Case Reports

To the Editor:

Alopecia areata (AA), an autoimmune disease characterized by inflammatory and nonscarring hair loss, can have a considerable impact on quality of life.¹ Baricitinib is a Janus kinase inhibitor that recently was approved by the US Food and Drug Administration for treatment of severe AA in adult patients, becoming the only on-label treatment available.² So far, the most common adverse effects reported in phase 3 trials have been acne, upper respiratory tract infections, headaches, urinary tract infections, and elevated creatine kinase levels.³

At our trichology unit in the dermatology department of a Spanish tertiary-care hospital in Seville, we have successfully used baricitinib to treat 18 patients with severe, therapy-resistant AA. Herein, we present a case of trichilemmal cyst reactivation in one of our patients following successful treatment with baricitinib.

A 53-year-old woman with a history of trichilemmal cysts presented to the dermatology department with total body hair loss of 5 years' duration that was diagnosed as AA universalis (Figure, A). The patient reported that the trichilemmal cysts had shrunk drastically 1 month after complete loss of body hair (Severity of Alopecia Tool [SALT] score, 100)(Figure, B). The largest cyst was surgically removed, and the diagnosis was histologically confirmed by a pathologist. Her mother and sister also had a history of multiple trichilemmal cysts.

The patient previously had failed treatment with oral prednisone 50 mg/d, oral cyclosporine 4 mg/kg/d, oral dexamethasone 4 mg twice weekly, and oral azathioprine 300 mg/wk. Due to the new indication of baricitinib for AA, we opted to start the patient on oral baricitinib 4 mg/d. By week 8 of treatment, she had achieved total hair regrowth (SALT score, 0). This rapid response might indicate a quick-responder phenotype, referring to a subset of patients who exhibit a fast and robust response to treatment (SALT90), generally before week 16, although more evidence is needed.

Notably, we observed the reactivation of 4 trichilemmal cysts on the scalp 6 weeks after starting baricitinib. To our knowledge, this side effect has not previously been reported. We hypothesize that reactivation of the cysts may have been due to the inhibition of the Janus kinase/signal transducer and activator of transcription pathway, which reduces the effects of cytokines and leads to reactivation of hair follicles that were inactive because of inflammation.⁴ As a result, the outer root sheath of the hair follicle can once again be filled with keratin, thereby reactivating the trichilemmal cysts. Based on our experience with this case, it may be relevant to consider personal and family history of trichilemmal cysts before starting treatment with baricitinib for AA and advise the patient about the possibility of this adverse effect.

To the Editor:

Alopecia areata (AA), an autoimmune disease characterized by inflammatory and nonscarring hair loss, can have a considerable impact on quality of life.¹ Baricitinib is a Janus kinase inhibitor that recently was approved by the US Food and Drug Administration for treatment of severe AA in adult patients, becoming the only on-label treatment available.² So far, the most common adverse effects reported in phase 3 trials have been acne, upper respiratory tract infections, headaches, urinary tract infections, and elevated creatine kinase levels.³

At our trichology unit in the dermatology department of a Spanish tertiary-care hospital in Seville, we have successfully used baricitinib to treat 18 patients with severe, therapy-resistant AA. Herein, we present a case of trichilemmal cyst reactivation in one of our patients following successful treatment with baricitinib.

A 53-year-old woman with a history of trichilemmal cysts presented to the dermatology department with total body hair loss of 5 years' duration that was diagnosed as AA universalis (Figure, A). The patient reported that the trichilemmal cysts had shrunk drastically 1 month after complete loss of body hair (Severity of Alopecia Tool [SALT] score, 100)(Figure, B). The largest cyst was surgically removed, and the diagnosis was histologically confirmed by a pathologist. Her mother and sister also had a history of multiple trichilemmal cysts.

The patient previously had failed treatment with oral prednisone 50 mg/d, oral cyclosporine 4 mg/kg/d, oral dexamethasone 4 mg twice weekly, and oral azathioprine 300 mg/wk. Due to the new indication of baricitinib for AA, we opted to start the patient on oral baricitinib 4 mg/d. By week 8 of treatment, she had achieved total hair regrowth (SALT score, 0). This rapid response might indicate a quick-responder phenotype, referring to a subset of patients who exhibit a fast and robust response to treatment (SALT90), generally before week 16, although more evidence is needed.

Notably, we observed the reactivation of 4 trichilemmal cysts on the scalp 6 weeks after starting baricitinib. To our knowledge, this side effect has not previously been reported. We hypothesize that reactivation of the cysts may have been due to the inhibition of the Janus kinase/signal transducer and activator of transcription pathway, which reduces the effects of cytokines and leads to reactivation of hair follicles that were inactive because of inflammation.⁴ As a result, the outer root sheath of the hair follicle can once again be filled with keratin, thereby reactivating the trichilemmal cysts. Based on our experience with this case, it may be relevant to consider personal and family history of trichilemmal cysts before starting treatment with baricitinib for AA and advise the patient about the possibility of this adverse effect.

To the Editor:

Alopecia areata (AA), an autoimmune disease characterized by inflammatory and nonscarring hair loss, can have a considerable impact on quality of life.¹ Baricitinib is a Janus kinase inhibitor that recently was approved by the US Food and Drug Administration for treatment of severe AA in adult patients, becoming the only on-label treatment available.² So far, the most common adverse effects reported in phase 3 trials have been acne, upper respiratory tract infections, headaches, urinary tract infections, and elevated creatine kinase levels.³

At our trichology unit in the dermatology department of a Spanish tertiary-care hospital in Seville, we have successfully used baricitinib to treat 18 patients with severe, therapy-resistant AA. Herein, we present a case of trichilemmal cyst reactivation in one of our patients following successful treatment with baricitinib.

A 53-year-old woman with a history of trichilemmal cysts presented to the dermatology department with total body hair loss of 5 years' duration that was diagnosed as AA universalis (Figure, A). The patient reported that the trichilemmal cysts had shrunk drastically 1 month after complete loss of body hair (Severity of Alopecia Tool [SALT] score, 100)(Figure, B). The largest cyst was surgically removed, and the diagnosis was histologically confirmed by a pathologist. Her mother and sister also had a history of multiple trichilemmal cysts.

The patient previously had failed treatment with oral prednisone 50 mg/d, oral cyclosporine 4 mg/kg/d, oral dexamethasone 4 mg twice weekly, and oral azathioprine 300 mg/wk. Due to the new indication of baricitinib for AA, we opted to start the patient on oral baricitinib 4 mg/d. By week 8 of treatment, she had achieved total hair regrowth (SALT score, 0). This rapid response might indicate a quick-responder phenotype, referring to a subset of patients who exhibit a fast and robust response to treatment (SALT90), generally before week 16, although more evidence is needed.

Notably, we observed the reactivation of 4 trichilemmal cysts on the scalp 6 weeks after starting baricitinib. To our knowledge, this side effect has not previously been reported. We hypothesize that reactivation of the cysts may have been due to the inhibition of the Janus kinase/signal transducer and activator of transcription pathway, which reduces the effects of cytokines and leads to reactivation of hair follicles that were inactive because of inflammation.⁴ As a result, the outer root sheath of the hair follicle can once again be filled with keratin, thereby reactivating the trichilemmal cysts. Based on our experience with this case, it may be relevant to consider personal and family history of trichilemmal cysts before starting treatment with baricitinib for AA and advise the patient about the possibility of this adverse effect.

Hypertrophic cardiomyopathy (HCM) is a relatively common inherited condition characterized by abnormal asymmetric left ventricular (LV) thickening. This can lead to LV outflow tract (LVOT) obstruction, which has important implications for anesthesia management. This article describes a case of previously undiagnosed HCM discovered during a preoperative physical examination prior to a routine surveillance colonoscopy.

CASE PRESENTATION

A 55-year-old Army veteran with a history of a sessile serrated colon adenoma presented to the preadmission testing clinic prior to planned surveillance colonoscopy under monitored anesthesia care. His medical history included untreated severe obstructive sleep apnea (53 apnea-hypopnea index score), diet-controlled hypertension, prediabetes (6.3% hemoglobin A_1c), hypogonadism, and obesity (41 body mass index). Medications included semaglutide 1.7 mg injected subcutaneously weekly and testosterone 200 mg injected intramuscularly every 2 weeks, as well as lisinopril-hydrochlorothiazide 10 to 12.5 mg daily, which had recently been discontinued because his blood pressure had improved with a low-sodium diet.

A review of systems was unremarkable except for progressive weight gain. The patient had no family history of sudden cardiac death. On physical examination, the patient’s blood pressure was 119/81 mm Hg, pulse was 86 beats/min, and respiratory rate was 18 breaths/min. The patient was clinically euvolemic, with no jugular venous distention or peripheral edema, and his lungs were clear to auscultation. There was, however, a soft, nonradiating grade 2/6 systolic murmur that had not been previously documented. The murmur decreased substantially with the Valsalva maneuver, with no change in hand grip.

