Commentary

This editorial could have quite a negative impact on my fellow endocrinologists. That’s because it could result in a significant reduction in the number of referrals to endocrinologists for patients with low thyroid-stimulating hormone (TSH) levels, at least that’s a best-case scenario. Despite the potentially negative impact on endocrine referrals, I feel compelled to suggest that you may be overreacting to low TSH levels in many of your patients.

You know what I mean—you see moderately suppressed TSH levels all of the time in day-to-day clinical practice. And of course, as a faithful provider, you harken back to your training days and remember the basics of the thyroid-pituitary axis. Theoretically at least, the pituitary gland secretes TSH in proportion to the need for the thyroid gland to put out more thyroid hormone. If the thyroid gland starts to fail for any reason (Hashimoto’s thyroiditis, an autoimmune disease, is by far the most common cause), the pituitary will detect that there is an insufficient amount of thyroid hormone floating around and will secrete more TSH to try to stimulate the thyroid to pump out more hormone.

Conversely, if the thyroid gland becomes overactive for any reason (Graves’ disease, another autoimmune phenomenon, is the most common cause here), then the secretion of TSH will be suppressed by the excess thyroid hormone. It is seemingly straightforward: An elevated TSH means hypothyroidism, and a suppressed TSH means an overactive thyroid gland.

Alas, dear reader, if only it were so simple! It turns out that a very large fraction of the low TSH levels seen in clinical practice are not related at all to an overactive thyroid gland, and no therapeutic intervention of any sort is indicated. In light of the intricate feedback loop, which controls the delicate balance between the secretion of thyroid hormone on the one hand and that of TSH on the other, how can that possibly be true?

The answer is that the feedback loop is nowhere near as simple and straightforward as you were taught as an eager student of human physiology. The thyrotroph cells in the pituitary, the ones that secrete TSH, do indeed respond rather exquisitely to the ambient levels of circulating thyroid hormones. But they are also very susceptible to a number of other circulating compounds that are quite capable of suppressing their output of TSH every bit as effectively as thyroid hormones.

The classic setting in which TSH levels are suppressed in the absence of true thyrotoxicosis is euthyroid sick syndrome (ESS). I always tell my trainees that the surest way to find patients with ESS is simply to ask for directions to the intensive care unit (ICU). Assuming that the patients in the ICU truly need to be there, every single one of them will display thyroid hormone changes consistent with ESS. It’s still not clear whether or not ESS is an adaptive or protective mechanism, but it occurs in virtually all patients who are sufficiently sick.

The first manifestation of ESS is low T3 syndrome, wherein the conversion of T4 to the more metabolically potent T3 is markedly reduced. Since T3 is by far the more physiologically active of these 2 thyroid hormones, the net effect of the block in conversion to T3 is a down-regulation of the thyroid axis. The dialing back of thyroid effect may well be a protective physiologic mechanism so the body can focus on defending against whatever severe physiologic insult set the whole process in motion in the first place. It may represent a turning down of the metabolic thermometer or burn rate.

If the underlying illness persists or worsens, usually the next manifestations of ESS are a suppression of TSH, and then a concomitant suppression of the production of T4 from the thyroid gland. So most truly ill individuals experience an uncoupling of the usual relationship between TSH levels and thyroid hormone levels. The suppression of the TSH levels in ESS is generally attributed to the circulating presence of abnormally high levels of cytokines associated with severe illness, including interleukins and a number of other potent mediators of inflammation.

It also turns out that less ill patients can also experience a suppression of TSH levels due to a number of circulating compounds, prominent among them are corticosteroids, catecholamines, and opioids. Thus, many patients who have chronically elevated levels of corticosteroids, catecholamines, or opioids will also have relatively suppressed levels of TSH without a hint that they are suffering from thyrotoxicosis.

Any endocrinologist who has been reading this is probably bored, but hopefully the rest of you have gained just a small bit of insight into the multiplicity of factors that can lead to low levels of TSH. In a perfectly healthy person with no reason to have elevated levels of corticosteroids or catecholamines, a low TSH level does indeed raise the concern for thyrotoxicosis, especially if the TSH is not measurable, as it usually is with true thyrotoxicosis. But in patients who are ill, all bets are off. A low TSH level is very probably not an indicator of excess circulating thyroid hormone.

It is hoped my fellow endocrinologists will now receive fewer consults for low TSH levels, and they can concentrate on something more important, such as trying to tame those pesky glucose levels in our ever-increasing glut of diabetic patients.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

This editorial could have quite a negative impact on my fellow endocrinologists. That’s because it could result in a significant reduction in the number of referrals to endocrinologists for patients with low thyroid-stimulating hormone (TSH) levels, at least that’s a best-case scenario. Despite the potentially negative impact on endocrine referrals, I feel compelled to suggest that you may be overreacting to low TSH levels in many of your patients.

You know what I mean—you see moderately suppressed TSH levels all of the time in day-to-day clinical practice. And of course, as a faithful provider, you harken back to your training days and remember the basics of the thyroid-pituitary axis. Theoretically at least, the pituitary gland secretes TSH in proportion to the need for the thyroid gland to put out more thyroid hormone. If the thyroid gland starts to fail for any reason (Hashimoto’s thyroiditis, an autoimmune disease, is by far the most common cause), the pituitary will detect that there is an insufficient amount of thyroid hormone floating around and will secrete more TSH to try to stimulate the thyroid to pump out more hormone.

Conversely, if the thyroid gland becomes overactive for any reason (Graves’ disease, another autoimmune phenomenon, is the most common cause here), then the secretion of TSH will be suppressed by the excess thyroid hormone. It is seemingly straightforward: An elevated TSH means hypothyroidism, and a suppressed TSH means an overactive thyroid gland.

Alas, dear reader, if only it were so simple! It turns out that a very large fraction of the low TSH levels seen in clinical practice are not related at all to an overactive thyroid gland, and no therapeutic intervention of any sort is indicated. In light of the intricate feedback loop, which controls the delicate balance between the secretion of thyroid hormone on the one hand and that of TSH on the other, how can that possibly be true?

The answer is that the feedback loop is nowhere near as simple and straightforward as you were taught as an eager student of human physiology. The thyrotroph cells in the pituitary, the ones that secrete TSH, do indeed respond rather exquisitely to the ambient levels of circulating thyroid hormones. But they are also very susceptible to a number of other circulating compounds that are quite capable of suppressing their output of TSH every bit as effectively as thyroid hormones.

The classic setting in which TSH levels are suppressed in the absence of true thyrotoxicosis is euthyroid sick syndrome (ESS). I always tell my trainees that the surest way to find patients with ESS is simply to ask for directions to the intensive care unit (ICU). Assuming that the patients in the ICU truly need to be there, every single one of them will display thyroid hormone changes consistent with ESS. It’s still not clear whether or not ESS is an adaptive or protective mechanism, but it occurs in virtually all patients who are sufficiently sick.

The first manifestation of ESS is low T3 syndrome, wherein the conversion of T4 to the more metabolically potent T3 is markedly reduced. Since T3 is by far the more physiologically active of these 2 thyroid hormones, the net effect of the block in conversion to T3 is a down-regulation of the thyroid axis. The dialing back of thyroid effect may well be a protective physiologic mechanism so the body can focus on defending against whatever severe physiologic insult set the whole process in motion in the first place. It may represent a turning down of the metabolic thermometer or burn rate.

If the underlying illness persists or worsens, usually the next manifestations of ESS are a suppression of TSH, and then a concomitant suppression of the production of T4 from the thyroid gland. So most truly ill individuals experience an uncoupling of the usual relationship between TSH levels and thyroid hormone levels. The suppression of the TSH levels in ESS is generally attributed to the circulating presence of abnormally high levels of cytokines associated with severe illness, including interleukins and a number of other potent mediators of inflammation.

It also turns out that less ill patients can also experience a suppression of TSH levels due to a number of circulating compounds, prominent among them are corticosteroids, catecholamines, and opioids. Thus, many patients who have chronically elevated levels of corticosteroids, catecholamines, or opioids will also have relatively suppressed levels of TSH without a hint that they are suffering from thyrotoxicosis.

Any endocrinologist who has been reading this is probably bored, but hopefully the rest of you have gained just a small bit of insight into the multiplicity of factors that can lead to low levels of TSH. In a perfectly healthy person with no reason to have elevated levels of corticosteroids or catecholamines, a low TSH level does indeed raise the concern for thyrotoxicosis, especially if the TSH is not measurable, as it usually is with true thyrotoxicosis. But in patients who are ill, all bets are off. A low TSH level is very probably not an indicator of excess circulating thyroid hormone.

It is hoped my fellow endocrinologists will now receive fewer consults for low TSH levels, and they can concentrate on something more important, such as trying to tame those pesky glucose levels in our ever-increasing glut of diabetic patients.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

This editorial could have quite a negative impact on my fellow endocrinologists. That’s because it could result in a significant reduction in the number of referrals to endocrinologists for patients with low thyroid-stimulating hormone (TSH) levels, at least that’s a best-case scenario. Despite the potentially negative impact on endocrine referrals, I feel compelled to suggest that you may be overreacting to low TSH levels in many of your patients.

