biologic effects by weirdly disrupting our finely balanced immune system.

Everyone seems to know statins cause muscle pain. The phenomenon of statin myopathy remains, at least in part, a conundrum to me—but apparently not to many patients with hypercholesterolemia who fear the muscle problems.

Given the perception that statin myopathy is common, the incidence of significant myalgias in clinical trials is surprisingly low and similar to that with placebo (generally less than 5%), and that of myositis or rhabdomyolysis is much rarer.

In this issue of the Journal, Dr. Genaro Fernandez and colleagues discuss possible reasons for the discrepancy between the prevalence of statin-associated myalgias in clinical trials vs real practice. They suggest that patients more likely to develop myalgias are weeded out in the screening phase of clinical trials and that the trials may be too small and too short to capture this information. Yet in practice, many patients develop muscle pain shortly after starting statin therapy. I suggest another explanation—ie, that volunteers in clinical trials want to take the medication, while in the clinic my patients are reluctant to take one more medication and have trepidations about starting one that they “know” causes muscle pain.

But I don’t think all statin myopathy is due to the power of suggestion. Some patients clearly have drug-elicited elevations in creatine kinase (CK), and others (including me) experience significant myalgias with one statin but can tolerate another.

A challenge in my rheumatology clinic is distinguishing statin myopathy from other underlying problems in patients referred for evaluation of pain, weakness, or elevated CK. I first establish a temporal relationship between the drug initiation and the start of symptoms, and I look for other drugs or possible drug interactions that could be causing the problem, such as colchicine vacuolar myopathy in the setting of newly initiated statin therapy. I look for an alternative explanation for the pain syndrome, such as upper-arm pain and physical findings that suggest rotator cuff disease, or lateral hip-area pain due to bursitis. In some patients, statins may pose a metabolic challenge that unmasks (or brings to the physician’s attention) an underlying biochemical disorder of the muscle, such as myotonic dystrophy or even polymyositis.

Dr. Fernandez et al offer sound advice, as they suggest keeping an open diagnostic mind when evaluating patients with apparent statin myopathy. In particular, with these authors, I urge you to perform a careful personal and family history and a focused examination, ask about vigorous physical exercise, check the CK, and withhold and then rechallenge with the statin before ordering a slew of serologic and metabolic tests.

Everyone seems to know statins cause muscle pain. The phenomenon of statin myopathy remains, at least in part, a conundrum to me—but apparently not to many patients with hypercholesterolemia who fear the muscle problems.

Given the perception that statin myopathy is common, the incidence of significant myalgias in clinical trials is surprisingly low and similar to that with placebo (generally less than 5%), and that of myositis or rhabdomyolysis is much rarer.

In this issue of the Journal, Dr. Genaro Fernandez and colleagues discuss possible reasons for the discrepancy between the prevalence of statin-associated myalgias in clinical trials vs real practice. They suggest that patients more likely to develop myalgias are weeded out in the screening phase of clinical trials and that the trials may be too small and too short to capture this information. Yet in practice, many patients develop muscle pain shortly after starting statin therapy. I suggest another explanation—ie, that volunteers in clinical trials want to take the medication, while in the clinic my patients are reluctant to take one more medication and have trepidations about starting one that they “know” causes muscle pain.

But I don’t think all statin myopathy is due to the power of suggestion. Some patients clearly have drug-elicited elevations in creatine kinase (CK), and others (including me) experience significant myalgias with one statin but can tolerate another.

A challenge in my rheumatology clinic is distinguishing statin myopathy from other underlying problems in patients referred for evaluation of pain, weakness, or elevated CK. I first establish a temporal relationship between the drug initiation and the start of symptoms, and I look for other drugs or possible drug interactions that could be causing the problem, such as colchicine vacuolar myopathy in the setting of newly initiated statin therapy. I look for an alternative explanation for the pain syndrome, such as upper-arm pain and physical findings that suggest rotator cuff disease, or lateral hip-area pain due to bursitis. In some patients, statins may pose a metabolic challenge that unmasks (or brings to the physician’s attention) an underlying biochemical disorder of the muscle, such as myotonic dystrophy or even polymyositis.

Dr. Fernandez et al offer sound advice, as they suggest keeping an open diagnostic mind when evaluating patients with apparent statin myopathy. In particular, with these authors, I urge you to perform a careful personal and family history and a focused examination, ask about vigorous physical exercise, check the CK, and withhold and then rechallenge with the statin before ordering a slew of serologic and metabolic tests.

Everyone seems to know statins cause muscle pain. The phenomenon of statin myopathy remains, at least in part, a conundrum to me—but apparently not to many patients with hypercholesterolemia who fear the muscle problems.

Given the perception that statin myopathy is common, the incidence of significant myalgias in clinical trials is surprisingly low and similar to that with placebo (generally less than 5%), and that of myositis or rhabdomyolysis is much rarer.

In this issue of the Journal, Dr. Genaro Fernandez and colleagues discuss possible reasons for the discrepancy between the prevalence of statin-associated myalgias in clinical trials vs real practice. They suggest that patients more likely to develop myalgias are weeded out in the screening phase of clinical trials and that the trials may be too small and too short to capture this information. Yet in practice, many patients develop muscle pain shortly after starting statin therapy. I suggest another explanation—ie, that volunteers in clinical trials want to take the medication, while in the clinic my patients are reluctant to take one more medication and have trepidations about starting one that they “know” causes muscle pain.

But I don’t think all statin myopathy is due to the power of suggestion. Some patients clearly have drug-elicited elevations in creatine kinase (CK), and others (including me) experience significant myalgias with one statin but can tolerate another.