Laboratory studies revealed hemoglobin and renal function were within the reference range. A routine 12-lead electrocardiogram (ECG) was unremarkable. A transthoracic echocardiogram revealed moderate pulmonary hypertension (59 mm Hg right ventricular systolic pressure), asymmetric LV hypertrophy (2.1 cm septal thickness), and severe LVOT obstruction (131.8 mm Hg gradient). Severe systolic anterior motion of the mitral valve was also present. The LV ejection fraction was 60% to 65%, with normal cavity size and systolic function. These findings were consistent with severe hypertrophic obstructive cardiomyopathy (HOCM). Upon more detailed questioning, the patient reported that over the previous 5 years he had experienced gradually decreasing exercise tolerance and mild dyspnea on exertion, particularly in hot weather, which he attributed to weight gain. He also reported a presyncopal episode the previous month while working in his garage in hot weather for a prolonged period of time.

The patient’s elective colonoscopy was canceled, and he was referred to cardiology. While awaiting cardiac consultation, he was instructed to maintain good hydration and avoid any heavy physical activity beyond walking. He was told not to resume his use of lisinopril-hydrochlorothiazide. A screening 7-day Holter monitor showed no ventricular or supraventricular ectopy. After cardiology consultation, the patient was referred to a HCM specialty clinic, where a cardiac magnetic resonance imaging confirmed severe asymmetric hypertrophy with resting obstruction (Figures 1-4). Treatment options were discussed with the patient, and he underwent a trial with the Β—blocker metoprolol 50 mg daily, which he could not tolerate. Verapamil extended-release 180 mg orally once daily was then initiated; however, his dyspnea persisted. He was amenable to surgical therapy and underwent septal myectomy, with 12 g of septal myocardium removed. He did well postoperatively, with a follow-up echocardiogram showing normal LV systolic function and no LVOT gradient detectable at rest or with Valsalva maneuver. His fatigue and exertional dyspnea significantly improved. Once the patient underwent septal myectomy and was determined to have no detectable LVOT gradient, he was approved for colonoscopy which has been scheduled but not completed.

DISCUSSION

Once thought rare, HCM is now considered to be a relatively common inherited disorder, occurring in about 1 in 500 persons, with some suggesting that the actual prevalence is closer to 1 in 200 persons.^1,2 Most often caused by mutations in ≥ 1 of 11 genes responsible for encoding cardiac sarcomere proteins, HCM is characterized by abnormal LV thickening without chamber enlargement in the absence of any identifiable cause, such as aortic valve stenosis or uncontrolled hypertension. The hypertrophy is often asymmetric, and in cases of asymmetric septal hypertrophy, dynamic LVOT obstruction can occur (known as HOCM). The condition is inherited in an autosomal dominant pattern with variable expression and is associated with myocardial fiber disarray, which can occur years before symptom onset.³ This myocardial disarray can lead to remodeling and an increased wall-to-lumen ratio of the coronary arteries, resulting in impaired coronary reserve.

Depending on the degree of LVOT obstruction, patients with HCM may be classified as nonobstructive, labile, or obstructive at rest. Patients without obstruction have an outflow gradient ≤ 30 mm Hg that is not provoked with Valsalva maneuver, administration of amyl nitrite, or exercise treadmill testing.³ Patients classified as labile do not have LVOT obstruction at rest, but obstruction may be induced by provocative measures. Finally, about one-third of patients with HCM will have LVOT gradients of > 30 mm Hg at rest. These patients are at increased risk for progression to symptomatic heart failure and may be candidates for surgical myectomy or catheter-based alcohol septal ablation.⁴ The patient in this case had a resting LVOT gradient of 131.8 mm Hg on echocardiography. The magnitude of this gradient placed the patient at a significantly higher risk of ventricular dysrhythmias and sudden cardiac death.⁵

Wall thickness also has prognostic implications. ⁶ Although any area of the myocardium can be affected, the septum is involved in about 90% cases. In their series of 48 patients followed over 6.5 years, Spirito et al found that the risk of sudden death in patients with HCM increased as wall thickness increased. For patients with a wall thickness of < 15 mm, the risk of death was 0 per 1000 person-years; however, this increased to 18.2 per 1000 person-years for patients with a wall thickness of > 30 mm.⁷

While many patients with HCM are asymptomatic, others may report dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, chest pain, palpitations, presyncope/ syncope, postural lightheadedness, fatigue, or edema. Symptomatology, however, is quite variable and does not necessarily correlate with the degree of outflow obstruction. Surprisingly, some patients with significant LVOT may have minimal symptoms, such as the patient in this case, while others with a lesser degree of LVOT obstruction may be very symptomatic.^3,4

Physical examination of a patient with HCM may be normal or may reveal nonspecific findings such as a fourth heart sound or a systolic murmur. In general, physical examination abnormalities are related to LVOT obstruction. Those patients without significant outflow obstruction may have a normal cardiac examination. While patients with HCM may have a variety of systolic murmurs, the 2 most common are those related to outflow tract obstruction and mitral regurgitation caused by systolic anterior motion of the mitral valve.⁴ The systolic murmur associated with significant LVOT obstruction has been described as a harsh, crescendo-decrescendo type that begins just after S1 and is heard best at the apex and lower left sternal border.⁴ It may radiate to the axilla and base but not generally into the neck. The murmur usually increases with Valsalva maneuver and decreases with handgrip or going from a standing to a sitting/ squatting position. The initial examination of the patient in this case was not suggestive of HOCM, as confirmed by 2 practitioners (a cardiologist and an internist), each with > 30 years of clinical experience. This may have been related to the patient’s hydration status at the time, with Valsalva maneuver increasing obstruction to the point of reduced flow.

About 90% of patients with HCM will have abnormalities on ECG, most commonly LV hypertrophy with a strain pattern. Other ECG findings include: (1) prominent abnormal Q waves, particularly in the inferior (II, III, and aVF) and lateral leads (I, aVL, and V4-V6), reflecting depolarization of a hypertrophied septum; (2) left axis deviation; (3) deeply inverted T waves in leads V2 through V4; and (4) P wave abnormalities indicative of left atrial (LA) or biatrial enlargement. ⁸ It is notable that the patient in this case had a normal ECG, given that a minority of patients with HCM have been shown to have a normal ECG.⁹

Echocardiography plays an important role in diagnosing HCM. Diagnostic criteria include the presence of asymmetric hypertrophy (most commonly with anterior septal involvement), systolic anterior motion of the mitral valve, a nondilated LV cavity, septal immobility, and premature closure of the aortic valve. LV thickness is measured at both the septum and free wall; values ≥ 15 mm, with a septal-to-free wall thickness ratio of ≥ 1.3, are suggestive of HCM. Asymmetric LV hypertrophy can also be seen in other segments besides the septum, such as the apex.¹⁰

HCM/HOCM is the most common cause of sudden cardiac death in young people. The condition also contributes to significant functional morbidity due to heart failure and increases the risk of atrial fibrillation and subsequent stroke. Treatments tend to focus on symptom relief and slowing disease progression and include the use of medications such as Β—blockers, nondihydropyridine calcium channel blockers, and the myosin inhibitor mavacamten.¹¹ Select patients, such as those with severe LVOT obstruction and symptoms despite treatment with Β—blockers or nondihydropyridine calcium channel blockers, may be offered septal myectomy or catheter-based alcohol septal ablation, coupled with insertion of an implantable cardiac defibrillator to prevent sudden cardiac death in patients at high arrhythmic risk.^1,12

Patients with HCM, particularly those with LVOT obstruction, pose distinct challenges to the anesthesiologist because they are highly sensitive to decreases in preload and afterload. These patients frequently experience adverse perioperative events such as myocardial ischemia, systemic hypotension, and supraventricular or ventricular arrhythmias. Acute congestive heart failure may also occur, presumably due to concomitant diastolic dysfunction. Patients with previously unrecognized HCM are of particular concern, as they may manifest unexpected and sudden hypotension with the induction of anesthesia. There may then be a paradoxical response to vasoactive drugs and anesthetic agents, which accentuate LVOT obstruction. In these circumstances, undiagnosed HCM should be considered, and intraoperative rescue transesophageal echocardiography be performed.¹³ Once the diagnosis is confirmed, efforts should be made to reduce myocardial contractility and sympathetic discharge (eg, with Β—blockers), increase afterload (eg, with α1 agonists), and improve preload with adequate hydration. Proper resuscitation of hypotensive patients with HCM requires a thorough understanding of disease pathology, as effective interventions may seem to be counterintuitive. Inotropic agents such as epinephrine are contraindicated in HCM because increased inotropy and chronotropy worsen LVOT obstruction. Volume status is often tenuous; while adequate preload is important, overly aggressive fluid resuscitation may promote heart failure. It is important to keep in mind that even patients without resting LVOT obstruction may develop dynamic obstruction with anesthesia induction due to sudden reductions in preload and afterload. It is also important to note that the degree of LV hypertrophy is directly correlated with arrhythmic sudden death. Those patients with LV wall thickness ≥ 30 mm are at increased risk for potentially lethal tachyarrhythmias in the operating room.¹⁴

These considerations reinforce the need for proper preoperative identification of patients with HCM. Heightened awareness is key, given the fact that HCM is relatively common and tends to be underdiagnosed in the general population. These patients are generally young, otherwise healthy, and often undergo minor operative procedures in outpatient settings. It is incumbent upon the preoperative evaluator to take a thorough medical history and perform a careful physical examination. Clues to the diagnosis include exertional dyspnea, fatigue, angina, syncope/presyncope, or a family history of sudden cardiac death or HCM. A systolic ejection murmur, particularly one that increases with standing or Valsalva maneuver, and decreases with squatting or handgrip may also raise clinical suspicion. These patients should undergo a full cardiac evaluation, including echocardiography.