You know what I mean—you see moderately suppressed TSH levels all of the time in day-to-day clinical practice. And of course, as a faithful provider, you harken back to your training days and remember the basics of the thyroid-pituitary axis. Theoretically at least, the pituitary gland secretes TSH in proportion to the need for the thyroid gland to put out more thyroid hormone. If the thyroid gland starts to fail for any reason (Hashimoto’s thyroiditis, an autoimmune disease, is by far the most common cause), the pituitary will detect that there is an insufficient amount of thyroid hormone floating around and will secrete more TSH to try to stimulate the thyroid to pump out more hormone.

Conversely, if the thyroid gland becomes overactive for any reason (Graves’ disease, another autoimmune phenomenon, is the most common cause here), then the secretion of TSH will be suppressed by the excess thyroid hormone. It is seemingly straightforward: An elevated TSH means hypothyroidism, and a suppressed TSH means an overactive thyroid gland.

Alas, dear reader, if only it were so simple! It turns out that a very large fraction of the low TSH levels seen in clinical practice are not related at all to an overactive thyroid gland, and no therapeutic intervention of any sort is indicated. In light of the intricate feedback loop, which controls the delicate balance between the secretion of thyroid hormone on the one hand and that of TSH on the other, how can that possibly be true?

The answer is that the feedback loop is nowhere near as simple and straightforward as you were taught as an eager student of human physiology. The thyrotroph cells in the pituitary, the ones that secrete TSH, do indeed respond rather exquisitely to the ambient levels of circulating thyroid hormones. But they are also very susceptible to a number of other circulating compounds that are quite capable of suppressing their output of TSH every bit as effectively as thyroid hormones.

The classic setting in which TSH levels are suppressed in the absence of true thyrotoxicosis is euthyroid sick syndrome (ESS). I always tell my trainees that the surest way to find patients with ESS is simply to ask for directions to the intensive care unit (ICU). Assuming that the patients in the ICU truly need to be there, every single one of them will display thyroid hormone changes consistent with ESS. It’s still not clear whether or not ESS is an adaptive or protective mechanism, but it occurs in virtually all patients who are sufficiently sick.

The first manifestation of ESS is low T3 syndrome, wherein the conversion of T4 to the more metabolically potent T3 is markedly reduced. Since T3 is by far the more physiologically active of these 2 thyroid hormones, the net effect of the block in conversion to T3 is a down-regulation of the thyroid axis. The dialing back of thyroid effect may well be a protective physiologic mechanism so the body can focus on defending against whatever severe physiologic insult set the whole process in motion in the first place. It may represent a turning down of the metabolic thermometer or burn rate.

If the underlying illness persists or worsens, usually the next manifestations of ESS are a suppression of TSH, and then a concomitant suppression of the production of T4 from the thyroid gland. So most truly ill individuals experience an uncoupling of the usual relationship between TSH levels and thyroid hormone levels. The suppression of the TSH levels in ESS is generally attributed to the circulating presence of abnormally high levels of cytokines associated with severe illness, including interleukins and a number of other potent mediators of inflammation.

It also turns out that less ill patients can also experience a suppression of TSH levels due to a number of circulating compounds, prominent among them are corticosteroids, catecholamines, and opioids. Thus, many patients who have chronically elevated levels of corticosteroids, catecholamines, or opioids will also have relatively suppressed levels of TSH without a hint that they are suffering from thyrotoxicosis.

Any endocrinologist who has been reading this is probably bored, but hopefully the rest of you have gained just a small bit of insight into the multiplicity of factors that can lead to low levels of TSH. In a perfectly healthy person with no reason to have elevated levels of corticosteroids or catecholamines, a low TSH level does indeed raise the concern for thyrotoxicosis, especially if the TSH is not measurable, as it usually is with true thyrotoxicosis. But in patients who are ill, all bets are off. A low TSH level is very probably not an indicator of excess circulating thyroid hormone.

It is hoped my fellow endocrinologists will now receive fewer consults for low TSH levels, and they can concentrate on something more important, such as trying to tame those pesky glucose levels in our ever-increasing glut of diabetic patients.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

I don’t want a TV in my waiting room. Absolutely, positively, not.

I get plenty of letters, calls, and faxes offering me a “free” one. Recently, it’s even expanded to include tablets connected to the programming, so patients can continue watching the same stuff after being taken back.

Still, I’m not interested.

Why? Maybe other doctors would jump at the opportunity, but not me. Visits to the doctor can be very stressful for some people, and I try to keep things as tranquil as possible. Silence, the sound of my secretary on the phone muted by the glass window, the quiet hum of the air conditioner ... I think that’s enough.

I see migraine patients, and the last thing they want during a headache is extraneous noise. Likewise, I see a lot of the older crowd with hearing problems. Trying to keep sound down, so they can understand my secretary, helps a lot.

I try hard to run on time, so the wait usually isn’t more than a few minutes. It’s easy to fill that with one of the literary offerings I keep around, and many people bring their own books and iPads anyway these days. I don’t see a need to provide video entertainment.

The choice of programming also concerns me. While they tell me it’s customizable, that still doesn’t mean I’ll agree with everything they show. And since I’m not about to watch it all myself to check, I don’t even want to start.

I worry about the “free” part. It isn’t free. Nothing is. The TV, and tablets, and their programming, are all paid for by advertising. This is primarily from drug companies. While many of them have useful products, those decisions are between me and my patients, not them and a commercial that ends with “ask your doctor.” They’re here for my advice, not to be told what brand-name medications they should be on (which often aren’t covered by their insurance) when a generic I might suggest is better. Advertising often portrays products in an unrealistic light, with the TV leaving me the dirty job of putting a damper on expectations.

And the last thing I want is them seeing a charlatan selling snake oil, using their MD title to give it legitimacy (but I’m not going to name names).

The world is full of medical information sources, and my patients can find them easily without me forcing one upon them. My lobby may be their only quiet moment in a tumultuous day, and I’ll try to preserve that. It’s the least I can do.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I don’t want a TV in my waiting room. Absolutely, positively, not.

I get plenty of letters, calls, and faxes offering me a “free” one. Recently, it’s even expanded to include tablets connected to the programming, so patients can continue watching the same stuff after being taken back.

Still, I’m not interested.

Why? Maybe other doctors would jump at the opportunity, but not me. Visits to the doctor can be very stressful for some people, and I try to keep things as tranquil as possible. Silence, the sound of my secretary on the phone muted by the glass window, the quiet hum of the air conditioner ... I think that’s enough.

I see migraine patients, and the last thing they want during a headache is extraneous noise. Likewise, I see a lot of the older crowd with hearing problems. Trying to keep sound down, so they can understand my secretary, helps a lot.

I try hard to run on time, so the wait usually isn’t more than a few minutes. It’s easy to fill that with one of the literary offerings I keep around, and many people bring their own books and iPads anyway these days. I don’t see a need to provide video entertainment.

The choice of programming also concerns me. While they tell me it’s customizable, that still doesn’t mean I’ll agree with everything they show. And since I’m not about to watch it all myself to check, I don’t even want to start.

I worry about the “free” part. It isn’t free. Nothing is. The TV, and tablets, and their programming, are all paid for by advertising. This is primarily from drug companies. While many of them have useful products, those decisions are between me and my patients, not them and a commercial that ends with “ask your doctor.” They’re here for my advice, not to be told what brand-name medications they should be on (which often aren’t covered by their insurance) when a generic I might suggest is better. Advertising often portrays products in an unrealistic light, with the TV leaving me the dirty job of putting a damper on expectations.

And the last thing I want is them seeing a charlatan selling snake oil, using their MD title to give it legitimacy (but I’m not going to name names).

The world is full of medical information sources, and my patients can find them easily without me forcing one upon them. My lobby may be their only quiet moment in a tumultuous day, and I’ll try to preserve that. It’s the least I can do.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I don’t want a TV in my waiting room. Absolutely, positively, not.

I get plenty of letters, calls, and faxes offering me a “free” one. Recently, it’s even expanded to include tablets connected to the programming, so patients can continue watching the same stuff after being taken back.

Still, I’m not interested.

Why? Maybe other doctors would jump at the opportunity, but not me. Visits to the doctor can be very stressful for some people, and I try to keep things as tranquil as possible. Silence, the sound of my secretary on the phone muted by the glass window, the quiet hum of the air conditioner ... I think that’s enough.

I see migraine patients, and the last thing they want during a headache is extraneous noise. Likewise, I see a lot of the older crowd with hearing problems. Trying to keep sound down, so they can understand my secretary, helps a lot.