A challenge in my rheumatology clinic is distinguishing statin myopathy from other underlying problems in patients referred for evaluation of pain, weakness, or elevated CK. I first establish a temporal relationship between the drug initiation and the start of symptoms, and I look for other drugs or possible drug interactions that could be causing the problem, such as colchicine vacuolar myopathy in the setting of newly initiated statin therapy. I look for an alternative explanation for the pain syndrome, such as upper-arm pain and physical findings that suggest rotator cuff disease, or lateral hip-area pain due to bursitis. In some patients, statins may pose a metabolic challenge that unmasks (or brings to the physician’s attention) an underlying biochemical disorder of the muscle, such as myotonic dystrophy or even polymyositis.

Dr. Fernandez et al offer sound advice, as they suggest keeping an open diagnostic mind when evaluating patients with apparent statin myopathy. In particular, with these authors, I urge you to perform a careful personal and family history and a focused examination, ask about vigorous physical exercise, check the CK, and withhold and then rechallenge with the statin before ordering a slew of serologic and metabolic tests.

The discussion of angiotensin-converting enzyme (ACE) inhibitor therapy and visceral angioedema by Korniyenko et al in this issue of the Journal prompted me to consider the diagnostic epiphany.

This group had a patient with unexplained abdominal pain who ultimately underwent laparotomy, which did not reveal the diagnosis. I can reconstruct the thought processes that led to the decision for surgery, but far more intriguing is what provoked the “aha” moment when the true diagnosis—ACE inhibitor-associated angioedema—finally occurred to someone.

This is a rare complication of a common therapy, perhaps read about but not reasonable to expect all physicians to recall. If that is true, why can’t we incorporate technology into our care system to intelligently supplement the individual physician’s memory? What would have been the result if a “smart” electronic record had flagged the combination of ACE inhibitor therapy and recurrent abdominal pain and provided a citation on visceral angioedema?

We have all experienced a diagnostic epiphany, the sudden recognition of an arcane or unexpected diagnosis—as on the TV show House, but without the sneer or commercials. Some epiphanies result from suddenly seeing theretofore disconnected dots as a recognizable pattern. Some result from sudden recall of “I saw something like this once.” The superb diagnosticians seem to have these experiences more than the rest of us. Their powers of clinical reasoning are not always transparent. Some are based on the gestalt born of perception and experience, others are the result of incredibly compulsive structured analysis. Both require experience, contextual knowledge, and accurate historical information. These components will need to be incorporated into any diagnostic assistive software. But is this possible?

Those who have read my previous commentaries know that I value highly the clinical skills of history-taking and examination. I believe that these fundamental processes should be used to direct laboratory and imaging studies. I also optimistically expect that electronic medical records will evolve to become far more useful than most currently are, ultimately acting as true auxiliary brains, able to remind us of facts that we can’t recall (eg, that visceral angioedema is associated with ACE inhibitors). But there will never be a substitute for the artful and compulsive interview that establishes whether our patient is actually taking his or her medication, and whether there is a relationship between when a medication is ingested and when symptoms appear. The quality of the data entered into our electronic medical record (or other auxiliary brains), to then be associated with various informational databases, will always depend on the skill of the listening and examining clinician.

The discussion of angiotensin-converting enzyme (ACE) inhibitor therapy and visceral angioedema by Korniyenko et al in this issue of the Journal prompted me to consider the diagnostic epiphany.

This group had a patient with unexplained abdominal pain who ultimately underwent laparotomy, which did not reveal the diagnosis. I can reconstruct the thought processes that led to the decision for surgery, but far more intriguing is what provoked the “aha” moment when the true diagnosis—ACE inhibitor-associated angioedema—finally occurred to someone.

This is a rare complication of a common therapy, perhaps read about but not reasonable to expect all physicians to recall. If that is true, why can’t we incorporate technology into our care system to intelligently supplement the individual physician’s memory? What would have been the result if a “smart” electronic record had flagged the combination of ACE inhibitor therapy and recurrent abdominal pain and provided a citation on visceral angioedema?

We have all experienced a diagnostic epiphany, the sudden recognition of an arcane or unexpected diagnosis—as on the TV show House, but without the sneer or commercials. Some epiphanies result from suddenly seeing theretofore disconnected dots as a recognizable pattern. Some result from sudden recall of “I saw something like this once.” The superb diagnosticians seem to have these experiences more than the rest of us. Their powers of clinical reasoning are not always transparent. Some are based on the gestalt born of perception and experience, others are the result of incredibly compulsive structured analysis. Both require experience, contextual knowledge, and accurate historical information. These components will need to be incorporated into any diagnostic assistive software. But is this possible?

Those who have read my previous commentaries know that I value highly the clinical skills of history-taking and examination. I believe that these fundamental processes should be used to direct laboratory and imaging studies. I also optimistically expect that electronic medical records will evolve to become far more useful than most currently are, ultimately acting as true auxiliary brains, able to remind us of facts that we can’t recall (eg, that visceral angioedema is associated with ACE inhibitors). But there will never be a substitute for the artful and compulsive interview that establishes whether our patient is actually taking his or her medication, and whether there is a relationship between when a medication is ingested and when symptoms appear. The quality of the data entered into our electronic medical record (or other auxiliary brains), to then be associated with various informational databases, will always depend on the skill of the listening and examining clinician.

The discussion of angiotensin-converting enzyme (ACE) inhibitor therapy and visceral angioedema by Korniyenko et al in this issue of the Journal prompted me to consider the diagnostic epiphany.

This group had a patient with unexplained abdominal pain who ultimately underwent laparotomy, which did not reveal the diagnosis. I can reconstruct the thought processes that led to the decision for surgery, but far more intriguing is what provoked the “aha” moment when the true diagnosis—ACE inhibitor-associated angioedema—finally occurred to someone.