CONCLUSIONS

HCM is a common condition that is important to diagnose in the preoperative clinic. Failure to do so can lead to catastrophic complications during induction of anesthesia due to the sudden reduction in preload and afterload, which may cause a significant increase in LVOT obstruction. A high index of suspicion is essential, as clinical diagnosis can be challenging. The physical examination may be deceiving and symptoms are often subtle and nonspecific. It is imperative to alert the anesthesiologist before surgery so the complex hemodynamic management of patients with HOCM can be appropriately managed.

Hypertrophic cardiomyopathy (HCM) is a relatively common inherited condition characterized by abnormal asymmetric left ventricular (LV) thickening. This can lead to LV outflow tract (LVOT) obstruction, which has important implications for anesthesia management. This article describes a case of previously undiagnosed HCM discovered during a preoperative physical examination prior to a routine surveillance colonoscopy.

CASE PRESENTATION

A 55-year-old Army veteran with a history of a sessile serrated colon adenoma presented to the preadmission testing clinic prior to planned surveillance colonoscopy under monitored anesthesia care. His medical history included untreated severe obstructive sleep apnea (53 apnea-hypopnea index score), diet-controlled hypertension, prediabetes (6.3% hemoglobin A_1c), hypogonadism, and obesity (41 body mass index). Medications included semaglutide 1.7 mg injected subcutaneously weekly and testosterone 200 mg injected intramuscularly every 2 weeks, as well as lisinopril-hydrochlorothiazide 10 to 12.5 mg daily, which had recently been discontinued because his blood pressure had improved with a low-sodium diet.

A review of systems was unremarkable except for progressive weight gain. The patient had no family history of sudden cardiac death. On physical examination, the patient’s blood pressure was 119/81 mm Hg, pulse was 86 beats/min, and respiratory rate was 18 breaths/min. The patient was clinically euvolemic, with no jugular venous distention or peripheral edema, and his lungs were clear to auscultation. There was, however, a soft, nonradiating grade 2/6 systolic murmur that had not been previously documented. The murmur decreased substantially with the Valsalva maneuver, with no change in hand grip.

Laboratory studies revealed hemoglobin and renal function were within the reference range. A routine 12-lead electrocardiogram (ECG) was unremarkable. A transthoracic echocardiogram revealed moderate pulmonary hypertension (59 mm Hg right ventricular systolic pressure), asymmetric LV hypertrophy (2.1 cm septal thickness), and severe LVOT obstruction (131.8 mm Hg gradient). Severe systolic anterior motion of the mitral valve was also present. The LV ejection fraction was 60% to 65%, with normal cavity size and systolic function. These findings were consistent with severe hypertrophic obstructive cardiomyopathy (HOCM). Upon more detailed questioning, the patient reported that over the previous 5 years he had experienced gradually decreasing exercise tolerance and mild dyspnea on exertion, particularly in hot weather, which he attributed to weight gain. He also reported a presyncopal episode the previous month while working in his garage in hot weather for a prolonged period of time.

The patient’s elective colonoscopy was canceled, and he was referred to cardiology. While awaiting cardiac consultation, he was instructed to maintain good hydration and avoid any heavy physical activity beyond walking. He was told not to resume his use of lisinopril-hydrochlorothiazide. A screening 7-day Holter monitor showed no ventricular or supraventricular ectopy. After cardiology consultation, the patient was referred to a HCM specialty clinic, where a cardiac magnetic resonance imaging confirmed severe asymmetric hypertrophy with resting obstruction (Figures 1-4). Treatment options were discussed with the patient, and he underwent a trial with the Β—blocker metoprolol 50 mg daily, which he could not tolerate. Verapamil extended-release 180 mg orally once daily was then initiated; however, his dyspnea persisted. He was amenable to surgical therapy and underwent septal myectomy, with 12 g of septal myocardium removed. He did well postoperatively, with a follow-up echocardiogram showing normal LV systolic function and no LVOT gradient detectable at rest or with Valsalva maneuver. His fatigue and exertional dyspnea significantly improved. Once the patient underwent septal myectomy and was determined to have no detectable LVOT gradient, he was approved for colonoscopy which has been scheduled but not completed.

DISCUSSION

Once thought rare, HCM is now considered to be a relatively common inherited disorder, occurring in about 1 in 500 persons, with some suggesting that the actual prevalence is closer to 1 in 200 persons.^1,2 Most often caused by mutations in ≥ 1 of 11 genes responsible for encoding cardiac sarcomere proteins, HCM is characterized by abnormal LV thickening without chamber enlargement in the absence of any identifiable cause, such as aortic valve stenosis or uncontrolled hypertension. The hypertrophy is often asymmetric, and in cases of asymmetric septal hypertrophy, dynamic LVOT obstruction can occur (known as HOCM). The condition is inherited in an autosomal dominant pattern with variable expression and is associated with myocardial fiber disarray, which can occur years before symptom onset.³ This myocardial disarray can lead to remodeling and an increased wall-to-lumen ratio of the coronary arteries, resulting in impaired coronary reserve.

Depending on the degree of LVOT obstruction, patients with HCM may be classified as nonobstructive, labile, or obstructive at rest. Patients without obstruction have an outflow gradient ≤ 30 mm Hg that is not provoked with Valsalva maneuver, administration of amyl nitrite, or exercise treadmill testing.³ Patients classified as labile do not have LVOT obstruction at rest, but obstruction may be induced by provocative measures. Finally, about one-third of patients with HCM will have LVOT gradients of > 30 mm Hg at rest. These patients are at increased risk for progression to symptomatic heart failure and may be candidates for surgical myectomy or catheter-based alcohol septal ablation.⁴ The patient in this case had a resting LVOT gradient of 131.8 mm Hg on echocardiography. The magnitude of this gradient placed the patient at a significantly higher risk of ventricular dysrhythmias and sudden cardiac death.⁵

Wall thickness also has prognostic implications. ⁶ Although any area of the myocardium can be affected, the septum is involved in about 90% cases. In their series of 48 patients followed over 6.5 years, Spirito et al found that the risk of sudden death in patients with HCM increased as wall thickness increased. For patients with a wall thickness of < 15 mm, the risk of death was 0 per 1000 person-years; however, this increased to 18.2 per 1000 person-years for patients with a wall thickness of > 30 mm.⁷

While many patients with HCM are asymptomatic, others may report dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, chest pain, palpitations, presyncope/ syncope, postural lightheadedness, fatigue, or edema. Symptomatology, however, is quite variable and does not necessarily correlate with the degree of outflow obstruction. Surprisingly, some patients with significant LVOT may have minimal symptoms, such as the patient in this case, while others with a lesser degree of LVOT obstruction may be very symptomatic.^3,4

Physical examination of a patient with HCM may be normal or may reveal nonspecific findings such as a fourth heart sound or a systolic murmur. In general, physical examination abnormalities are related to LVOT obstruction. Those patients without significant outflow obstruction may have a normal cardiac examination. While patients with HCM may have a variety of systolic murmurs, the 2 most common are those related to outflow tract obstruction and mitral regurgitation caused by systolic anterior motion of the mitral valve.⁴ The systolic murmur associated with significant LVOT obstruction has been described as a harsh, crescendo-decrescendo type that begins just after S1 and is heard best at the apex and lower left sternal border.⁴ It may radiate to the axilla and base but not generally into the neck. The murmur usually increases with Valsalva maneuver and decreases with handgrip or going from a standing to a sitting/ squatting position. The initial examination of the patient in this case was not suggestive of HOCM, as confirmed by 2 practitioners (a cardiologist and an internist), each with > 30 years of clinical experience. This may have been related to the patient’s hydration status at the time, with Valsalva maneuver increasing obstruction to the point of reduced flow.