I try hard to run on time, so the wait usually isn’t more than a few minutes. It’s easy to fill that with one of the literary offerings I keep around, and many people bring their own books and iPads anyway these days. I don’t see a need to provide video entertainment.

The choice of programming also concerns me. While they tell me it’s customizable, that still doesn’t mean I’ll agree with everything they show. And since I’m not about to watch it all myself to check, I don’t even want to start.

I worry about the “free” part. It isn’t free. Nothing is. The TV, and tablets, and their programming, are all paid for by advertising. This is primarily from drug companies. While many of them have useful products, those decisions are between me and my patients, not them and a commercial that ends with “ask your doctor.” They’re here for my advice, not to be told what brand-name medications they should be on (which often aren’t covered by their insurance) when a generic I might suggest is better. Advertising often portrays products in an unrealistic light, with the TV leaving me the dirty job of putting a damper on expectations.

And the last thing I want is them seeing a charlatan selling snake oil, using their MD title to give it legitimacy (but I’m not going to name names).

The world is full of medical information sources, and my patients can find them easily without me forcing one upon them. My lobby may be their only quiet moment in a tumultuous day, and I’ll try to preserve that. It’s the least I can do.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Insistence on prior authorization (PA) when prescribing certain pharmaceuticals has grown considerably over the past 5 years. Most requests for PA are issued by phar­macy benefit management (PBM) companies that have been contracted by an insurer. A PA can be triggered when a physician orders:
   • a brand-name medication
   • a medication not on the formulary of the PBM
   • a quantity above an arbitrary ceiling
   • a medication that has multiple indications (that is, the PBM won’t pay for indication X but will pay for indi­cation Y).

What are the problems caused by PAs? I outline a num­ber of them, and their potential consequences, in this “Commentary.” What can we do, in our practices, to lessen the disruption they cause and the time and money they cost us (Box)?

’Prior authorization’—a misleading, disingenuous term
The physician’s prescription is legal authorization for the patient to receive the medicine. It would be more accu­rate if PBMs labeled what they do “prior approval for reimbursement.”

PBMs exist to manipulate and coordinate the demand for medication generated, on one hand, by patients and their physician and, on the other, by the cost of supplying portion of that demand. The cost of a medication to the PBM is controlled by:  
   • negotiating rebates with drug manufacturers
   • advantageous contracting with pharmacies
   • denying payment, when feasible, using the PA system.

The goal of the PA is to boost the prof­its of the PBM—not to pay for the best fit between the needs of the patient and the medications available, as determined by the treating physician.

The games begin!
The PA process usually begins when the patient goes to the pharmacy, prescription in hand, and gives it to the pharmacist, who enters it into the computer. At that point, if the PBM has put a block on pay­ing for the medication, 3 things happen in sequence:
   1. The computer alerts the pharmacist about the block (or that a higher copay is required).
   2. The pharmacist tells the patient some­thing about the block—although not nec­essarily the whole story.
   3. The pharmacist tells the physician’s office (by fax, e-mail, or telephone) that the PBM wants authorization and that the physician must call a toll-free telephone number to obtain that authorization.

The physician’s office then makes the initial call to the PBM. That call can take 10 to 20 minutes, answering preliminary questions. The call generates a question­naire from the PBM that is faxed to the office, filled with questions that one could characterize as loaded. The questionnaire is intended to provide grounds for disap­proval or approval—not to obtain in-depth understanding of the individual patient’s needs.

Playing pieces on a chessboard
Note that the physician and pharmacist, thrust unwillingly into the middle of this gambit, spend considerable uncompen­sated time on the PA process. (Primary care physicians and their nursing and clerical staff, spent, on average, 19.8 hours a week obtaining PAs in 2006.¹)

PBMs have shifted responsibility for communication to physicians and phar­macists by requiring that the physician always contact the PBM. A PBM will not contact a physician directly, either to begin the PA or ask questions during the process.

If the request for authorization is denied, what’s the outcome? The physician’s office and the pharmacist have spent uncompen­sated time taking action that resulted in the PBM and the insurer improving their bottom line without benefit to anyone else.

Communication breakdown. The cum­bersome, multistep PA process opens the door to miscommunication. This happens often, I’ve found: The physician wastes time because the pharmacist passed along an incomplete message, or a patient gives vague or confusing information in try­ing to transmit what the pharmacist said. Sometimes, when physicians get through to a live person at the PBM, they are told that the pharmacist misinformed the office: No, the medication didn’t require PA after all.

Why can’t PBMs streamline the process, sparing busy physicians’ offices the time spent on initial telephone calls, by install­ing software that would allow the pharma­cist who first encounters a payment block to, with a few keystrokes, instantly send the relevant questionnaire to the physi­cian’s fax machine or computer?

Obstacles to satisfaction
From the perspective of the patient, the word that probably best characterizes his emotional response to the PA process is “helpless.” He wasn’t expecting a denial; it’s likely that he hadn’t been fully or clearly informed at the time he selected the insurer that he might someday face such an obstacle. Even though he had a legal prescription, written by a physician, any attempt to go back to the insurer or the PBM to complain is rarely successful. If he tried, he would likely get no satisfaction: The clerk at the other end of the telephone would swiftly inform him that there were a number of complicated rules, policies, or “step programs” that must be adhered to before the PBM pays for a prescription.

Even if the medication is covered, the patient might be told that there are “quan­tity limits” that prevent reimbursement for the prescription as written—limits that were not made explicit when he signed up for the insurance plan. All these obstacles can generate confusion, anxiety, frustra­tion, and anger—understandably so.

The ‘safety’ catch. Obstacles do not necessarily end when the medication is approved; such approval is merely a “coverage eligibility review.” In addition, PBMs make it clear that every prescription also undergoes a so-called safety review by a pharmacist before it is dispensed. If the PBM’s pharmacist identifies a safety concern, the medication “might not be dispensed,” Express Scripts says, “or your patient could receive less than what you prescribed.”

That is an ominous statement: The PBM is openly and arrogantly taking for itself the right to unilaterally determine what is safe and to override the physician’s judgment as it sees fit. We all know that there are rel­ative risks in taking most medications that we prescribe; the degree of that risk needs to be carefully calculated against the likely benefits for a given patient, whose detailed history is known to the treating physi­cian. History and risk-benefit calculation are not available to the reviewing pharma­cist. The existence of “safety concerns” by itself, outside of the full context of care, is insufficient justification for a PBM to stop payment for a medication.

“Approved”—but… Equally ominous is that, after a medication has been approved through the PA process, some PBMs add these words in their notification to the physician:

    This medication is approved for coverage until [insert date],
    or until coverage for the medication is no longer available
    under the benefit plan or the medication becomes subject
    to a pharmacy benefit cov­erage requirement, such as supply
    limits or notification, whichever occurs first.

In other words, the approval is provi­sional, and shouldn’t be counted on to remain in place for the entire period for which dispensing has been approved. Imagine the uncertainty and anxiety of a patient who reads that statement and real­izes that the medication that, at last, has relieved her symptoms might be with­drawn from coverage at any time for rea­sons unrelated to effectiveness.

The patient can appeal the decision of a PBM or insurer that refuses to pay for a medication, but that patient, and his phy­sician, might ask themselves whether the considerable time required to appeal is jus­tified, given that the criteria used for deni­als are arbitrary and one-sided.

Serious consequences can ensue after a PBM denies coverage for a medication. Some patients cannot afford hundreds of dollars out of pocket for 1 month of 1 medicine. When their supply runs out, they become vulnerable to symptoms of withdrawal or exacerbation of underlying illness.

Armchair care. A PBM, after it has denied approval of payment, might “ask” the phy­sician to choose another medication that the PBM does cover. For a non-physician administrator who has never seen the patient to propose such a switch is micro­management—to say the least. Such an action is also disrespectful of the physi­cian’s judgment.

Loss of possible placebo effect. If the phy­sician goes along and makes the switch pro­posed by the PBM, the patient will know that the new medication is the physician’s second (or third) choice. Any potential posi­tive placebo effect is thus lost. Does that matter? It might—a lot.

Most physicians would be glad to have a positive placebo effect assist or augment the physiologic effects of a medication, especially at the start of treatment when the patient might feel helpless or hopeless. Such negative feelings are likely to be mag­nified if the patient knows that he has been coerced into taking a second-line therapy. A positive placebo effect, on the other hand, might well have lowered levels of his stress hormones for a few weeks—and that effect could have made a positive difference.

Casualties for the physician are time, money, and morale. PAs consume large chunks of time. Some of the PA forms require that 20 or more questions be answered; a few of those questions can take significant time to answer, having to look through a thick chart to research prior medications.

PAs also cost money: directly to pay the salary of staff that share the PA work, indirectly by crowding out the doctor’s potential billing time and replacing it with uncompensated PA work.