This is a rare complication of a common therapy, perhaps read about but not reasonable to expect all physicians to recall. If that is true, why can’t we incorporate technology into our care system to intelligently supplement the individual physician’s memory? What would have been the result if a “smart” electronic record had flagged the combination of ACE inhibitor therapy and recurrent abdominal pain and provided a citation on visceral angioedema?

We have all experienced a diagnostic epiphany, the sudden recognition of an arcane or unexpected diagnosis—as on the TV show House, but without the sneer or commercials. Some epiphanies result from suddenly seeing theretofore disconnected dots as a recognizable pattern. Some result from sudden recall of “I saw something like this once.” The superb diagnosticians seem to have these experiences more than the rest of us. Their powers of clinical reasoning are not always transparent. Some are based on the gestalt born of perception and experience, others are the result of incredibly compulsive structured analysis. Both require experience, contextual knowledge, and accurate historical information. These components will need to be incorporated into any diagnostic assistive software. But is this possible?

Those who have read my previous commentaries know that I value highly the clinical skills of history-taking and examination. I believe that these fundamental processes should be used to direct laboratory and imaging studies. I also optimistically expect that electronic medical records will evolve to become far more useful than most currently are, ultimately acting as true auxiliary brains, able to remind us of facts that we can’t recall (eg, that visceral angioedema is associated with ACE inhibitors). But there will never be a substitute for the artful and compulsive interview that establishes whether our patient is actually taking his or her medication, and whether there is a relationship between when a medication is ingested and when symptoms appear. The quality of the data entered into our electronic medical record (or other auxiliary brains), to then be associated with various informational databases, will always depend on the skill of the listening and examining clinician.

We often dose drugs empirically, starting at a historically defined dose and then titrating to a desired effect, drug level, or absolute amount. Some drugs we dose on the basis of weight or estimated glomerular filtration rate, but many drugs we start with a “one-strength-fits-most” approach. For relatively few drugs can we measure circulating or relevant tissue levels or a real-time pharmacodynamic response such as a change in blood pressure or in the level of serum glucose or low-density lipoprotein cholesterol.

For some drugs there is a key step in metabolism, often in a rate-limiting pathway, with an enzyme that has known and detectable polymorphisms that differ dramatically in their ability to affect the drug’s degradation. In theory, by determining the patient’s specific genotype ahead of time, the initial dose of the drug can be determined more rationally. In this issue of the Journal, Kitzmiller et al describe several drugs for which this may be true.

However, for this approach to be practical and cost-effective, several conditions should be met. The drug must be one that needs to be dosed to its therapeutic level rapidly: if there is time to titrate slowly, then there is little need for the extra expense associated with genotyping in order to titrate it more rapidly. Also, it should be proven that dosing based on advance knowledge of the genotype of the target actually results in safer or more efficacious dosing.

For carbamazepine (Tegretol, Equetro) and allopurinol (Zyloprim), specific human leukocyte antigen haplotypes are associated with a strikingly increased frequency of serious hypersensitivity reactions. In some patients, these should be checked before giving the drug.

But the concept of pharmacogenomics is broad, and it may yet explain many vagaries of drug-responsiveness in individual patients. Polymorphisms in renal anion transporters may dictate the level of anionic drugs. Drug-receptor polymorphisms may determine the affinity of a drug for its target and, hence, its efficacy. Cell-membrane transporters, which may have functionally different stable alleles or polymorphisms, may regulate intracellular drug levels by pumping the drug into or out of cells with different efficiencies.

As the entire human genome is dissected and analyzed, and as more and more genes (with their polymorphisms) are linked to specific functions readily detectable in specific patients, we will have more opportunities to match the right drug and dose to the right patient. We are not there yet, but that day is coming.

We often dose drugs empirically, starting at a historically defined dose and then titrating to a desired effect, drug level, or absolute amount. Some drugs we dose on the basis of weight or estimated glomerular filtration rate, but many drugs we start with a “one-strength-fits-most” approach. For relatively few drugs can we measure circulating or relevant tissue levels or a real-time pharmacodynamic response such as a change in blood pressure or in the level of serum glucose or low-density lipoprotein cholesterol.

For some drugs there is a key step in metabolism, often in a rate-limiting pathway, with an enzyme that has known and detectable polymorphisms that differ dramatically in their ability to affect the drug’s degradation. In theory, by determining the patient’s specific genotype ahead of time, the initial dose of the drug can be determined more rationally. In this issue of the Journal, Kitzmiller et al describe several drugs for which this may be true.

However, for this approach to be practical and cost-effective, several conditions should be met. The drug must be one that needs to be dosed to its therapeutic level rapidly: if there is time to titrate slowly, then there is little need for the extra expense associated with genotyping in order to titrate it more rapidly. Also, it should be proven that dosing based on advance knowledge of the genotype of the target actually results in safer or more efficacious dosing.

For carbamazepine (Tegretol, Equetro) and allopurinol (Zyloprim), specific human leukocyte antigen haplotypes are associated with a strikingly increased frequency of serious hypersensitivity reactions. In some patients, these should be checked before giving the drug.

But the concept of pharmacogenomics is broad, and it may yet explain many vagaries of drug-responsiveness in individual patients. Polymorphisms in renal anion transporters may dictate the level of anionic drugs. Drug-receptor polymorphisms may determine the affinity of a drug for its target and, hence, its efficacy. Cell-membrane transporters, which may have functionally different stable alleles or polymorphisms, may regulate intracellular drug levels by pumping the drug into or out of cells with different efficiencies.

As the entire human genome is dissected and analyzed, and as more and more genes (with their polymorphisms) are linked to specific functions readily detectable in specific patients, we will have more opportunities to match the right drug and dose to the right patient. We are not there yet, but that day is coming.