About 90% of patients with HCM will have abnormalities on ECG, most commonly LV hypertrophy with a strain pattern. Other ECG findings include: (1) prominent abnormal Q waves, particularly in the inferior (II, III, and aVF) and lateral leads (I, aVL, and V4-V6), reflecting depolarization of a hypertrophied septum; (2) left axis deviation; (3) deeply inverted T waves in leads V2 through V4; and (4) P wave abnormalities indicative of left atrial (LA) or biatrial enlargement. ⁸ It is notable that the patient in this case had a normal ECG, given that a minority of patients with HCM have been shown to have a normal ECG.⁹

Echocardiography plays an important role in diagnosing HCM. Diagnostic criteria include the presence of asymmetric hypertrophy (most commonly with anterior septal involvement), systolic anterior motion of the mitral valve, a nondilated LV cavity, septal immobility, and premature closure of the aortic valve. LV thickness is measured at both the septum and free wall; values ≥ 15 mm, with a septal-to-free wall thickness ratio of ≥ 1.3, are suggestive of HCM. Asymmetric LV hypertrophy can also be seen in other segments besides the septum, such as the apex.¹⁰

HCM/HOCM is the most common cause of sudden cardiac death in young people. The condition also contributes to significant functional morbidity due to heart failure and increases the risk of atrial fibrillation and subsequent stroke. Treatments tend to focus on symptom relief and slowing disease progression and include the use of medications such as Β—blockers, nondihydropyridine calcium channel blockers, and the myosin inhibitor mavacamten.¹¹ Select patients, such as those with severe LVOT obstruction and symptoms despite treatment with Β—blockers or nondihydropyridine calcium channel blockers, may be offered septal myectomy or catheter-based alcohol septal ablation, coupled with insertion of an implantable cardiac defibrillator to prevent sudden cardiac death in patients at high arrhythmic risk.^1,12

Patients with HCM, particularly those with LVOT obstruction, pose distinct challenges to the anesthesiologist because they are highly sensitive to decreases in preload and afterload. These patients frequently experience adverse perioperative events such as myocardial ischemia, systemic hypotension, and supraventricular or ventricular arrhythmias. Acute congestive heart failure may also occur, presumably due to concomitant diastolic dysfunction. Patients with previously unrecognized HCM are of particular concern, as they may manifest unexpected and sudden hypotension with the induction of anesthesia. There may then be a paradoxical response to vasoactive drugs and anesthetic agents, which accentuate LVOT obstruction. In these circumstances, undiagnosed HCM should be considered, and intraoperative rescue transesophageal echocardiography be performed.¹³ Once the diagnosis is confirmed, efforts should be made to reduce myocardial contractility and sympathetic discharge (eg, with Β—blockers), increase afterload (eg, with α1 agonists), and improve preload with adequate hydration. Proper resuscitation of hypotensive patients with HCM requires a thorough understanding of disease pathology, as effective interventions may seem to be counterintuitive. Inotropic agents such as epinephrine are contraindicated in HCM because increased inotropy and chronotropy worsen LVOT obstruction. Volume status is often tenuous; while adequate preload is important, overly aggressive fluid resuscitation may promote heart failure. It is important to keep in mind that even patients without resting LVOT obstruction may develop dynamic obstruction with anesthesia induction due to sudden reductions in preload and afterload. It is also important to note that the degree of LV hypertrophy is directly correlated with arrhythmic sudden death. Those patients with LV wall thickness ≥ 30 mm are at increased risk for potentially lethal tachyarrhythmias in the operating room.¹⁴

These considerations reinforce the need for proper preoperative identification of patients with HCM. Heightened awareness is key, given the fact that HCM is relatively common and tends to be underdiagnosed in the general population. These patients are generally young, otherwise healthy, and often undergo minor operative procedures in outpatient settings. It is incumbent upon the preoperative evaluator to take a thorough medical history and perform a careful physical examination. Clues to the diagnosis include exertional dyspnea, fatigue, angina, syncope/presyncope, or a family history of sudden cardiac death or HCM. A systolic ejection murmur, particularly one that increases with standing or Valsalva maneuver, and decreases with squatting or handgrip may also raise clinical suspicion. These patients should undergo a full cardiac evaluation, including echocardiography.

CONCLUSIONS

HCM is a common condition that is important to diagnose in the preoperative clinic. Failure to do so can lead to catastrophic complications during induction of anesthesia due to the sudden reduction in preload and afterload, which may cause a significant increase in LVOT obstruction. A high index of suspicion is essential, as clinical diagnosis can be challenging. The physical examination may be deceiving and symptoms are often subtle and nonspecific. It is imperative to alert the anesthesiologist before surgery so the complex hemodynamic management of patients with HOCM can be appropriately managed.

Hypertrophic cardiomyopathy (HCM) is a relatively common inherited condition characterized by abnormal asymmetric left ventricular (LV) thickening. This can lead to LV outflow tract (LVOT) obstruction, which has important implications for anesthesia management. This article describes a case of previously undiagnosed HCM discovered during a preoperative physical examination prior to a routine surveillance colonoscopy.

CASE PRESENTATION

A 55-year-old Army veteran with a history of a sessile serrated colon adenoma presented to the preadmission testing clinic prior to planned surveillance colonoscopy under monitored anesthesia care. His medical history included untreated severe obstructive sleep apnea (53 apnea-hypopnea index score), diet-controlled hypertension, prediabetes (6.3% hemoglobin A_1c), hypogonadism, and obesity (41 body mass index). Medications included semaglutide 1.7 mg injected subcutaneously weekly and testosterone 200 mg injected intramuscularly every 2 weeks, as well as lisinopril-hydrochlorothiazide 10 to 12.5 mg daily, which had recently been discontinued because his blood pressure had improved with a low-sodium diet.

A review of systems was unremarkable except for progressive weight gain. The patient had no family history of sudden cardiac death. On physical examination, the patient’s blood pressure was 119/81 mm Hg, pulse was 86 beats/min, and respiratory rate was 18 breaths/min. The patient was clinically euvolemic, with no jugular venous distention or peripheral edema, and his lungs were clear to auscultation. There was, however, a soft, nonradiating grade 2/6 systolic murmur that had not been previously documented. The murmur decreased substantially with the Valsalva maneuver, with no change in hand grip.

Laboratory studies revealed hemoglobin and renal function were within the reference range. A routine 12-lead electrocardiogram (ECG) was unremarkable. A transthoracic echocardiogram revealed moderate pulmonary hypertension (59 mm Hg right ventricular systolic pressure), asymmetric LV hypertrophy (2.1 cm septal thickness), and severe LVOT obstruction (131.8 mm Hg gradient). Severe systolic anterior motion of the mitral valve was also present. The LV ejection fraction was 60% to 65%, with normal cavity size and systolic function. These findings were consistent with severe hypertrophic obstructive cardiomyopathy (HOCM). Upon more detailed questioning, the patient reported that over the previous 5 years he had experienced gradually decreasing exercise tolerance and mild dyspnea on exertion, particularly in hot weather, which he attributed to weight gain. He also reported a presyncopal episode the previous month while working in his garage in hot weather for a prolonged period of time.

The patient’s elective colonoscopy was canceled, and he was referred to cardiology. While awaiting cardiac consultation, he was instructed to maintain good hydration and avoid any heavy physical activity beyond walking. He was told not to resume his use of lisinopril-hydrochlorothiazide. A screening 7-day Holter monitor showed no ventricular or supraventricular ectopy. After cardiology consultation, the patient was referred to a HCM specialty clinic, where a cardiac magnetic resonance imaging confirmed severe asymmetric hypertrophy with resting obstruction (Figures 1-4). Treatment options were discussed with the patient, and he underwent a trial with the Β—blocker metoprolol 50 mg daily, which he could not tolerate. Verapamil extended-release 180 mg orally once daily was then initiated; however, his dyspnea persisted. He was amenable to surgical therapy and underwent septal myectomy, with 12 g of septal myocardium removed. He did well postoperatively, with a follow-up echocardiogram showing normal LV systolic function and no LVOT gradient detectable at rest or with Valsalva maneuver. His fatigue and exertional dyspnea significantly improved. Once the patient underwent septal myectomy and was determined to have no detectable LVOT gradient, he was approved for colonoscopy which has been scheduled but not completed.

DISCUSSION

Once thought rare, HCM is now considered to be a relatively common inherited disorder, occurring in about 1 in 500 persons, with some suggesting that the actual prevalence is closer to 1 in 200 persons.^1,2 Most often caused by mutations in ≥ 1 of 11 genes responsible for encoding cardiac sarcomere proteins, HCM is characterized by abnormal LV thickening without chamber enlargement in the absence of any identifiable cause, such as aortic valve stenosis or uncontrolled hypertension. The hypertrophy is often asymmetric, and in cases of asymmetric septal hypertrophy, dynamic LVOT obstruction can occur (known as HOCM). The condition is inherited in an autosomal dominant pattern with variable expression and is associated with myocardial fiber disarray, which can occur years before symptom onset.³ This myocardial disarray can lead to remodeling and an increased wall-to-lumen ratio of the coronary arteries, resulting in impaired coronary reserve.