Worse, in my opinion, is the cost to morale. Physicians express their annoy­ance, aggravation, frustration, and anger at meetings and in postings at the end of journal articles on the subject. Some speak of becoming numb from the daily hassle of dealing with PAs.² The disrespect for the physician’s decisions inherent in the PA process, the implicit humiliation of appeal­ing to someone who doesn’t know the patient to approve payment for a medica­tion that’s been legally prescribed, and the cost in time and money all provoke emo­tions that are damaging to morale.

Much to do in limited time
Time isn’t elastic; setting priorities is vital. Most physicians would, I think, agree that their priorities are:
   • giving patients adequate time at office visits
   • returning calls from patients with urgent messages
   • communicating with professional col­leagues about shared patients
   • returning calls from pharmacists who have questions about prescriptions
   • researching solutions to clinical problems
   • keeping up with the literature.

Physicians must decide where complet­ing PAs—intrusive, time-consuming, and a threat to morale—fits in that list. Should PAs be allowed to supplant, or delay, the completion of other vital, positive clinical priorities?

Until we are able to introduce improve­ments that speed up the PA process, patients will have the supply of their med­ications disrupted and physicians will pay in time, money, and morale.

Disclosure
Dr. Mode reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Insistence on prior authorization (PA) when prescribing certain pharmaceuticals has grown considerably over the past 5 years. Most requests for PA are issued by phar­macy benefit management (PBM) companies that have been contracted by an insurer. A PA can be triggered when a physician orders:
   • a brand-name medication
   • a medication not on the formulary of the PBM
   • a quantity above an arbitrary ceiling
   • a medication that has multiple indications (that is, the PBM won’t pay for indication X but will pay for indi­cation Y).

What are the problems caused by PAs? I outline a num­ber of them, and their potential consequences, in this “Commentary.” What can we do, in our practices, to lessen the disruption they cause and the time and money they cost us (Box)?

’Prior authorization’—a misleading, disingenuous term
The physician’s prescription is legal authorization for the patient to receive the medicine. It would be more accu­rate if PBMs labeled what they do “prior approval for reimbursement.”

PBMs exist to manipulate and coordinate the demand for medication generated, on one hand, by patients and their physician and, on the other, by the cost of supplying portion of that demand. The cost of a medication to the PBM is controlled by:  
   • negotiating rebates with drug manufacturers
   • advantageous contracting with pharmacies
   • denying payment, when feasible, using the PA system.

The goal of the PA is to boost the prof­its of the PBM—not to pay for the best fit between the needs of the patient and the medications available, as determined by the treating physician.

The games begin!
The PA process usually begins when the patient goes to the pharmacy, prescription in hand, and gives it to the pharmacist, who enters it into the computer. At that point, if the PBM has put a block on pay­ing for the medication, 3 things happen in sequence:
   1. The computer alerts the pharmacist about the block (or that a higher copay is required).
   2. The pharmacist tells the patient some­thing about the block—although not nec­essarily the whole story.
   3. The pharmacist tells the physician’s office (by fax, e-mail, or telephone) that the PBM wants authorization and that the physician must call a toll-free telephone number to obtain that authorization.

The physician’s office then makes the initial call to the PBM. That call can take 10 to 20 minutes, answering preliminary questions. The call generates a question­naire from the PBM that is faxed to the office, filled with questions that one could characterize as loaded. The questionnaire is intended to provide grounds for disap­proval or approval—not to obtain in-depth understanding of the individual patient’s needs.

Playing pieces on a chessboard
Note that the physician and pharmacist, thrust unwillingly into the middle of this gambit, spend considerable uncompen­sated time on the PA process. (Primary care physicians and their nursing and clerical staff, spent, on average, 19.8 hours a week obtaining PAs in 2006.¹)

PBMs have shifted responsibility for communication to physicians and phar­macists by requiring that the physician always contact the PBM. A PBM will not contact a physician directly, either to begin the PA or ask questions during the process.

If the request for authorization is denied, what’s the outcome? The physician’s office and the pharmacist have spent uncompen­sated time taking action that resulted in the PBM and the insurer improving their bottom line without benefit to anyone else.

Communication breakdown. The cum­bersome, multistep PA process opens the door to miscommunication. This happens often, I’ve found: The physician wastes time because the pharmacist passed along an incomplete message, or a patient gives vague or confusing information in try­ing to transmit what the pharmacist said. Sometimes, when physicians get through to a live person at the PBM, they are told that the pharmacist misinformed the office: No, the medication didn’t require PA after all.

Why can’t PBMs streamline the process, sparing busy physicians’ offices the time spent on initial telephone calls, by install­ing software that would allow the pharma­cist who first encounters a payment block to, with a few keystrokes, instantly send the relevant questionnaire to the physi­cian’s fax machine or computer?

Obstacles to satisfaction
From the perspective of the patient, the word that probably best characterizes his emotional response to the PA process is “helpless.” He wasn’t expecting a denial; it’s likely that he hadn’t been fully or clearly informed at the time he selected the insurer that he might someday face such an obstacle. Even though he had a legal prescription, written by a physician, any attempt to go back to the insurer or the PBM to complain is rarely successful. If he tried, he would likely get no satisfaction: The clerk at the other end of the telephone would swiftly inform him that there were a number of complicated rules, policies, or “step programs” that must be adhered to before the PBM pays for a prescription.

Even if the medication is covered, the patient might be told that there are “quan­tity limits” that prevent reimbursement for the prescription as written—limits that were not made explicit when he signed up for the insurance plan. All these obstacles can generate confusion, anxiety, frustra­tion, and anger—understandably so.

The ‘safety’ catch. Obstacles do not necessarily end when the medication is approved; such approval is merely a “coverage eligibility review.” In addition, PBMs make it clear that every prescription also undergoes a so-called safety review by a pharmacist before it is dispensed. If the PBM’s pharmacist identifies a safety concern, the medication “might not be dispensed,” Express Scripts says, “or your patient could receive less than what you prescribed.”

That is an ominous statement: The PBM is openly and arrogantly taking for itself the right to unilaterally determine what is safe and to override the physician’s judgment as it sees fit. We all know that there are rel­ative risks in taking most medications that we prescribe; the degree of that risk needs to be carefully calculated against the likely benefits for a given patient, whose detailed history is known to the treating physi­cian. History and risk-benefit calculation are not available to the reviewing pharma­cist. The existence of “safety concerns” by itself, outside of the full context of care, is insufficient justification for a PBM to stop payment for a medication.

“Approved”—but… Equally ominous is that, after a medication has been approved through the PA process, some PBMs add these words in their notification to the physician:

    This medication is approved for coverage until [insert date],
    or until coverage for the medication is no longer available
    under the benefit plan or the medication becomes subject
    to a pharmacy benefit cov­erage requirement, such as supply
    limits or notification, whichever occurs first.

In other words, the approval is provi­sional, and shouldn’t be counted on to remain in place for the entire period for which dispensing has been approved. Imagine the uncertainty and anxiety of a patient who reads that statement and real­izes that the medication that, at last, has relieved her symptoms might be with­drawn from coverage at any time for rea­sons unrelated to effectiveness.

The patient can appeal the decision of a PBM or insurer that refuses to pay for a medication, but that patient, and his phy­sician, might ask themselves whether the considerable time required to appeal is jus­tified, given that the criteria used for deni­als are arbitrary and one-sided.

Serious consequences can ensue after a PBM denies coverage for a medication. Some patients cannot afford hundreds of dollars out of pocket for 1 month of 1 medicine. When their supply runs out, they become vulnerable to symptoms of withdrawal or exacerbation of underlying illness.

Armchair care. A PBM, after it has denied approval of payment, might “ask” the phy­sician to choose another medication that the PBM does cover. For a non-physician administrator who has never seen the patient to propose such a switch is micro­management—to say the least. Such an action is also disrespectful of the physi­cian’s judgment.

Loss of possible placebo effect. If the phy­sician goes along and makes the switch pro­posed by the PBM, the patient will know that the new medication is the physician’s second (or third) choice. Any potential posi­tive placebo effect is thus lost. Does that matter? It might—a lot.

Most physicians would be glad to have a positive placebo effect assist or augment the physiologic effects of a medication, especially at the start of treatment when the patient might feel helpless or hopeless. Such negative feelings are likely to be mag­nified if the patient knows that he has been coerced into taking a second-line therapy. A positive placebo effect, on the other hand, might well have lowered levels of his stress hormones for a few weeks—and that effect could have made a positive difference.

Casualties for the physician are time, money, and morale. PAs consume large chunks of time. Some of the PA forms require that 20 or more questions be answered; a few of those questions can take significant time to answer, having to look through a thick chart to research prior medications.

PAs also cost money: directly to pay the salary of staff that share the PA work, indirectly by crowding out the doctor’s potential billing time and replacing it with uncompensated PA work.

Worse, in my opinion, is the cost to morale. Physicians express their annoy­ance, aggravation, frustration, and anger at meetings and in postings at the end of journal articles on the subject. Some speak of becoming numb from the daily hassle of dealing with PAs.² The disrespect for the physician’s decisions inherent in the PA process, the implicit humiliation of appeal­ing to someone who doesn’t know the patient to approve payment for a medica­tion that’s been legally prescribed, and the cost in time and money all provoke emo­tions that are damaging to morale.