We often dose drugs empirically, starting at a historically defined dose and then titrating to a desired effect, drug level, or absolute amount. Some drugs we dose on the basis of weight or estimated glomerular filtration rate, but many drugs we start with a “one-strength-fits-most” approach. For relatively few drugs can we measure circulating or relevant tissue levels or a real-time pharmacodynamic response such as a change in blood pressure or in the level of serum glucose or low-density lipoprotein cholesterol.

For some drugs there is a key step in metabolism, often in a rate-limiting pathway, with an enzyme that has known and detectable polymorphisms that differ dramatically in their ability to affect the drug’s degradation. In theory, by determining the patient’s specific genotype ahead of time, the initial dose of the drug can be determined more rationally. In this issue of the Journal, Kitzmiller et al describe several drugs for which this may be true.

However, for this approach to be practical and cost-effective, several conditions should be met. The drug must be one that needs to be dosed to its therapeutic level rapidly: if there is time to titrate slowly, then there is little need for the extra expense associated with genotyping in order to titrate it more rapidly. Also, it should be proven that dosing based on advance knowledge of the genotype of the target actually results in safer or more efficacious dosing.

For carbamazepine (Tegretol, Equetro) and allopurinol (Zyloprim), specific human leukocyte antigen haplotypes are associated with a strikingly increased frequency of serious hypersensitivity reactions. In some patients, these should be checked before giving the drug.

But the concept of pharmacogenomics is broad, and it may yet explain many vagaries of drug-responsiveness in individual patients. Polymorphisms in renal anion transporters may dictate the level of anionic drugs. Drug-receptor polymorphisms may determine the affinity of a drug for its target and, hence, its efficacy. Cell-membrane transporters, which may have functionally different stable alleles or polymorphisms, may regulate intracellular drug levels by pumping the drug into or out of cells with different efficiencies.

As the entire human genome is dissected and analyzed, and as more and more genes (with their polymorphisms) are linked to specific functions readily detectable in specific patients, we will have more opportunities to match the right drug and dose to the right patient. We are not there yet, but that day is coming.

Reading the 1-Minute Consult article by Daoud et al on iron therapy in the setting of infection got me thinking about how concepts get incorporated into practice and about the urge and challenge to stay aware of advances in pathophysiology.

If you are one who avoids giving iron to patients with infection, you will be interested in knowing why Daoud et al argue that giving iron is OK. If you hadn’t thought about it recently, this is an excellent opportunity to consider why there has been concern. And why does the serum iron level drop with infection?

Patients with hemochromatosis, characterized by total body overload of iron, are reported to be at risk of overwhelming infection from Vibrio vulnificus. This may well hold true for patients with chronic severe liver disease of other etiologies as well. Vibrio and certain other bacteria (Listeria, Yersinia, Legionella) can demonstrate rapid growth and increased intracellular resistance to killing in the setting of excess iron. Macrophages, in the setting of chronic infection or inflammation, retain excess iron, which may reduce their bactericidal functions. Thus, there has been concern about iron supplementation (including transfusion) in the setting of infection, even in patients with low iron levels and anemia.

The circulating level of the liver protein hepcidin increases as part of the acute-phase response to infection, perhaps with the physiologic “goal” of reducing the availability of free iron to microbial invaders. Hepcidin binds and blocks the function of the membrane iron exporter ferroportin, and iron is functionally trapped within intestinal enterocytes (reducing its absorption) and macrophages (reducing its availability to erythrocyte precursors).

For some of us out of medical school for more than 10 years, the work of Ganz and others^1,2 describing the seminal role of hepcidin in iron metabolism may be only partially known. The short article by Daoud and colleagues may urge us to read more about the pathophysiologic foundation of a clinical conundrum. I hope so, for it is that urge to understand that helps define our professional identity as physicians.

Reading the 1-Minute Consult article by Daoud et al on iron therapy in the setting of infection got me thinking about how concepts get incorporated into practice and about the urge and challenge to stay aware of advances in pathophysiology.

If you are one who avoids giving iron to patients with infection, you will be interested in knowing why Daoud et al argue that giving iron is OK. If you hadn’t thought about it recently, this is an excellent opportunity to consider why there has been concern. And why does the serum iron level drop with infection?

Patients with hemochromatosis, characterized by total body overload of iron, are reported to be at risk of overwhelming infection from Vibrio vulnificus. This may well hold true for patients with chronic severe liver disease of other etiologies as well. Vibrio and certain other bacteria (Listeria, Yersinia, Legionella) can demonstrate rapid growth and increased intracellular resistance to killing in the setting of excess iron. Macrophages, in the setting of chronic infection or inflammation, retain excess iron, which may reduce their bactericidal functions. Thus, there has been concern about iron supplementation (including transfusion) in the setting of infection, even in patients with low iron levels and anemia.

The circulating level of the liver protein hepcidin increases as part of the acute-phase response to infection, perhaps with the physiologic “goal” of reducing the availability of free iron to microbial invaders. Hepcidin binds and blocks the function of the membrane iron exporter ferroportin, and iron is functionally trapped within intestinal enterocytes (reducing its absorption) and macrophages (reducing its availability to erythrocyte precursors).

For some of us out of medical school for more than 10 years, the work of Ganz and others^1,2 describing the seminal role of hepcidin in iron metabolism may be only partially known. The short article by Daoud and colleagues may urge us to read more about the pathophysiologic foundation of a clinical conundrum. I hope so, for it is that urge to understand that helps define our professional identity as physicians.

Reading the 1-Minute Consult article by Daoud et al on iron therapy in the setting of infection got me thinking about how concepts get incorporated into practice and about the urge and challenge to stay aware of advances in pathophysiology.