Depending on the degree of LVOT obstruction, patients with HCM may be classified as nonobstructive, labile, or obstructive at rest. Patients without obstruction have an outflow gradient ≤ 30 mm Hg that is not provoked with Valsalva maneuver, administration of amyl nitrite, or exercise treadmill testing.³ Patients classified as labile do not have LVOT obstruction at rest, but obstruction may be induced by provocative measures. Finally, about one-third of patients with HCM will have LVOT gradients of > 30 mm Hg at rest. These patients are at increased risk for progression to symptomatic heart failure and may be candidates for surgical myectomy or catheter-based alcohol septal ablation.⁴ The patient in this case had a resting LVOT gradient of 131.8 mm Hg on echocardiography. The magnitude of this gradient placed the patient at a significantly higher risk of ventricular dysrhythmias and sudden cardiac death.⁵

Wall thickness also has prognostic implications. ⁶ Although any area of the myocardium can be affected, the septum is involved in about 90% cases. In their series of 48 patients followed over 6.5 years, Spirito et al found that the risk of sudden death in patients with HCM increased as wall thickness increased. For patients with a wall thickness of < 15 mm, the risk of death was 0 per 1000 person-years; however, this increased to 18.2 per 1000 person-years for patients with a wall thickness of > 30 mm.⁷

While many patients with HCM are asymptomatic, others may report dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, chest pain, palpitations, presyncope/ syncope, postural lightheadedness, fatigue, or edema. Symptomatology, however, is quite variable and does not necessarily correlate with the degree of outflow obstruction. Surprisingly, some patients with significant LVOT may have minimal symptoms, such as the patient in this case, while others with a lesser degree of LVOT obstruction may be very symptomatic.^3,4

Physical examination of a patient with HCM may be normal or may reveal nonspecific findings such as a fourth heart sound or a systolic murmur. In general, physical examination abnormalities are related to LVOT obstruction. Those patients without significant outflow obstruction may have a normal cardiac examination. While patients with HCM may have a variety of systolic murmurs, the 2 most common are those related to outflow tract obstruction and mitral regurgitation caused by systolic anterior motion of the mitral valve.⁴ The systolic murmur associated with significant LVOT obstruction has been described as a harsh, crescendo-decrescendo type that begins just after S1 and is heard best at the apex and lower left sternal border.⁴ It may radiate to the axilla and base but not generally into the neck. The murmur usually increases with Valsalva maneuver and decreases with handgrip or going from a standing to a sitting/ squatting position. The initial examination of the patient in this case was not suggestive of HOCM, as confirmed by 2 practitioners (a cardiologist and an internist), each with > 30 years of clinical experience. This may have been related to the patient’s hydration status at the time, with Valsalva maneuver increasing obstruction to the point of reduced flow.

About 90% of patients with HCM will have abnormalities on ECG, most commonly LV hypertrophy with a strain pattern. Other ECG findings include: (1) prominent abnormal Q waves, particularly in the inferior (II, III, and aVF) and lateral leads (I, aVL, and V4-V6), reflecting depolarization of a hypertrophied septum; (2) left axis deviation; (3) deeply inverted T waves in leads V2 through V4; and (4) P wave abnormalities indicative of left atrial (LA) or biatrial enlargement. ⁸ It is notable that the patient in this case had a normal ECG, given that a minority of patients with HCM have been shown to have a normal ECG.⁹

Echocardiography plays an important role in diagnosing HCM. Diagnostic criteria include the presence of asymmetric hypertrophy (most commonly with anterior septal involvement), systolic anterior motion of the mitral valve, a nondilated LV cavity, septal immobility, and premature closure of the aortic valve. LV thickness is measured at both the septum and free wall; values ≥ 15 mm, with a septal-to-free wall thickness ratio of ≥ 1.3, are suggestive of HCM. Asymmetric LV hypertrophy can also be seen in other segments besides the septum, such as the apex.¹⁰

HCM/HOCM is the most common cause of sudden cardiac death in young people. The condition also contributes to significant functional morbidity due to heart failure and increases the risk of atrial fibrillation and subsequent stroke. Treatments tend to focus on symptom relief and slowing disease progression and include the use of medications such as Β—blockers, nondihydropyridine calcium channel blockers, and the myosin inhibitor mavacamten.¹¹ Select patients, such as those with severe LVOT obstruction and symptoms despite treatment with Β—blockers or nondihydropyridine calcium channel blockers, may be offered septal myectomy or catheter-based alcohol septal ablation, coupled with insertion of an implantable cardiac defibrillator to prevent sudden cardiac death in patients at high arrhythmic risk.^1,12

Patients with HCM, particularly those with LVOT obstruction, pose distinct challenges to the anesthesiologist because they are highly sensitive to decreases in preload and afterload. These patients frequently experience adverse perioperative events such as myocardial ischemia, systemic hypotension, and supraventricular or ventricular arrhythmias. Acute congestive heart failure may also occur, presumably due to concomitant diastolic dysfunction. Patients with previously unrecognized HCM are of particular concern, as they may manifest unexpected and sudden hypotension with the induction of anesthesia. There may then be a paradoxical response to vasoactive drugs and anesthetic agents, which accentuate LVOT obstruction. In these circumstances, undiagnosed HCM should be considered, and intraoperative rescue transesophageal echocardiography be performed.¹³ Once the diagnosis is confirmed, efforts should be made to reduce myocardial contractility and sympathetic discharge (eg, with Β—blockers), increase afterload (eg, with α1 agonists), and improve preload with adequate hydration. Proper resuscitation of hypotensive patients with HCM requires a thorough understanding of disease pathology, as effective interventions may seem to be counterintuitive. Inotropic agents such as epinephrine are contraindicated in HCM because increased inotropy and chronotropy worsen LVOT obstruction. Volume status is often tenuous; while adequate preload is important, overly aggressive fluid resuscitation may promote heart failure. It is important to keep in mind that even patients without resting LVOT obstruction may develop dynamic obstruction with anesthesia induction due to sudden reductions in preload and afterload. It is also important to note that the degree of LV hypertrophy is directly correlated with arrhythmic sudden death. Those patients with LV wall thickness ≥ 30 mm are at increased risk for potentially lethal tachyarrhythmias in the operating room.¹⁴

These considerations reinforce the need for proper preoperative identification of patients with HCM. Heightened awareness is key, given the fact that HCM is relatively common and tends to be underdiagnosed in the general population. These patients are generally young, otherwise healthy, and often undergo minor operative procedures in outpatient settings. It is incumbent upon the preoperative evaluator to take a thorough medical history and perform a careful physical examination. Clues to the diagnosis include exertional dyspnea, fatigue, angina, syncope/presyncope, or a family history of sudden cardiac death or HCM. A systolic ejection murmur, particularly one that increases with standing or Valsalva maneuver, and decreases with squatting or handgrip may also raise clinical suspicion. These patients should undergo a full cardiac evaluation, including echocardiography.

CONCLUSIONS

HCM is a common condition that is important to diagnose in the preoperative clinic. Failure to do so can lead to catastrophic complications during induction of anesthesia due to the sudden reduction in preload and afterload, which may cause a significant increase in LVOT obstruction. A high index of suspicion is essential, as clinical diagnosis can be challenging. The physical examination may be deceiving and symptoms are often subtle and nonspecific. It is imperative to alert the anesthesiologist before surgery so the complex hemodynamic management of patients with HOCM can be appropriately managed.

Muscle-related complaints occur in 7% to 25% of patients taking statin medications.¹ In most instances, these adverse effects are quickly resolved when the medication is discontinued, but in rare occurrences, the statin can trigger an autoimmune response that progresses even after stopping use. This uncommon condition is typically accompanied by symmetrical proximal muscle weakness and an elevated CPK leading to a necrotizing myopathy requiring treatment with immunosuppressive therapy. Although less common, some patients may also present with dysphagia, myalgia, weight loss, and/or skin rash.¹

Statin medications have been the cornerstone of lipid-lowering therapy due to their mechanism of inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), which is the rate-limiting step within the cholesterol synthesis pathway to produce mevalonic acid. There is a proven genetic association with human leukocyte antigen (HLA)-DRB1*11:01 in adults and anti-HMGCR–associated myopathy.¹ The incidence of statin-induced necrotizing autoimmune myopathy (SINAM) in relation to each specific statin agent remains unknown; however, a systematic review of case reports found higher correlations for atorvastatin and simvastatin.²

There are 2 ways to confirm a SINAM diagnosis. The first and simplest includes checking for the presence of antibodies against HMGCR. The anti-HMGCR antibody test is typically used as a definitive diagnosis because it has a high specificity for SINAM.³ The second and more invasive diagnosis method involves a muscle biopsy, which is identified as positive if the biopsy shows the presence of necrotic muscle fibers.^1,3

The anti-HMGCR antibody test can serve as a marker for disease activity because the antibodies are strongly correlated with CPK levels.¹ CPK levels indicate the severity of muscle injury and is often used in addition to either of the confirmatory tests because it is faster and less expensive. Anti-HMGCR titers may remain positive while CPK returns to baseline when SINAM is dormant. In addition, clinicians may use an electromyography (EMG) test to measure the muscle response in association to nerve stimulation. ¹ This test can show potential features of myopathic lesions such as positive sharp waves, spontaneous fibrillations, or myotonic repetitive potentials.

Typical treatment includes glucocorticoids as first-line agents, but SINAM can be difficult to treat due to its complicated pathophysiology processes.³ Escalation of therapy is sometimes required beyond a single agent; in these complex scenarios, methotrexate and/or intravenous (IV) immunoglobulin (IVIG) therapy are frequently added to the steroid therapy. There have been concerns with steroid use in specific patient populations due to the undesired adverse effect (AE) profile, and as a result IVIG has been used as monotherapy at a dose of 2 g/kg per month.³ Studies looking at IVIG monotherapy showed a reduction in CPK levels and improvement in strength after just 2 to 3 rounds of monthly treatment.³ Some patients receiving IVIG monotherapy even achieved baseline strength and no longer reported muscle-related symptoms, although the total treatment duration varied. A systematic review of 39 articles where glucocorticoids, IVIG, methotrexate and/or a combination were used to treat SINAM found an average time to remission of 8.6 months. Additionally, this systematic review observed more patients returned to baseline or experienced improvement in symptoms when being treated with a combination of glucocorticoid plus IVIG plus methotrexate.² Suggested dosing recommendations are available in Table 1.