Much to do in limited time
Time isn’t elastic; setting priorities is vital. Most physicians would, I think, agree that their priorities are:
   • giving patients adequate time at office visits
   • returning calls from patients with urgent messages
   • communicating with professional col­leagues about shared patients
   • returning calls from pharmacists who have questions about prescriptions
   • researching solutions to clinical problems
   • keeping up with the literature.

Physicians must decide where complet­ing PAs—intrusive, time-consuming, and a threat to morale—fits in that list. Should PAs be allowed to supplant, or delay, the completion of other vital, positive clinical priorities?

Until we are able to introduce improve­ments that speed up the PA process, patients will have the supply of their med­ications disrupted and physicians will pay in time, money, and morale.

Disclosure
Dr. Mode reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Insistence on prior authorization (PA) when prescribing certain pharmaceuticals has grown considerably over the past 5 years. Most requests for PA are issued by phar­macy benefit management (PBM) companies that have been contracted by an insurer. A PA can be triggered when a physician orders:
   • a brand-name medication
   • a medication not on the formulary of the PBM
   • a quantity above an arbitrary ceiling
   • a medication that has multiple indications (that is, the PBM won’t pay for indication X but will pay for indi­cation Y).

What are the problems caused by PAs? I outline a num­ber of them, and their potential consequences, in this “Commentary.” What can we do, in our practices, to lessen the disruption they cause and the time and money they cost us (Box)?

’Prior authorization’—a misleading, disingenuous term
The physician’s prescription is legal authorization for the patient to receive the medicine. It would be more accu­rate if PBMs labeled what they do “prior approval for reimbursement.”

PBMs exist to manipulate and coordinate the demand for medication generated, on one hand, by patients and their physician and, on the other, by the cost of supplying portion of that demand. The cost of a medication to the PBM is controlled by:  
   • negotiating rebates with drug manufacturers
   • advantageous contracting with pharmacies
   • denying payment, when feasible, using the PA system.

The goal of the PA is to boost the prof­its of the PBM—not to pay for the best fit between the needs of the patient and the medications available, as determined by the treating physician.

The games begin!
The PA process usually begins when the patient goes to the pharmacy, prescription in hand, and gives it to the pharmacist, who enters it into the computer. At that point, if the PBM has put a block on pay­ing for the medication, 3 things happen in sequence:
   1. The computer alerts the pharmacist about the block (or that a higher copay is required).
   2. The pharmacist tells the patient some­thing about the block—although not nec­essarily the whole story.
   3. The pharmacist tells the physician’s office (by fax, e-mail, or telephone) that the PBM wants authorization and that the physician must call a toll-free telephone number to obtain that authorization.

The physician’s office then makes the initial call to the PBM. That call can take 10 to 20 minutes, answering preliminary questions. The call generates a question­naire from the PBM that is faxed to the office, filled with questions that one could characterize as loaded. The questionnaire is intended to provide grounds for disap­proval or approval—not to obtain in-depth understanding of the individual patient’s needs.

Playing pieces on a chessboard
Note that the physician and pharmacist, thrust unwillingly into the middle of this gambit, spend considerable uncompen­sated time on the PA process. (Primary care physicians and their nursing and clerical staff, spent, on average, 19.8 hours a week obtaining PAs in 2006.¹)

PBMs have shifted responsibility for communication to physicians and phar­macists by requiring that the physician always contact the PBM. A PBM will not contact a physician directly, either to begin the PA or ask questions during the process.

If the request for authorization is denied, what’s the outcome? The physician’s office and the pharmacist have spent uncompen­sated time taking action that resulted in the PBM and the insurer improving their bottom line without benefit to anyone else.

Communication breakdown. The cum­bersome, multistep PA process opens the door to miscommunication. This happens often, I’ve found: The physician wastes time because the pharmacist passed along an incomplete message, or a patient gives vague or confusing information in try­ing to transmit what the pharmacist said. Sometimes, when physicians get through to a live person at the PBM, they are told that the pharmacist misinformed the office: No, the medication didn’t require PA after all.

Why can’t PBMs streamline the process, sparing busy physicians’ offices the time spent on initial telephone calls, by install­ing software that would allow the pharma­cist who first encounters a payment block to, with a few keystrokes, instantly send the relevant questionnaire to the physi­cian’s fax machine or computer?

Obstacles to satisfaction
From the perspective of the patient, the word that probably best characterizes his emotional response to the PA process is “helpless.” He wasn’t expecting a denial; it’s likely that he hadn’t been fully or clearly informed at the time he selected the insurer that he might someday face such an obstacle. Even though he had a legal prescription, written by a physician, any attempt to go back to the insurer or the PBM to complain is rarely successful. If he tried, he would likely get no satisfaction: The clerk at the other end of the telephone would swiftly inform him that there were a number of complicated rules, policies, or “step programs” that must be adhered to before the PBM pays for a prescription.

Even if the medication is covered, the patient might be told that there are “quan­tity limits” that prevent reimbursement for the prescription as written—limits that were not made explicit when he signed up for the insurance plan. All these obstacles can generate confusion, anxiety, frustra­tion, and anger—understandably so.

The ‘safety’ catch. Obstacles do not necessarily end when the medication is approved; such approval is merely a “coverage eligibility review.” In addition, PBMs make it clear that every prescription also undergoes a so-called safety review by a pharmacist before it is dispensed. If the PBM’s pharmacist identifies a safety concern, the medication “might not be dispensed,” Express Scripts says, “or your patient could receive less than what you prescribed.”

That is an ominous statement: The PBM is openly and arrogantly taking for itself the right to unilaterally determine what is safe and to override the physician’s judgment as it sees fit. We all know that there are rel­ative risks in taking most medications that we prescribe; the degree of that risk needs to be carefully calculated against the likely benefits for a given patient, whose detailed history is known to the treating physi­cian. History and risk-benefit calculation are not available to the reviewing pharma­cist. The existence of “safety concerns” by itself, outside of the full context of care, is insufficient justification for a PBM to stop payment for a medication.

“Approved”—but… Equally ominous is that, after a medication has been approved through the PA process, some PBMs add these words in their notification to the physician:

    This medication is approved for coverage until [insert date],
    or until coverage for the medication is no longer available
    under the benefit plan or the medication becomes subject
    to a pharmacy benefit cov­erage requirement, such as supply
    limits or notification, whichever occurs first.

In other words, the approval is provi­sional, and shouldn’t be counted on to remain in place for the entire period for which dispensing has been approved. Imagine the uncertainty and anxiety of a patient who reads that statement and real­izes that the medication that, at last, has relieved her symptoms might be with­drawn from coverage at any time for rea­sons unrelated to effectiveness.

The patient can appeal the decision of a PBM or insurer that refuses to pay for a medication, but that patient, and his phy­sician, might ask themselves whether the considerable time required to appeal is jus­tified, given that the criteria used for deni­als are arbitrary and one-sided.

Serious consequences can ensue after a PBM denies coverage for a medication. Some patients cannot afford hundreds of dollars out of pocket for 1 month of 1 medicine. When their supply runs out, they become vulnerable to symptoms of withdrawal or exacerbation of underlying illness.

Armchair care. A PBM, after it has denied approval of payment, might “ask” the phy­sician to choose another medication that the PBM does cover. For a non-physician administrator who has never seen the patient to propose such a switch is micro­management—to say the least. Such an action is also disrespectful of the physi­cian’s judgment.

Loss of possible placebo effect. If the phy­sician goes along and makes the switch pro­posed by the PBM, the patient will know that the new medication is the physician’s second (or third) choice. Any potential posi­tive placebo effect is thus lost. Does that matter? It might—a lot.

Most physicians would be glad to have a positive placebo effect assist or augment the physiologic effects of a medication, especially at the start of treatment when the patient might feel helpless or hopeless. Such negative feelings are likely to be mag­nified if the patient knows that he has been coerced into taking a second-line therapy. A positive placebo effect, on the other hand, might well have lowered levels of his stress hormones for a few weeks—and that effect could have made a positive difference.

Casualties for the physician are time, money, and morale. PAs consume large chunks of time. Some of the PA forms require that 20 or more questions be answered; a few of those questions can take significant time to answer, having to look through a thick chart to research prior medications.

PAs also cost money: directly to pay the salary of staff that share the PA work, indirectly by crowding out the doctor’s potential billing time and replacing it with uncompensated PA work.

Worse, in my opinion, is the cost to morale. Physicians express their annoy­ance, aggravation, frustration, and anger at meetings and in postings at the end of journal articles on the subject. Some speak of becoming numb from the daily hassle of dealing with PAs.² The disrespect for the physician’s decisions inherent in the PA process, the implicit humiliation of appeal­ing to someone who doesn’t know the patient to approve payment for a medica­tion that’s been legally prescribed, and the cost in time and money all provoke emo­tions that are damaging to morale.