If you are one who avoids giving iron to patients with infection, you will be interested in knowing why Daoud et al argue that giving iron is OK. If you hadn’t thought about it recently, this is an excellent opportunity to consider why there has been concern. And why does the serum iron level drop with infection?

Patients with hemochromatosis, characterized by total body overload of iron, are reported to be at risk of overwhelming infection from Vibrio vulnificus. This may well hold true for patients with chronic severe liver disease of other etiologies as well. Vibrio and certain other bacteria (Listeria, Yersinia, Legionella) can demonstrate rapid growth and increased intracellular resistance to killing in the setting of excess iron. Macrophages, in the setting of chronic infection or inflammation, retain excess iron, which may reduce their bactericidal functions. Thus, there has been concern about iron supplementation (including transfusion) in the setting of infection, even in patients with low iron levels and anemia.

The circulating level of the liver protein hepcidin increases as part of the acute-phase response to infection, perhaps with the physiologic “goal” of reducing the availability of free iron to microbial invaders. Hepcidin binds and blocks the function of the membrane iron exporter ferroportin, and iron is functionally trapped within intestinal enterocytes (reducing its absorption) and macrophages (reducing its availability to erythrocyte precursors).

For some of us out of medical school for more than 10 years, the work of Ganz and others^1,2 describing the seminal role of hepcidin in iron metabolism may be only partially known. The short article by Daoud and colleagues may urge us to read more about the pathophysiologic foundation of a clinical conundrum. I hope so, for it is that urge to understand that helps define our professional identity as physicians.

In treating cardiovascular risk factors, we keep making our targets more aggressive. Epidemiologic data have established a link between high blood pressure (and high blood sugar) and a variety of bad outcomes. Since we now have many drugs to lower blood pressure and blood glucose, it would seem that aggressive treatment goals should be both achievable and beneficial.

But some have long suspected too-aggressive treatment would have an adverse effect—the so called “J curve” seen when drug effect is plotted against adverse outcome. The validity of this concept at the extreme is obvious: excessive hypotension or hypoglycemia is not clinically tolerated. So where is the cutoff between benefit and complications, where treatment becomes too aggressive and causes complications that outweigh the benefits?

In this issue of the Journal, Dr. Edward J. Filippone and colleagues discuss the treatment of hypertension with proposed aggressive but seemingly reasonable blood pressure targets. Surprisingly, interventional trials have not jibed with observational data that suggest a beneficial continuous relationship between blood-pressure-lowering within the physiologic range and cardiac outcomes. Potential explanations for this are many. Organs differ in their response to blood-pressure-lowering. The brain, despite considerable autoregulatory circulatory control, benefits from lowered blood pressure with reduced stroke frequency. The heart, uniquely dependent on diastolic flow for perfusion, can be compromised with aggressive lowering of the diastolic pressure, ie, to below 85 mm Hg, although lowering the systolic pressure may be beneficial. Specific drugs may have beneficial or detrimental effects, particularly in combinations needed to control blood pressure in patients with stiff arteries and multiple comorbidities.

In the clinic, attention to the individual’s physiology and clinical response to therapy needs to be paramount in our mind as we determine treatment targets—possibly a source of dissonance, as we are held accountable to external agencies for our practice performance in a depersonalized manner.

Proposed aggressive blood pressure targets remain contentious, but a far greater problem is that we are still not successfully treating hypertension to even a conservative target. In a recent analysis of the National Health and Nutrition Examination Survey database from 2003 to 2006, only about 44% of treated hypertensive patients were appropriately controlled.¹ As a community of physicians, we have a way to go before we hit the J point.

In treating cardiovascular risk factors, we keep making our targets more aggressive. Epidemiologic data have established a link between high blood pressure (and high blood sugar) and a variety of bad outcomes. Since we now have many drugs to lower blood pressure and blood glucose, it would seem that aggressive treatment goals should be both achievable and beneficial.

But some have long suspected too-aggressive treatment would have an adverse effect—the so called “J curve” seen when drug effect is plotted against adverse outcome. The validity of this concept at the extreme is obvious: excessive hypotension or hypoglycemia is not clinically tolerated. So where is the cutoff between benefit and complications, where treatment becomes too aggressive and causes complications that outweigh the benefits?

In this issue of the Journal, Dr. Edward J. Filippone and colleagues discuss the treatment of hypertension with proposed aggressive but seemingly reasonable blood pressure targets. Surprisingly, interventional trials have not jibed with observational data that suggest a beneficial continuous relationship between blood-pressure-lowering within the physiologic range and cardiac outcomes. Potential explanations for this are many. Organs differ in their response to blood-pressure-lowering. The brain, despite considerable autoregulatory circulatory control, benefits from lowered blood pressure with reduced stroke frequency. The heart, uniquely dependent on diastolic flow for perfusion, can be compromised with aggressive lowering of the diastolic pressure, ie, to below 85 mm Hg, although lowering the systolic pressure may be beneficial. Specific drugs may have beneficial or detrimental effects, particularly in combinations needed to control blood pressure in patients with stiff arteries and multiple comorbidities.

In the clinic, attention to the individual’s physiology and clinical response to therapy needs to be paramount in our mind as we determine treatment targets—possibly a source of dissonance, as we are held accountable to external agencies for our practice performance in a depersonalized manner.

Proposed aggressive blood pressure targets remain contentious, but a far greater problem is that we are still not successfully treating hypertension to even a conservative target. In a recent analysis of the National Health and Nutrition Examination Survey database from 2003 to 2006, only about 44% of treated hypertensive patients were appropriately controlled.¹ As a community of physicians, we have a way to go before we hit the J point.