Patients diagnosed with HMGCR antibody myopathy are contraindicated for future statin therapy.¹ Rechallenge of statins in this patient population has led to worsening of disease and therefore these patients should have a severe statin allergy listed in their medical documentation record.

CASE PRESENTATION

A 59-year-old male patient with a medical history including atrial fibrillation, peripheral vascular disease, type 2 diabetes mellitus (T2DM), hypertension, and peripheral neuropathy was referred by his primary care clinical pharmacist practitioner for an outpatient neurology consult. The patient reported a 4-month history of fatigue, lower extremity paresthesia, and progressive proximal muscle weakness which began in his legs, mostly noticeable when walking upstairs but quickly developed into bilateral arm weakness. The patient reported significant impact on his quality of life: he could no longer lift his arms above his head and had difficulty with daily activities such as brushing his hair or getting up from a chair. He reported multiple falls at home, and began to use a cane for assistance with ambulation. He confirmed adherence to atorvastatin over the past year. Laboratory testing on the day of the visit revealed an elevated CPK level at 9729 mcg/L (reference range for men, 30-300 mcg/L).

The patient was urged to go to the emergency department where his CPK level had increased to 12,990 mcg/L (Figure 1). The workup began to find the source of rhabdomyolysis and elevated liver enzymes differentiating autoimmune vs medication-induced myopathy. Upon admission atorvastatin was discontinued, anti-HMGCR antibody level was ordered, and IV fluids were started.

After 8 days of hospital admission with minimal improvement, Rheumatology and Neurology services were consulted in the setting of persistent CPK elevation and the potential neuropathic component of muscle weakness. Both consulting services agreed to consider muscle biopsy and EMG if the patient did not begin to show signs of improvement. The patient’s CPK levels remained elevated with minimal change in muscle weakness. The next step was a right quadricep muscle biopsy performed on Day 14 of admission. Sixteen days after admission, the anti-HMGCR antibody test (originally obtained upon admission) was positive and elevated at 249 CU/mL (reference range, < 20 CU/mL negative; reference range, ≥ 60 CU/mL strong positive), which confirmed the SINAM diagnosis (Table 2).

On Day 17 of hospitalization, the Neurology service initiated IVIG monotherapy to avoid the undesired glycemic AEs associated with glucocorticoids. The patient had a history of T2DM that was difficult to manage and his hemoglobin A_1c level was the best it had ever been (6.2%) relative to a peak A_1c of 11.0% 9 months prior. The patient was treated with a total IVIG dose of 2 g/kg divided into 3 daily doses while still obtaining CPK levels with daily laboratory tests to assist with trending the extent of disease severity improvement (Figures 2-4). After a 20-day hospital stay, the patient was discharged home with rehabilitation services and a scheduled outpatient EMG the following week.

The patient continued to report generalized body weakness, pain, and deconditioning upon discharge and was unable to attend the EMG neurology appointment. The patient did eventually attend a follow-up appointment about 6 weeks after hospital discharge and reported continued weakness. The Neurology service prescribed a 2-day IVIG regimen (total dose = 2 g/kg) monthly for the next 2 months. The patient returned to the neurology clinic 8 weeks later following 2 rounds of IVIG posthospitalization and reported that his muscle strength was returning, and he was able to slowly reintroduce exercise into his daily routine. During a follow-up appointment about 11 months after the initial hospitalization, the patient’s primary care clinical pharmacist provided education of effective management of cholesterol without statins, including use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors as recommended by the Neurology service. At this time, the patient’s calculated low-density lipoprotein (LDL) was 110 mg/dL (reference range, 0-99 mg/dL). The patient preferred to work on a healthy diet and positive lifestyle choices before trialing any lipid lowering therapies.

The patient appeared to tolerate this treatment regimen following 7 rounds of IVIG. He noted fatigue for about 24 hours after his infusion sessions but otherwise reported no additional AEs. He has continued to attend weekly physical therapy sessions and is able to walk without the assistance of a cane. He can now walk a mile before he begins to feel fatigued or experience bilateral lower leg pain. The pain appears neuropathic in nature, as the patient reports ongoing “pins and needles” sensation in his legs and feet. The patient has noticed a major improvement in his overall function, strength, and exercise tolerance since starting IVIG treatments and although he is not yet back to his baseline, he is motivated to continue his recovery. Neurology is considering ongoing treatment with IVIG monthly infusions given his continued clinical improvement.

DISCUSSION

There is limited evidence on the use of IVIG monotherapy for SINAM, although it may be a viable option for patients deemed poor candidates for glucocorticoid or methotrexate therapy. This particularly applies to patients with DM for which there may be concerns for managing blood glucose levels with steroid use. The Johns Hopkins Myositis Center evaluated 3 patients with SINAM who declined glucocorticoid therapy and had documented DM and weakness in the proximal arms and legs. Following 2 to 3 monthly rounds of IVIG 2 g/kg monotherapy, these patients had reduced CPK levels and had improvement in both arm and hip-flexion strength. Two patients reported no muscle-related symptoms after completing IVIG monotherapy treatment for 9 and 19 months.³

The optimal treatment duration for IVIG monotherapy for SINAM is still uncertain given the limited available data. The patient in this case report showed clinically significant muscle-related improvement following 7 monthly rounds of 2 g/kg IVIG treatments. The mechanism of action for IVIG in this setting is still unknown, although the medication may allow muscle regeneration to surpass muscle destruction, thus leading to resolution of the muscle-related symptoms.³

There are numerous concerns with IVIG use to consider prior to initiating treatment, including expense, AEs, patient response, and comorbidities. IVIG is considerably more expensive than glucocorticoid and methotrexate alternatives. Systemic reactions have been shown to occur in 5% to 15% of patients receiving IVIG infusion.⁴ The majority of these infusion reactions occur early during infusion or within a few hours after administration is complete.⁵ Early AEs to monitor for include injection site reactions, flu-like symptoms, dermatologic reactions, anaphylaxis, transfusion-related acute lung injury, and transfusion-associated circulatory overload. Additional AEs may be delayed, including thromboembolic events, acute kidney injury, aseptic meningitis, hemolysis, neutropenia, and blood-borne infection.⁶ IVIG has a boxed warning for thrombosis, renal dysfunction, and acute renal failure risk.⁷ There are multiple strategies documented to reduce the risk of IVIG reactions including slowing the infusion rate, ensuring adequate hydration, and/or giving analgesics, antihistamines, or steroids prior to infusion.⁶ The patient in this case had monthly IVIG infusions without the need of any pretreatment medications and only reported fatigue for about 24 hours following the infusion.

An essential question is how to provide safe cholesterol management for patients with SINAM. Some evidence has suggested that other lipid-lowering medications that avoid the mevalonate pathway, such as fenofibrate or ezetimibe, may be used cautiously initially at lower doses.¹ Due to the severity of SINAM, it is crucial to closely monitor and ensure tolerability as new lipid-lowering agents are introduced. More evidence suggests that PCSK9 inhibitors are a safer option.⁸ PCSK9 inhibitors avoid the mevalonate pathway and block PCSK9 from binding to LDL receptors, allowing LDL to be removed from circulation.

Tiniakou et al followed 8 individuals for a mean 1.5 years who had anti-HMGCR immune-mediated myopathy at high cardiovascular risk. Muscle strength, CPK levels, and serum anti-HMGCR antibody titers were assessed at baseline and again after initiation of PCSK9 inhibitor. None of the patients experienced a decline in their muscle strength. CPK, anti-HMGCR antibody levels, and LDL trended down in all participants and 2 patients were able to reduce their immunosuppression treatment while still achieving clinical improvement. Tiniakou et al suggest that PCSK9 inhibitors are a safe and effective option to lower cholesterol in patients with SINAM.⁸

Alirocumab is the preferred PCSK9 inhibitor for patients at the US Department of Veterans Affairs (VA). The VA Pharmacy Benefits Management (PBM) Service guidance recommends alirocumab for patients with a history of atherosclerotic cardiovascular disease (ASCVD) or severe hypercholesterolemia.⁹ PBM guidance suggests alirocumab use for patients with a contraindication, intolerance, or insufficient LDL reduction with a maximally tolerated dose of statin and ezetimibe with a desire to reduce ASCVD risk by lowering LDL. Per the PBM Criteria for Use guidance, patients should follow the stepwise approach and trial ezetimibe prior to being considered for PCSK9 inhibitor therapy. Given the patient’s contraindication to future statin use and severity of myopathy, in this case the Neurology Service felt that the safest option to reach goal LDL reduction would be a PCSK9 inhibitor. Consideration can be made for alirocumab use when considering an alternative lipid lowering therapy.

CONCLUSIONS

This report demonstrates a case of SINAM caused by atorvastatin therapy. Patients presenting with proximal muscle weakness and elevated CPK even after statin discontinuation should be considered for a full workup to determine whether SINAM may be involved. This uncommon form of myopathy can be diagnosed based on the detection of anti-HMGCR antibodies and/or presence of necrosis on muscle biopsy. A combination of glucocorticoid, methotrexate, and IVIG is recommended for a patient’s best chance of muscle symptom improvement. IVIG monotherapy should be considered for patients with glycemic control concerns.