Much to do in limited time
Time isn’t elastic; setting priorities is vital. Most physicians would, I think, agree that their priorities are:
   • giving patients adequate time at office visits
   • returning calls from patients with urgent messages
   • communicating with professional col­leagues about shared patients
   • returning calls from pharmacists who have questions about prescriptions
   • researching solutions to clinical problems
   • keeping up with the literature.

Physicians must decide where complet­ing PAs—intrusive, time-consuming, and a threat to morale—fits in that list. Should PAs be allowed to supplant, or delay, the completion of other vital, positive clinical priorities?

Until we are able to introduce improve­ments that speed up the PA process, patients will have the supply of their med­ications disrupted and physicians will pay in time, money, and morale.

Disclosure
Dr. Mode reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acne vulgaris is a chronic inflammatory disease that affects the majority of the population at some point in their lifetime. It is characterized by comedones, pustules, and papules. Acne pathogenesis is multifactorial with 4 primary factors that play a pivotal role in the formation of acne lesions: excess sebum production, abnormal keratinization, inflammation, and bacterial colonization of Propionibacterium acnes in the pilosebaceous unit.¹ Although there is a general consensus on the pathogenic factors, the sequence of events in acne development is controversial. Traditionally it was believed that abnormal keratinization resulted in the creation of the microcomedone, the earliest subclinical acne lesion.² Activation of sebaceous glands by androgens, excess sebum production, and keratin plug formation then were followed by P acnes colonization, with induction of the innate immune system culminating in inflammation.² Androgen-induced sebum production and follicular hyperkeratinization and plugging have been cited as initial events that alter the pilosebaceous milieu, favoring the proliferation of P acnes^1,3; however, evidence suggests inflammation as the inciting factor, with proof of significant inflammatory factors surrounding the pilosebaceous unit even in clinically uninvolved skin units in acne patients.⁴ Herein we will briefly review the most recent data and translational applications pertaining to the P acnes–triggered innate immune response via activation of toll-like receptor 2 (TLR2)⁵ and importantly the inflammasome.^6,7

A new understanding of how P acnes induces the inflammatory cascade may represent a paradigm shift in the management of acne. Recognition of microbes, namely P acnes, by the innate immune system is the body’s first line of defense against pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs).⁶ Although these pathways combat infection and prevent foreign invasion, they also result in inflammation and tissue injury. The inflammatory response to PAMPs and DAMPs is mediated by the inflammasome, a caspase 1–activating cytoplasmic complex that induces the secretion of crucial proinflammatory cytokines.⁷ The exact mechanism by which P acnes exerts its proinflammatory activity has been somewhat unclear, though P acnes–induced inflammation has been shown to be mediated by proinflammatory cytokines tumor necrosis factor α, IL-1, IL-6, IL-8, and IL-12.^5,8 However, remarkable evidence recently was presented regarding triggers of inflammation and the precise mechanism involved. Qin et al⁹ showed that P acnes is a potent trigger of IL-1β generation via activation of the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome. Specifically, the study showed that human monocytes respond to P acnes by upregulating caspase 1, an inflammatory caspase required for proteolytic cleavage of IL-1β. The authors correlated their in vitro findings with clinical evidence of caspase 1 and NLRP3 expression in the dermis surrounding the pilosebaceous units of biopsied lesions.⁹ Kistowska et al⁶ confirmed and expanded on these data by showing the inability of NLRP3-deficient myeloid cells to secrete IL-1β and induce an inflammatory response in vivo. A recent investigation demonstrated that human sebocytes can function as constituents of the innate immune response, with P acnes triggering sebocyte NLRP3-inflammasome activation and subsequent IL-1β secretion. These observations were further confirmed in vivo with NLRP3-deficient mice displaying an impaired inflammatory response to P acnes.¹⁰

Our understanding of TLR2 signaling in the pathogenesis of acne also has expanded. It is well established that recognition of extracellular PAMPs and DAMPs is mediated by the expression of toll-like receptors on the surface of a variety of cells within the skin.¹¹ Prior research demonstrated how P acnes increases TLR2 expression in keratinocytes, even in vivo.¹² Stimulation by P acnes was shown to induce secretion of IL-8 (promoting a T_H1 response) and IL-12 (promoting neutrophil chemotaxis) via TLR2 activation.⁵ Selway et al¹¹ validated this finding by demonstrating that infundibular keratinocytes secrete IL-1α in response to the peptidoglycan cell wall of P acnes. Interestingly, Qin et al⁹ determined TLR2 inhibition resulted in partial suppression of IL-1β, possibly providing new evidence of TLR2-mediated activation of the NLRP3 inflammasome. Therefore, P acnes activates both extracellular and intracellular triggers of the innate immune response: TLR2 activation (requiring extracellular recognition of pathogens) and inflammasome-mediated activation (requiring internalization and access of the bacterium to the interior compartments of the cells).

Overall, these findings suggest that P acnes–induced inflammation can be selectively targeted by agents directed at inflammasome components, IL-1β, or toll-like receptors. A phase 2 double-blind, placebo-controlled trial assessing the efficacy of the anti–IL-1β monoclonal antibody gevokizumab found that 0.6 mg/kg administered subcutaneously resulted in a significant reduction in mean inflammatory lesion count compared to placebo (P=.077).¹³ The success of the IL-1 receptor antagonist anakinra against rare genetic autoinflammatory syndromes such as PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome, an NLRP3 inflammasomopathy, sheds light onto new therapeutics that may be used to target acne vulgaris.¹⁴ Current topical therapies such as retinoids, which have already proven efficacious in the treatment of inflammatory acne, target these pathways. In vivo data revealed that treatment with isotretinoin significantly decreased TLR2 expression in monocytes (P<.001) and suppressed inflammatory cytokine responses to P acnes (P<.001).¹⁵ Adapalene, with or without benzoyl peroxide, also was shown to exert anti-inflammatory effects via TLR2 downregulation.¹⁶

These data and observations highlight a paradigm shift in our perception of acne. All acne is truly inflammatory, and by identifying aberrations in the immune response, we can develop targeted treatments for this chronic debilitating disease.

Acne vulgaris is a chronic inflammatory disease that affects the majority of the population at some point in their lifetime. It is characterized by comedones, pustules, and papules. Acne pathogenesis is multifactorial with 4 primary factors that play a pivotal role in the formation of acne lesions: excess sebum production, abnormal keratinization, inflammation, and bacterial colonization of Propionibacterium acnes in the pilosebaceous unit.¹ Although there is a general consensus on the pathogenic factors, the sequence of events in acne development is controversial. Traditionally it was believed that abnormal keratinization resulted in the creation of the microcomedone, the earliest subclinical acne lesion.² Activation of sebaceous glands by androgens, excess sebum production, and keratin plug formation then were followed by P acnes colonization, with induction of the innate immune system culminating in inflammation.² Androgen-induced sebum production and follicular hyperkeratinization and plugging have been cited as initial events that alter the pilosebaceous milieu, favoring the proliferation of P acnes^1,3; however, evidence suggests inflammation as the inciting factor, with proof of significant inflammatory factors surrounding the pilosebaceous unit even in clinically uninvolved skin units in acne patients.⁴ Herein we will briefly review the most recent data and translational applications pertaining to the P acnes–triggered innate immune response via activation of toll-like receptor 2 (TLR2)⁵ and importantly the inflammasome.^6,7

A new understanding of how P acnes induces the inflammatory cascade may represent a paradigm shift in the management of acne. Recognition of microbes, namely P acnes, by the innate immune system is the body’s first line of defense against pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs).⁶ Although these pathways combat infection and prevent foreign invasion, they also result in inflammation and tissue injury. The inflammatory response to PAMPs and DAMPs is mediated by the inflammasome, a caspase 1–activating cytoplasmic complex that induces the secretion of crucial proinflammatory cytokines.⁷ The exact mechanism by which P acnes exerts its proinflammatory activity has been somewhat unclear, though P acnes–induced inflammation has been shown to be mediated by proinflammatory cytokines tumor necrosis factor α, IL-1, IL-6, IL-8, and IL-12.^5,8 However, remarkable evidence recently was presented regarding triggers of inflammation and the precise mechanism involved. Qin et al⁹ showed that P acnes is a potent trigger of IL-1β generation via activation of the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome. Specifically, the study showed that human monocytes respond to P acnes by upregulating caspase 1, an inflammatory caspase required for proteolytic cleavage of IL-1β. The authors correlated their in vitro findings with clinical evidence of caspase 1 and NLRP3 expression in the dermis surrounding the pilosebaceous units of biopsied lesions.⁹ Kistowska et al⁶ confirmed and expanded on these data by showing the inability of NLRP3-deficient myeloid cells to secrete IL-1β and induce an inflammatory response in vivo. A recent investigation demonstrated that human sebocytes can function as constituents of the innate immune response, with P acnes triggering sebocyte NLRP3-inflammasome activation and subsequent IL-1β secretion. These observations were further confirmed in vivo with NLRP3-deficient mice displaying an impaired inflammatory response to P acnes.¹⁰