In treating cardiovascular risk factors, we keep making our targets more aggressive. Epidemiologic data have established a link between high blood pressure (and high blood sugar) and a variety of bad outcomes. Since we now have many drugs to lower blood pressure and blood glucose, it would seem that aggressive treatment goals should be both achievable and beneficial.

But some have long suspected too-aggressive treatment would have an adverse effect—the so called “J curve” seen when drug effect is plotted against adverse outcome. The validity of this concept at the extreme is obvious: excessive hypotension or hypoglycemia is not clinically tolerated. So where is the cutoff between benefit and complications, where treatment becomes too aggressive and causes complications that outweigh the benefits?

In this issue of the Journal, Dr. Edward J. Filippone and colleagues discuss the treatment of hypertension with proposed aggressive but seemingly reasonable blood pressure targets. Surprisingly, interventional trials have not jibed with observational data that suggest a beneficial continuous relationship between blood-pressure-lowering within the physiologic range and cardiac outcomes. Potential explanations for this are many. Organs differ in their response to blood-pressure-lowering. The brain, despite considerable autoregulatory circulatory control, benefits from lowered blood pressure with reduced stroke frequency. The heart, uniquely dependent on diastolic flow for perfusion, can be compromised with aggressive lowering of the diastolic pressure, ie, to below 85 mm Hg, although lowering the systolic pressure may be beneficial. Specific drugs may have beneficial or detrimental effects, particularly in combinations needed to control blood pressure in patients with stiff arteries and multiple comorbidities.

In the clinic, attention to the individual’s physiology and clinical response to therapy needs to be paramount in our mind as we determine treatment targets—possibly a source of dissonance, as we are held accountable to external agencies for our practice performance in a depersonalized manner.

Proposed aggressive blood pressure targets remain contentious, but a far greater problem is that we are still not successfully treating hypertension to even a conservative target. In a recent analysis of the National Health and Nutrition Examination Survey database from 2003 to 2006, only about 44% of treated hypertensive patients were appropriately controlled.¹ As a community of physicians, we have a way to go before we hit the J point.

In the 1980s, the eclectic rock band Talking Heads sang, “You may ask yourself, How did I get here?”—a reflective question appropriate now on the occasion of the 80th anniversary of the Cleveland Clinic Journal of Medicine. That question can be answered by reviewing a bit of history, and corollary questions addressing the current identity and status of the Journal can be (sort of) answered with a refrain from the same song: “Same as it ever was.”

The Journal is currently received by more than 100,000 general internists, cardiologists, hospitalists, and medical subspecialists. It is fully peer-reviewed, listed in MEDLINE, and freely available in complete format at www.ccjm.org. Cleveland Clinic supports the production and distribution of the Journal and provides free CME credits linked to selected articles in an effort to enhance the delivery of high-quality medical care to patients everywhere. The Journal is housed within Cleveland Clinic’s Education Institute, distinct from any direct influence of our marketing or public relations departments—a distinction that I, as editor-in-chief, take extremely seriously. Our primary editorial goal is, and has been, to provide relevant and useful clinical knowledge to the medical community.

The Journal began as the Cleveland Clinic Bulletin in 1931, morphing into the Cleveland Clinic Quarterly the following year and into the Cleveland Clinic Journal of Medicine in 1987. The Quarterly published reprints of papers published elsewhere, as well as case reports and scholarly work presented by Clinic physicians at their staff meetings. Perhaps the latter content was intended to compete with that published in the Proceedings of the Staff Meetings of the Mayo Clinic (first appearing in 1926). Dr. George Crile, one of the founders of Cleveland Clinic, was intent on putting the medical and scientific work of the Clinic in the limelight of American medicine. He felt back in 1931 the same as we feel now, 80 years later, that the Journal contributes to the three pillar missions of the Clinic: better care of the sick, investigation of their problems, and further education of those who serve.

In 1934, the Quarterly ceased publishing reprints from other journals, and Clinic staff were encouraged to publish their case reports, topic reviews, and clinical series in the Quarterly. Over the years, some articles reflected practice at the Clinic and included a description of 1,000 consecutive patients with irritable colon (1941), a description of 10,744 patients who underwent coronary revascularization (1976), and a report of cardiac complications in 951 patients who underwent peripheral vascular surgery (1982). Also notable was the description of the “LE prep test” for the diagnosis of systemic lupus erythematosus (1949).

I am the eighth physician editor-in-chief of the Journal. Three of us have been rheumatologists (perhaps we read more, and cost less). We each have had the opportunity, along with input from the Journal editorial staff, to change the appearance, the content, and sometimes the editorial direction of the Journal. Following the lead of my preceding editor Dr. John Clough and former publisher Linda K. Hengstler, we publish monthly, continue to expand our online content, and publish only peer-reviewed teaching articles and reviews—no longer case reports or original research. We try to address the practical challenges faced by our readers as they strive to deliver quality medical care. We continue to expand our CME offerings, linking with our CME center and working with Dr. Tim Gilligan (our deputy editor) to enhance the educational quality of the Journal-related CME activities.

And always, we emphasize the need for articles to be accurate, timely, relevant to our readership, and perhaps most important, readable. To accomplish the last, our editorial staff includes several talented medical editors and writers—notably Ray Borazanian, Phil Canuto, and Dave Huddleston—who work with our authors on every article we publish. Art directors Joe Pangrace and Ross Papalardo, our medical illustration department, and our production manager Bruce Marich continue to provide the high-quality images that enhance the written word. Our authors and our peer-reviewers include both experienced Clinic staff and nationally recognized clinical content experts.