Muscle-related complaints occur in 7% to 25% of patients taking statin medications.¹ In most instances, these adverse effects are quickly resolved when the medication is discontinued, but in rare occurrences, the statin can trigger an autoimmune response that progresses even after stopping use. This uncommon condition is typically accompanied by symmetrical proximal muscle weakness and an elevated CPK leading to a necrotizing myopathy requiring treatment with immunosuppressive therapy. Although less common, some patients may also present with dysphagia, myalgia, weight loss, and/or skin rash.¹

Statin medications have been the cornerstone of lipid-lowering therapy due to their mechanism of inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), which is the rate-limiting step within the cholesterol synthesis pathway to produce mevalonic acid. There is a proven genetic association with human leukocyte antigen (HLA)-DRB1*11:01 in adults and anti-HMGCR–associated myopathy.¹ The incidence of statin-induced necrotizing autoimmune myopathy (SINAM) in relation to each specific statin agent remains unknown; however, a systematic review of case reports found higher correlations for atorvastatin and simvastatin.²

There are 2 ways to confirm a SINAM diagnosis. The first and simplest includes checking for the presence of antibodies against HMGCR. The anti-HMGCR antibody test is typically used as a definitive diagnosis because it has a high specificity for SINAM.³ The second and more invasive diagnosis method involves a muscle biopsy, which is identified as positive if the biopsy shows the presence of necrotic muscle fibers.^1,3

The anti-HMGCR antibody test can serve as a marker for disease activity because the antibodies are strongly correlated with CPK levels.¹ CPK levels indicate the severity of muscle injury and is often used in addition to either of the confirmatory tests because it is faster and less expensive. Anti-HMGCR titers may remain positive while CPK returns to baseline when SINAM is dormant. In addition, clinicians may use an electromyography (EMG) test to measure the muscle response in association to nerve stimulation. ¹ This test can show potential features of myopathic lesions such as positive sharp waves, spontaneous fibrillations, or myotonic repetitive potentials.

Typical treatment includes glucocorticoids as first-line agents, but SINAM can be difficult to treat due to its complicated pathophysiology processes.³ Escalation of therapy is sometimes required beyond a single agent; in these complex scenarios, methotrexate and/or intravenous (IV) immunoglobulin (IVIG) therapy are frequently added to the steroid therapy. There have been concerns with steroid use in specific patient populations due to the undesired adverse effect (AE) profile, and as a result IVIG has been used as monotherapy at a dose of 2 g/kg per month.³ Studies looking at IVIG monotherapy showed a reduction in CPK levels and improvement in strength after just 2 to 3 rounds of monthly treatment.³ Some patients receiving IVIG monotherapy even achieved baseline strength and no longer reported muscle-related symptoms, although the total treatment duration varied. A systematic review of 39 articles where glucocorticoids, IVIG, methotrexate and/or a combination were used to treat SINAM found an average time to remission of 8.6 months. Additionally, this systematic review observed more patients returned to baseline or experienced improvement in symptoms when being treated with a combination of glucocorticoid plus IVIG plus methotrexate.² Suggested dosing recommendations are available in Table 1.

Patients diagnosed with HMGCR antibody myopathy are contraindicated for future statin therapy.¹ Rechallenge of statins in this patient population has led to worsening of disease and therefore these patients should have a severe statin allergy listed in their medical documentation record.

CASE PRESENTATION

A 59-year-old male patient with a medical history including atrial fibrillation, peripheral vascular disease, type 2 diabetes mellitus (T2DM), hypertension, and peripheral neuropathy was referred by his primary care clinical pharmacist practitioner for an outpatient neurology consult. The patient reported a 4-month history of fatigue, lower extremity paresthesia, and progressive proximal muscle weakness which began in his legs, mostly noticeable when walking upstairs but quickly developed into bilateral arm weakness. The patient reported significant impact on his quality of life: he could no longer lift his arms above his head and had difficulty with daily activities such as brushing his hair or getting up from a chair. He reported multiple falls at home, and began to use a cane for assistance with ambulation. He confirmed adherence to atorvastatin over the past year. Laboratory testing on the day of the visit revealed an elevated CPK level at 9729 mcg/L (reference range for men, 30-300 mcg/L).

The patient was urged to go to the emergency department where his CPK level had increased to 12,990 mcg/L (Figure 1). The workup began to find the source of rhabdomyolysis and elevated liver enzymes differentiating autoimmune vs medication-induced myopathy. Upon admission atorvastatin was discontinued, anti-HMGCR antibody level was ordered, and IV fluids were started.

After 8 days of hospital admission with minimal improvement, Rheumatology and Neurology services were consulted in the setting of persistent CPK elevation and the potential neuropathic component of muscle weakness. Both consulting services agreed to consider muscle biopsy and EMG if the patient did not begin to show signs of improvement. The patient’s CPK levels remained elevated with minimal change in muscle weakness. The next step was a right quadricep muscle biopsy performed on Day 14 of admission. Sixteen days after admission, the anti-HMGCR antibody test (originally obtained upon admission) was positive and elevated at 249 CU/mL (reference range, < 20 CU/mL negative; reference range, ≥ 60 CU/mL strong positive), which confirmed the SINAM diagnosis (Table 2).

On Day 17 of hospitalization, the Neurology service initiated IVIG monotherapy to avoid the undesired glycemic AEs associated with glucocorticoids. The patient had a history of T2DM that was difficult to manage and his hemoglobin A_1c level was the best it had ever been (6.2%) relative to a peak A_1c of 11.0% 9 months prior. The patient was treated with a total IVIG dose of 2 g/kg divided into 3 daily doses while still obtaining CPK levels with daily laboratory tests to assist with trending the extent of disease severity improvement (Figures 2-4). After a 20-day hospital stay, the patient was discharged home with rehabilitation services and a scheduled outpatient EMG the following week.

The patient continued to report generalized body weakness, pain, and deconditioning upon discharge and was unable to attend the EMG neurology appointment. The patient did eventually attend a follow-up appointment about 6 weeks after hospital discharge and reported continued weakness. The Neurology service prescribed a 2-day IVIG regimen (total dose = 2 g/kg) monthly for the next 2 months. The patient returned to the neurology clinic 8 weeks later following 2 rounds of IVIG posthospitalization and reported that his muscle strength was returning, and he was able to slowly reintroduce exercise into his daily routine. During a follow-up appointment about 11 months after the initial hospitalization, the patient’s primary care clinical pharmacist provided education of effective management of cholesterol without statins, including use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors as recommended by the Neurology service. At this time, the patient’s calculated low-density lipoprotein (LDL) was 110 mg/dL (reference range, 0-99 mg/dL). The patient preferred to work on a healthy diet and positive lifestyle choices before trialing any lipid lowering therapies.

The patient appeared to tolerate this treatment regimen following 7 rounds of IVIG. He noted fatigue for about 24 hours after his infusion sessions but otherwise reported no additional AEs. He has continued to attend weekly physical therapy sessions and is able to walk without the assistance of a cane. He can now walk a mile before he begins to feel fatigued or experience bilateral lower leg pain. The pain appears neuropathic in nature, as the patient reports ongoing “pins and needles” sensation in his legs and feet. The patient has noticed a major improvement in his overall function, strength, and exercise tolerance since starting IVIG treatments and although he is not yet back to his baseline, he is motivated to continue his recovery. Neurology is considering ongoing treatment with IVIG monthly infusions given his continued clinical improvement.

DISCUSSION

There is limited evidence on the use of IVIG monotherapy for SINAM, although it may be a viable option for patients deemed poor candidates for glucocorticoid or methotrexate therapy. This particularly applies to patients with DM for which there may be concerns for managing blood glucose levels with steroid use. The Johns Hopkins Myositis Center evaluated 3 patients with SINAM who declined glucocorticoid therapy and had documented DM and weakness in the proximal arms and legs. Following 2 to 3 monthly rounds of IVIG 2 g/kg monotherapy, these patients had reduced CPK levels and had improvement in both arm and hip-flexion strength. Two patients reported no muscle-related symptoms after completing IVIG monotherapy treatment for 9 and 19 months.³

The optimal treatment duration for IVIG monotherapy for SINAM is still uncertain given the limited available data. The patient in this case report showed clinically significant muscle-related improvement following 7 monthly rounds of 2 g/kg IVIG treatments. The mechanism of action for IVIG in this setting is still unknown, although the medication may allow muscle regeneration to surpass muscle destruction, thus leading to resolution of the muscle-related symptoms.³

There are numerous concerns with IVIG use to consider prior to initiating treatment, including expense, AEs, patient response, and comorbidities. IVIG is considerably more expensive than glucocorticoid and methotrexate alternatives. Systemic reactions have been shown to occur in 5% to 15% of patients receiving IVIG infusion.⁴ The majority of these infusion reactions occur early during infusion or within a few hours after administration is complete.⁵ Early AEs to monitor for include injection site reactions, flu-like symptoms, dermatologic reactions, anaphylaxis, transfusion-related acute lung injury, and transfusion-associated circulatory overload. Additional AEs may be delayed, including thromboembolic events, acute kidney injury, aseptic meningitis, hemolysis, neutropenia, and blood-borne infection.⁶ IVIG has a boxed warning for thrombosis, renal dysfunction, and acute renal failure risk.⁷ There are multiple strategies documented to reduce the risk of IVIG reactions including slowing the infusion rate, ensuring adequate hydration, and/or giving analgesics, antihistamines, or steroids prior to infusion.⁶ The patient in this case had monthly IVIG infusions without the need of any pretreatment medications and only reported fatigue for about 24 hours following the infusion.