Our understanding of TLR2 signaling in the pathogenesis of acne also has expanded. It is well established that recognition of extracellular PAMPs and DAMPs is mediated by the expression of toll-like receptors on the surface of a variety of cells within the skin.¹¹ Prior research demonstrated how P acnes increases TLR2 expression in keratinocytes, even in vivo.¹² Stimulation by P acnes was shown to induce secretion of IL-8 (promoting a T_H1 response) and IL-12 (promoting neutrophil chemotaxis) via TLR2 activation.⁵ Selway et al¹¹ validated this finding by demonstrating that infundibular keratinocytes secrete IL-1α in response to the peptidoglycan cell wall of P acnes. Interestingly, Qin et al⁹ determined TLR2 inhibition resulted in partial suppression of IL-1β, possibly providing new evidence of TLR2-mediated activation of the NLRP3 inflammasome. Therefore, P acnes activates both extracellular and intracellular triggers of the innate immune response: TLR2 activation (requiring extracellular recognition of pathogens) and inflammasome-mediated activation (requiring internalization and access of the bacterium to the interior compartments of the cells).

Overall, these findings suggest that P acnes–induced inflammation can be selectively targeted by agents directed at inflammasome components, IL-1β, or toll-like receptors. A phase 2 double-blind, placebo-controlled trial assessing the efficacy of the anti–IL-1β monoclonal antibody gevokizumab found that 0.6 mg/kg administered subcutaneously resulted in a significant reduction in mean inflammatory lesion count compared to placebo (P=.077).¹³ The success of the IL-1 receptor antagonist anakinra against rare genetic autoinflammatory syndromes such as PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome, an NLRP3 inflammasomopathy, sheds light onto new therapeutics that may be used to target acne vulgaris.¹⁴ Current topical therapies such as retinoids, which have already proven efficacious in the treatment of inflammatory acne, target these pathways. In vivo data revealed that treatment with isotretinoin significantly decreased TLR2 expression in monocytes (P<.001) and suppressed inflammatory cytokine responses to P acnes (P<.001).¹⁵ Adapalene, with or without benzoyl peroxide, also was shown to exert anti-inflammatory effects via TLR2 downregulation.¹⁶

These data and observations highlight a paradigm shift in our perception of acne. All acne is truly inflammatory, and by identifying aberrations in the immune response, we can develop targeted treatments for this chronic debilitating disease.

Acne vulgaris is a chronic inflammatory disease that affects the majority of the population at some point in their lifetime. It is characterized by comedones, pustules, and papules. Acne pathogenesis is multifactorial with 4 primary factors that play a pivotal role in the formation of acne lesions: excess sebum production, abnormal keratinization, inflammation, and bacterial colonization of Propionibacterium acnes in the pilosebaceous unit.¹ Although there is a general consensus on the pathogenic factors, the sequence of events in acne development is controversial. Traditionally it was believed that abnormal keratinization resulted in the creation of the microcomedone, the earliest subclinical acne lesion.² Activation of sebaceous glands by androgens, excess sebum production, and keratin plug formation then were followed by P acnes colonization, with induction of the innate immune system culminating in inflammation.² Androgen-induced sebum production and follicular hyperkeratinization and plugging have been cited as initial events that alter the pilosebaceous milieu, favoring the proliferation of P acnes^1,3; however, evidence suggests inflammation as the inciting factor, with proof of significant inflammatory factors surrounding the pilosebaceous unit even in clinically uninvolved skin units in acne patients.⁴ Herein we will briefly review the most recent data and translational applications pertaining to the P acnes–triggered innate immune response via activation of toll-like receptor 2 (TLR2)⁵ and importantly the inflammasome.^6,7

A new understanding of how P acnes induces the inflammatory cascade may represent a paradigm shift in the management of acne. Recognition of microbes, namely P acnes, by the innate immune system is the body’s first line of defense against pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs).⁶ Although these pathways combat infection and prevent foreign invasion, they also result in inflammation and tissue injury. The inflammatory response to PAMPs and DAMPs is mediated by the inflammasome, a caspase 1–activating cytoplasmic complex that induces the secretion of crucial proinflammatory cytokines.⁷ The exact mechanism by which P acnes exerts its proinflammatory activity has been somewhat unclear, though P acnes–induced inflammation has been shown to be mediated by proinflammatory cytokines tumor necrosis factor α, IL-1, IL-6, IL-8, and IL-12.^5,8 However, remarkable evidence recently was presented regarding triggers of inflammation and the precise mechanism involved. Qin et al⁹ showed that P acnes is a potent trigger of IL-1β generation via activation of the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome. Specifically, the study showed that human monocytes respond to P acnes by upregulating caspase 1, an inflammatory caspase required for proteolytic cleavage of IL-1β. The authors correlated their in vitro findings with clinical evidence of caspase 1 and NLRP3 expression in the dermis surrounding the pilosebaceous units of biopsied lesions.⁹ Kistowska et al⁶ confirmed and expanded on these data by showing the inability of NLRP3-deficient myeloid cells to secrete IL-1β and induce an inflammatory response in vivo. A recent investigation demonstrated that human sebocytes can function as constituents of the innate immune response, with P acnes triggering sebocyte NLRP3-inflammasome activation and subsequent IL-1β secretion. These observations were further confirmed in vivo with NLRP3-deficient mice displaying an impaired inflammatory response to P acnes.¹⁰

Our understanding of TLR2 signaling in the pathogenesis of acne also has expanded. It is well established that recognition of extracellular PAMPs and DAMPs is mediated by the expression of toll-like receptors on the surface of a variety of cells within the skin.¹¹ Prior research demonstrated how P acnes increases TLR2 expression in keratinocytes, even in vivo.¹² Stimulation by P acnes was shown to induce secretion of IL-8 (promoting a T_H1 response) and IL-12 (promoting neutrophil chemotaxis) via TLR2 activation.⁵ Selway et al¹¹ validated this finding by demonstrating that infundibular keratinocytes secrete IL-1α in response to the peptidoglycan cell wall of P acnes. Interestingly, Qin et al⁹ determined TLR2 inhibition resulted in partial suppression of IL-1β, possibly providing new evidence of TLR2-mediated activation of the NLRP3 inflammasome. Therefore, P acnes activates both extracellular and intracellular triggers of the innate immune response: TLR2 activation (requiring extracellular recognition of pathogens) and inflammasome-mediated activation (requiring internalization and access of the bacterium to the interior compartments of the cells).

Overall, these findings suggest that P acnes–induced inflammation can be selectively targeted by agents directed at inflammasome components, IL-1β, or toll-like receptors. A phase 2 double-blind, placebo-controlled trial assessing the efficacy of the anti–IL-1β monoclonal antibody gevokizumab found that 0.6 mg/kg administered subcutaneously resulted in a significant reduction in mean inflammatory lesion count compared to placebo (P=.077).¹³ The success of the IL-1 receptor antagonist anakinra against rare genetic autoinflammatory syndromes such as PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome, an NLRP3 inflammasomopathy, sheds light onto new therapeutics that may be used to target acne vulgaris.¹⁴ Current topical therapies such as retinoids, which have already proven efficacious in the treatment of inflammatory acne, target these pathways. In vivo data revealed that treatment with isotretinoin significantly decreased TLR2 expression in monocytes (P<.001) and suppressed inflammatory cytokine responses to P acnes (P<.001).¹⁵ Adapalene, with or without benzoyl peroxide, also was shown to exert anti-inflammatory effects via TLR2 downregulation.¹⁶

These data and observations highlight a paradigm shift in our perception of acne. All acne is truly inflammatory, and by identifying aberrations in the immune response, we can develop targeted treatments for this chronic debilitating disease.

When you are making nursery rounds, how do you greet a woman who has just delivered her first child? If you welcome her into the realm of parenthood by addressing her as “Mom,” as I often did, you might want to rethink your opening lines.

In a letter to the editor by Camela Zarcone on Nov. 10 responding to an opinion piece in the New York Times (“Our Mommy Problem,” Heather Havrilesky, Sunday Review, Nov 9, 2014), Ms. Zarcone, who is from Seattle and has three sons, described a scenario in which you or I might have unwittingly played the role of villain. The pediatrician made two mistakes that I hope we wouldn’t have made. First, as she remembers it, he failed to introduce himself. And second, he walked in on her with her breasts fully exposed as she was struggling to nurse her newborn.

I have tried to avoid both of these errors by announcing, in my most manly voice, “It’s Dr. Wilkoff, the pediatrician. May I come in?” But I must say that the vast majority of nursing mothers are so focused on their babies that they rarely made any attempt to cover their breasts.