The Journal in 2011 faces challenges. Advertising income, which has supported a significant portion of our expenses, has decreased, as it has for almost all medical journals. The complicated relationships between industry, academia, physicians, and medical education companies at times strain our ability to provide full disclosure and adequate peer review. The time constraints of authors and the widespread availability of cut-and-paste-ready electronic publications have led us to utilize duplication-recognition software in an effort to limit plagiarism and duplicate publication. The costs and complexity of production and publication of online and print versions of the Journal continue to rise. At the same time, the advances in technology offer the possibility of increased interactivity between reader and content, and we welcome this opportunity. But despite all the challenges, the spirit of the Clinic’s mission to further the education of those who serve is maintained, the same as it ever was.

In this 80th anniversary issue, we kick off a series of articles on the overall care of patients with cancer. Coincidentally, the 1931 seminal issue of the Cleveland Clinic Bulletin started with an article on page 1 by Dr. George Crile entitled, “Treatment of malignancy.” Fortunately, the care of patients with cancer in 2011 is not the same as it was in 1931.

As we start our 80th anniversary year, I offer our sincere wishes to all of you, our readers, for a year of peace and good health.

“Once in a Lifetime” is a song by Talking Heads, from their album Remain in Light. Written by David Byrne, Brian Eno, Chris Frantz, Jerry Harrison, and Tina Weymouth, it was named one of the 100 most important American musical works of the 20th century by National Public Radio. It made #14 in the UK charts and #31 in the Netherlands (Wikipedia).

In the 1980s, the eclectic rock band Talking Heads sang, “You may ask yourself, How did I get here?”—a reflective question appropriate now on the occasion of the 80th anniversary of the Cleveland Clinic Journal of Medicine. That question can be answered by reviewing a bit of history, and corollary questions addressing the current identity and status of the Journal can be (sort of) answered with a refrain from the same song: “Same as it ever was.”

The Journal is currently received by more than 100,000 general internists, cardiologists, hospitalists, and medical subspecialists. It is fully peer-reviewed, listed in MEDLINE, and freely available in complete format at www.ccjm.org. Cleveland Clinic supports the production and distribution of the Journal and provides free CME credits linked to selected articles in an effort to enhance the delivery of high-quality medical care to patients everywhere. The Journal is housed within Cleveland Clinic’s Education Institute, distinct from any direct influence of our marketing or public relations departments—a distinction that I, as editor-in-chief, take extremely seriously. Our primary editorial goal is, and has been, to provide relevant and useful clinical knowledge to the medical community.

The Journal began as the Cleveland Clinic Bulletin in 1931, morphing into the Cleveland Clinic Quarterly the following year and into the Cleveland Clinic Journal of Medicine in 1987. The Quarterly published reprints of papers published elsewhere, as well as case reports and scholarly work presented by Clinic physicians at their staff meetings. Perhaps the latter content was intended to compete with that published in the Proceedings of the Staff Meetings of the Mayo Clinic (first appearing in 1926). Dr. George Crile, one of the founders of Cleveland Clinic, was intent on putting the medical and scientific work of the Clinic in the limelight of American medicine. He felt back in 1931 the same as we feel now, 80 years later, that the Journal contributes to the three pillar missions of the Clinic: better care of the sick, investigation of their problems, and further education of those who serve.

In 1934, the Quarterly ceased publishing reprints from other journals, and Clinic staff were encouraged to publish their case reports, topic reviews, and clinical series in the Quarterly. Over the years, some articles reflected practice at the Clinic and included a description of 1,000 consecutive patients with irritable colon (1941), a description of 10,744 patients who underwent coronary revascularization (1976), and a report of cardiac complications in 951 patients who underwent peripheral vascular surgery (1982). Also notable was the description of the “LE prep test” for the diagnosis of systemic lupus erythematosus (1949).

I am the eighth physician editor-in-chief of the Journal. Three of us have been rheumatologists (perhaps we read more, and cost less). We each have had the opportunity, along with input from the Journal editorial staff, to change the appearance, the content, and sometimes the editorial direction of the Journal. Following the lead of my preceding editor Dr. John Clough and former publisher Linda K. Hengstler, we publish monthly, continue to expand our online content, and publish only peer-reviewed teaching articles and reviews—no longer case reports or original research. We try to address the practical challenges faced by our readers as they strive to deliver quality medical care. We continue to expand our CME offerings, linking with our CME center and working with Dr. Tim Gilligan (our deputy editor) to enhance the educational quality of the Journal-related CME activities.

And always, we emphasize the need for articles to be accurate, timely, relevant to our readership, and perhaps most important, readable. To accomplish the last, our editorial staff includes several talented medical editors and writers—notably Ray Borazanian, Phil Canuto, and Dave Huddleston—who work with our authors on every article we publish. Art directors Joe Pangrace and Ross Papalardo, our medical illustration department, and our production manager Bruce Marich continue to provide the high-quality images that enhance the written word. Our authors and our peer-reviewers include both experienced Clinic staff and nationally recognized clinical content experts.

The Journal in 2011 faces challenges. Advertising income, which has supported a significant portion of our expenses, has decreased, as it has for almost all medical journals. The complicated relationships between industry, academia, physicians, and medical education companies at times strain our ability to provide full disclosure and adequate peer review. The time constraints of authors and the widespread availability of cut-and-paste-ready electronic publications have led us to utilize duplication-recognition software in an effort to limit plagiarism and duplicate publication. The costs and complexity of production and publication of online and print versions of the Journal continue to rise. At the same time, the advances in technology offer the possibility of increased interactivity between reader and content, and we welcome this opportunity. But despite all the challenges, the spirit of the Clinic’s mission to further the education of those who serve is maintained, the same as it ever was.