According to the author of the letter, the most serious misdeed the pediatrician committed was referring to a woman he had never met as “Mom.” I suspect, like me, he uttered this three-letter word believing that he was doing so out of respect for her new status as a mother. However, in her eyes this was the first assault in her more than 2-decade struggle to make it clear that being a mother does not define who she is.

Before we get into the deeper question of personal identity, I admit that I share some of her discomfort. If you aren’t going to refer to me by my first name, please refer to me as “doctor” not “doc” (another three-letter word). But, her overriding concern is that regardless of whether you address her as “Mother” or “Mom,” by making a reference to the fact that she has delivered a child, you are ignoring that she is a multifaceted person with talents, emotions, and sensibilities that are unrelated to her reproductive status.

The problem for us as pediatricians is that our primary interface with women who have delivered children is dominated by their role as mothers. By addressing a woman as “Mom,” a pediatrician is not ignoring the fact that she is a marketing analyst who sings in the church choir and whose father is dying of lung cancer. He is merely using a shorthand that connotes respect for one of her roles that includes a wide range of responsibilities and concerns.

Unfortunately, not everyone is a pediatrician, and many people do expect that when a woman becomes a mother she has entered a nunnery of sorts in which she has taken vows to forsake all of the other pleasures and aspirations of her former self. What makes it most difficult is that some of those folks with tunnel vision are mothers themselves who equate motherhood with a life of self-sacrifice.

But, that leaves us with the issue of identity. Regardless of how you address me and regardless of how society views me, I am the one who defines my own identity. For 40 years I defined myself as a pediatrician. I probably wasn’t as complete a father and I certainly wasn’t as good a husband as I could have been because of the way I chose to define my role as a pediatrician. I could have defined myself as something else (such as a chess master or a bicycle racer) who was also a pediatrician. But, I am lucky enough to be married to a woman who was willing to define herself as a mother. That made it much easier for me to define myself as a pediatrician in the way I did.

I no longer consider myself a pediatrician. In fact, I don’t even refer to myself as a retired pediatrician. If asked I merely reply, “I was a pediatrician, a former identity for which I have no regrets.”

Being a mother is a special case far more complex than being a pediatrician. But, a woman should still be able to choose how she weaves motherhood into the identity she crafts for herself. When we refer to her as “Mom,” we aren’t defining her. We are simply offering a token of our respect.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” E-mail him at [email protected].

When you are making nursery rounds, how do you greet a woman who has just delivered her first child? If you welcome her into the realm of parenthood by addressing her as “Mom,” as I often did, you might want to rethink your opening lines.

In a letter to the editor by Camela Zarcone on Nov. 10 responding to an opinion piece in the New York Times (“Our Mommy Problem,” Heather Havrilesky, Sunday Review, Nov 9, 2014), Ms. Zarcone, who is from Seattle and has three sons, described a scenario in which you or I might have unwittingly played the role of villain. The pediatrician made two mistakes that I hope we wouldn’t have made. First, as she remembers it, he failed to introduce himself. And second, he walked in on her with her breasts fully exposed as she was struggling to nurse her newborn.

I have tried to avoid both of these errors by announcing, in my most manly voice, “It’s Dr. Wilkoff, the pediatrician. May I come in?” But I must say that the vast majority of nursing mothers are so focused on their babies that they rarely made any attempt to cover their breasts.

According to the author of the letter, the most serious misdeed the pediatrician committed was referring to a woman he had never met as “Mom.” I suspect, like me, he uttered this three-letter word believing that he was doing so out of respect for her new status as a mother. However, in her eyes this was the first assault in her more than 2-decade struggle to make it clear that being a mother does not define who she is.

Before we get into the deeper question of personal identity, I admit that I share some of her discomfort. If you aren’t going to refer to me by my first name, please refer to me as “doctor” not “doc” (another three-letter word). But, her overriding concern is that regardless of whether you address her as “Mother” or “Mom,” by making a reference to the fact that she has delivered a child, you are ignoring that she is a multifaceted person with talents, emotions, and sensibilities that are unrelated to her reproductive status.

The problem for us as pediatricians is that our primary interface with women who have delivered children is dominated by their role as mothers. By addressing a woman as “Mom,” a pediatrician is not ignoring the fact that she is a marketing analyst who sings in the church choir and whose father is dying of lung cancer. He is merely using a shorthand that connotes respect for one of her roles that includes a wide range of responsibilities and concerns.

Unfortunately, not everyone is a pediatrician, and many people do expect that when a woman becomes a mother she has entered a nunnery of sorts in which she has taken vows to forsake all of the other pleasures and aspirations of her former self. What makes it most difficult is that some of those folks with tunnel vision are mothers themselves who equate motherhood with a life of self-sacrifice.

But, that leaves us with the issue of identity. Regardless of how you address me and regardless of how society views me, I am the one who defines my own identity. For 40 years I defined myself as a pediatrician. I probably wasn’t as complete a father and I certainly wasn’t as good a husband as I could have been because of the way I chose to define my role as a pediatrician. I could have defined myself as something else (such as a chess master or a bicycle racer) who was also a pediatrician. But, I am lucky enough to be married to a woman who was willing to define herself as a mother. That made it much easier for me to define myself as a pediatrician in the way I did.

I no longer consider myself a pediatrician. In fact, I don’t even refer to myself as a retired pediatrician. If asked I merely reply, “I was a pediatrician, a former identity for which I have no regrets.”

Being a mother is a special case far more complex than being a pediatrician. But, a woman should still be able to choose how she weaves motherhood into the identity she crafts for herself. When we refer to her as “Mom,” we aren’t defining her. We are simply offering a token of our respect.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” E-mail him at [email protected].

When you are making nursery rounds, how do you greet a woman who has just delivered her first child? If you welcome her into the realm of parenthood by addressing her as “Mom,” as I often did, you might want to rethink your opening lines.

In a letter to the editor by Camela Zarcone on Nov. 10 responding to an opinion piece in the New York Times (“Our Mommy Problem,” Heather Havrilesky, Sunday Review, Nov 9, 2014), Ms. Zarcone, who is from Seattle and has three sons, described a scenario in which you or I might have unwittingly played the role of villain. The pediatrician made two mistakes that I hope we wouldn’t have made. First, as she remembers it, he failed to introduce himself. And second, he walked in on her with her breasts fully exposed as she was struggling to nurse her newborn.

I have tried to avoid both of these errors by announcing, in my most manly voice, “It’s Dr. Wilkoff, the pediatrician. May I come in?” But I must say that the vast majority of nursing mothers are so focused on their babies that they rarely made any attempt to cover their breasts.

According to the author of the letter, the most serious misdeed the pediatrician committed was referring to a woman he had never met as “Mom.” I suspect, like me, he uttered this three-letter word believing that he was doing so out of respect for her new status as a mother. However, in her eyes this was the first assault in her more than 2-decade struggle to make it clear that being a mother does not define who she is.

Before we get into the deeper question of personal identity, I admit that I share some of her discomfort. If you aren’t going to refer to me by my first name, please refer to me as “doctor” not “doc” (another three-letter word). But, her overriding concern is that regardless of whether you address her as “Mother” or “Mom,” by making a reference to the fact that she has delivered a child, you are ignoring that she is a multifaceted person with talents, emotions, and sensibilities that are unrelated to her reproductive status.

The problem for us as pediatricians is that our primary interface with women who have delivered children is dominated by their role as mothers. By addressing a woman as “Mom,” a pediatrician is not ignoring the fact that she is a marketing analyst who sings in the church choir and whose father is dying of lung cancer. He is merely using a shorthand that connotes respect for one of her roles that includes a wide range of responsibilities and concerns.

Unfortunately, not everyone is a pediatrician, and many people do expect that when a woman becomes a mother she has entered a nunnery of sorts in which she has taken vows to forsake all of the other pleasures and aspirations of her former self. What makes it most difficult is that some of those folks with tunnel vision are mothers themselves who equate motherhood with a life of self-sacrifice.

But, that leaves us with the issue of identity. Regardless of how you address me and regardless of how society views me, I am the one who defines my own identity. For 40 years I defined myself as a pediatrician. I probably wasn’t as complete a father and I certainly wasn’t as good a husband as I could have been because of the way I chose to define my role as a pediatrician. I could have defined myself as something else (such as a chess master or a bicycle racer) who was also a pediatrician. But, I am lucky enough to be married to a woman who was willing to define herself as a mother. That made it much easier for me to define myself as a pediatrician in the way I did.

I no longer consider myself a pediatrician. In fact, I don’t even refer to myself as a retired pediatrician. If asked I merely reply, “I was a pediatrician, a former identity for which I have no regrets.”

Being a mother is a special case far more complex than being a pediatrician. But, a woman should still be able to choose how she weaves motherhood into the identity she crafts for herself. When we refer to her as “Mom,” we aren’t defining her. We are simply offering a token of our respect.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” E-mail him at [email protected].