In this 80th anniversary issue, we kick off a series of articles on the overall care of patients with cancer. Coincidentally, the 1931 seminal issue of the Cleveland Clinic Bulletin started with an article on page 1 by Dr. George Crile entitled, “Treatment of malignancy.” Fortunately, the care of patients with cancer in 2011 is not the same as it was in 1931.

As we start our 80th anniversary year, I offer our sincere wishes to all of you, our readers, for a year of peace and good health.

“Once in a Lifetime” is a song by Talking Heads, from their album Remain in Light. Written by David Byrne, Brian Eno, Chris Frantz, Jerry Harrison, and Tina Weymouth, it was named one of the 100 most important American musical works of the 20th century by National Public Radio. It made #14 in the UK charts and #31 in the Netherlands (Wikipedia).

In the 1980s, the eclectic rock band Talking Heads sang, “You may ask yourself, How did I get here?”—a reflective question appropriate now on the occasion of the 80th anniversary of the Cleveland Clinic Journal of Medicine. That question can be answered by reviewing a bit of history, and corollary questions addressing the current identity and status of the Journal can be (sort of) answered with a refrain from the same song: “Same as it ever was.”

The Journal is currently received by more than 100,000 general internists, cardiologists, hospitalists, and medical subspecialists. It is fully peer-reviewed, listed in MEDLINE, and freely available in complete format at www.ccjm.org. Cleveland Clinic supports the production and distribution of the Journal and provides free CME credits linked to selected articles in an effort to enhance the delivery of high-quality medical care to patients everywhere. The Journal is housed within Cleveland Clinic’s Education Institute, distinct from any direct influence of our marketing or public relations departments—a distinction that I, as editor-in-chief, take extremely seriously. Our primary editorial goal is, and has been, to provide relevant and useful clinical knowledge to the medical community.

The Journal began as the Cleveland Clinic Bulletin in 1931, morphing into the Cleveland Clinic Quarterly the following year and into the Cleveland Clinic Journal of Medicine in 1987. The Quarterly published reprints of papers published elsewhere, as well as case reports and scholarly work presented by Clinic physicians at their staff meetings. Perhaps the latter content was intended to compete with that published in the Proceedings of the Staff Meetings of the Mayo Clinic (first appearing in 1926). Dr. George Crile, one of the founders of Cleveland Clinic, was intent on putting the medical and scientific work of the Clinic in the limelight of American medicine. He felt back in 1931 the same as we feel now, 80 years later, that the Journal contributes to the three pillar missions of the Clinic: better care of the sick, investigation of their problems, and further education of those who serve.

In 1934, the Quarterly ceased publishing reprints from other journals, and Clinic staff were encouraged to publish their case reports, topic reviews, and clinical series in the Quarterly. Over the years, some articles reflected practice at the Clinic and included a description of 1,000 consecutive patients with irritable colon (1941), a description of 10,744 patients who underwent coronary revascularization (1976), and a report of cardiac complications in 951 patients who underwent peripheral vascular surgery (1982). Also notable was the description of the “LE prep test” for the diagnosis of systemic lupus erythematosus (1949).

I am the eighth physician editor-in-chief of the Journal. Three of us have been rheumatologists (perhaps we read more, and cost less). We each have had the opportunity, along with input from the Journal editorial staff, to change the appearance, the content, and sometimes the editorial direction of the Journal. Following the lead of my preceding editor Dr. John Clough and former publisher Linda K. Hengstler, we publish monthly, continue to expand our online content, and publish only peer-reviewed teaching articles and reviews—no longer case reports or original research. We try to address the practical challenges faced by our readers as they strive to deliver quality medical care. We continue to expand our CME offerings, linking with our CME center and working with Dr. Tim Gilligan (our deputy editor) to enhance the educational quality of the Journal-related CME activities.

And always, we emphasize the need for articles to be accurate, timely, relevant to our readership, and perhaps most important, readable. To accomplish the last, our editorial staff includes several talented medical editors and writers—notably Ray Borazanian, Phil Canuto, and Dave Huddleston—who work with our authors on every article we publish. Art directors Joe Pangrace and Ross Papalardo, our medical illustration department, and our production manager Bruce Marich continue to provide the high-quality images that enhance the written word. Our authors and our peer-reviewers include both experienced Clinic staff and nationally recognized clinical content experts.

The Journal in 2011 faces challenges. Advertising income, which has supported a significant portion of our expenses, has decreased, as it has for almost all medical journals. The complicated relationships between industry, academia, physicians, and medical education companies at times strain our ability to provide full disclosure and adequate peer review. The time constraints of authors and the widespread availability of cut-and-paste-ready electronic publications have led us to utilize duplication-recognition software in an effort to limit plagiarism and duplicate publication. The costs and complexity of production and publication of online and print versions of the Journal continue to rise. At the same time, the advances in technology offer the possibility of increased interactivity between reader and content, and we welcome this opportunity. But despite all the challenges, the spirit of the Clinic’s mission to further the education of those who serve is maintained, the same as it ever was.

In this 80th anniversary issue, we kick off a series of articles on the overall care of patients with cancer. Coincidentally, the 1931 seminal issue of the Cleveland Clinic Bulletin started with an article on page 1 by Dr. George Crile entitled, “Treatment of malignancy.” Fortunately, the care of patients with cancer in 2011 is not the same as it was in 1931.

As we start our 80th anniversary year, I offer our sincere wishes to all of you, our readers, for a year of peace and good health.

“Once in a Lifetime” is a song by Talking Heads, from their album Remain in Light. Written by David Byrne, Brian Eno, Chris Frantz, Jerry Harrison, and Tina Weymouth, it was named one of the 100 most important American musical works of the 20th century by National Public Radio. It made #14 in the UK charts and #31 in the Netherlands (Wikipedia).