An essential question is how to provide safe cholesterol management for patients with SINAM. Some evidence has suggested that other lipid-lowering medications that avoid the mevalonate pathway, such as fenofibrate or ezetimibe, may be used cautiously initially at lower doses.¹ Due to the severity of SINAM, it is crucial to closely monitor and ensure tolerability as new lipid-lowering agents are introduced. More evidence suggests that PCSK9 inhibitors are a safer option.⁸ PCSK9 inhibitors avoid the mevalonate pathway and block PCSK9 from binding to LDL receptors, allowing LDL to be removed from circulation.

Tiniakou et al followed 8 individuals for a mean 1.5 years who had anti-HMGCR immune-mediated myopathy at high cardiovascular risk. Muscle strength, CPK levels, and serum anti-HMGCR antibody titers were assessed at baseline and again after initiation of PCSK9 inhibitor. None of the patients experienced a decline in their muscle strength. CPK, anti-HMGCR antibody levels, and LDL trended down in all participants and 2 patients were able to reduce their immunosuppression treatment while still achieving clinical improvement. Tiniakou et al suggest that PCSK9 inhibitors are a safe and effective option to lower cholesterol in patients with SINAM.⁸

Alirocumab is the preferred PCSK9 inhibitor for patients at the US Department of Veterans Affairs (VA). The VA Pharmacy Benefits Management (PBM) Service guidance recommends alirocumab for patients with a history of atherosclerotic cardiovascular disease (ASCVD) or severe hypercholesterolemia.⁹ PBM guidance suggests alirocumab use for patients with a contraindication, intolerance, or insufficient LDL reduction with a maximally tolerated dose of statin and ezetimibe with a desire to reduce ASCVD risk by lowering LDL. Per the PBM Criteria for Use guidance, patients should follow the stepwise approach and trial ezetimibe prior to being considered for PCSK9 inhibitor therapy. Given the patient’s contraindication to future statin use and severity of myopathy, in this case the Neurology Service felt that the safest option to reach goal LDL reduction would be a PCSK9 inhibitor. Consideration can be made for alirocumab use when considering an alternative lipid lowering therapy.

CONCLUSIONS

This report demonstrates a case of SINAM caused by atorvastatin therapy. Patients presenting with proximal muscle weakness and elevated CPK even after statin discontinuation should be considered for a full workup to determine whether SINAM may be involved. This uncommon form of myopathy can be diagnosed based on the detection of anti-HMGCR antibodies and/or presence of necrosis on muscle biopsy. A combination of glucocorticoid, methotrexate, and IVIG is recommended for a patient’s best chance of muscle symptom improvement. IVIG monotherapy should be considered for patients with glycemic control concerns.

Muscle-related complaints occur in 7% to 25% of patients taking statin medications.¹ In most instances, these adverse effects are quickly resolved when the medication is discontinued, but in rare occurrences, the statin can trigger an autoimmune response that progresses even after stopping use. This uncommon condition is typically accompanied by symmetrical proximal muscle weakness and an elevated CPK leading to a necrotizing myopathy requiring treatment with immunosuppressive therapy. Although less common, some patients may also present with dysphagia, myalgia, weight loss, and/or skin rash.¹

Statin medications have been the cornerstone of lipid-lowering therapy due to their mechanism of inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), which is the rate-limiting step within the cholesterol synthesis pathway to produce mevalonic acid. There is a proven genetic association with human leukocyte antigen (HLA)-DRB1*11:01 in adults and anti-HMGCR–associated myopathy.¹ The incidence of statin-induced necrotizing autoimmune myopathy (SINAM) in relation to each specific statin agent remains unknown; however, a systematic review of case reports found higher correlations for atorvastatin and simvastatin.²

There are 2 ways to confirm a SINAM diagnosis. The first and simplest includes checking for the presence of antibodies against HMGCR. The anti-HMGCR antibody test is typically used as a definitive diagnosis because it has a high specificity for SINAM.³ The second and more invasive diagnosis method involves a muscle biopsy, which is identified as positive if the biopsy shows the presence of necrotic muscle fibers.^1,3

The anti-HMGCR antibody test can serve as a marker for disease activity because the antibodies are strongly correlated with CPK levels.¹ CPK levels indicate the severity of muscle injury and is often used in addition to either of the confirmatory tests because it is faster and less expensive. Anti-HMGCR titers may remain positive while CPK returns to baseline when SINAM is dormant. In addition, clinicians may use an electromyography (EMG) test to measure the muscle response in association to nerve stimulation. ¹ This test can show potential features of myopathic lesions such as positive sharp waves, spontaneous fibrillations, or myotonic repetitive potentials.

Typical treatment includes glucocorticoids as first-line agents, but SINAM can be difficult to treat due to its complicated pathophysiology processes.³ Escalation of therapy is sometimes required beyond a single agent; in these complex scenarios, methotrexate and/or intravenous (IV) immunoglobulin (IVIG) therapy are frequently added to the steroid therapy. There have been concerns with steroid use in specific patient populations due to the undesired adverse effect (AE) profile, and as a result IVIG has been used as monotherapy at a dose of 2 g/kg per month.³ Studies looking at IVIG monotherapy showed a reduction in CPK levels and improvement in strength after just 2 to 3 rounds of monthly treatment.³ Some patients receiving IVIG monotherapy even achieved baseline strength and no longer reported muscle-related symptoms, although the total treatment duration varied. A systematic review of 39 articles where glucocorticoids, IVIG, methotrexate and/or a combination were used to treat SINAM found an average time to remission of 8.6 months. Additionally, this systematic review observed more patients returned to baseline or experienced improvement in symptoms when being treated with a combination of glucocorticoid plus IVIG plus methotrexate.² Suggested dosing recommendations are available in Table 1.

Patients diagnosed with HMGCR antibody myopathy are contraindicated for future statin therapy.¹ Rechallenge of statins in this patient population has led to worsening of disease and therefore these patients should have a severe statin allergy listed in their medical documentation record.

CASE PRESENTATION

A 59-year-old male patient with a medical history including atrial fibrillation, peripheral vascular disease, type 2 diabetes mellitus (T2DM), hypertension, and peripheral neuropathy was referred by his primary care clinical pharmacist practitioner for an outpatient neurology consult. The patient reported a 4-month history of fatigue, lower extremity paresthesia, and progressive proximal muscle weakness which began in his legs, mostly noticeable when walking upstairs but quickly developed into bilateral arm weakness. The patient reported significant impact on his quality of life: he could no longer lift his arms above his head and had difficulty with daily activities such as brushing his hair or getting up from a chair. He reported multiple falls at home, and began to use a cane for assistance with ambulation. He confirmed adherence to atorvastatin over the past year. Laboratory testing on the day of the visit revealed an elevated CPK level at 9729 mcg/L (reference range for men, 30-300 mcg/L).

The patient was urged to go to the emergency department where his CPK level had increased to 12,990 mcg/L (Figure 1). The workup began to find the source of rhabdomyolysis and elevated liver enzymes differentiating autoimmune vs medication-induced myopathy. Upon admission atorvastatin was discontinued, anti-HMGCR antibody level was ordered, and IV fluids were started.

After 8 days of hospital admission with minimal improvement, Rheumatology and Neurology services were consulted in the setting of persistent CPK elevation and the potential neuropathic component of muscle weakness. Both consulting services agreed to consider muscle biopsy and EMG if the patient did not begin to show signs of improvement. The patient’s CPK levels remained elevated with minimal change in muscle weakness. The next step was a right quadricep muscle biopsy performed on Day 14 of admission. Sixteen days after admission, the anti-HMGCR antibody test (originally obtained upon admission) was positive and elevated at 249 CU/mL (reference range, < 20 CU/mL negative; reference range, ≥ 60 CU/mL strong positive), which confirmed the SINAM diagnosis (Table 2).

On Day 17 of hospitalization, the Neurology service initiated IVIG monotherapy to avoid the undesired glycemic AEs associated with glucocorticoids. The patient had a history of T2DM that was difficult to manage and his hemoglobin A_1c level was the best it had ever been (6.2%) relative to a peak A_1c of 11.0% 9 months prior. The patient was treated with a total IVIG dose of 2 g/kg divided into 3 daily doses while still obtaining CPK levels with daily laboratory tests to assist with trending the extent of disease severity improvement (Figures 2-4). After a 20-day hospital stay, the patient was discharged home with rehabilitation services and a scheduled outpatient EMG the following week.

The patient continued to report generalized body weakness, pain, and deconditioning upon discharge and was unable to attend the EMG neurology appointment. The patient did eventually attend a follow-up appointment about 6 weeks after hospital discharge and reported continued weakness. The Neurology service prescribed a 2-day IVIG regimen (total dose = 2 g/kg) monthly for the next 2 months. The patient returned to the neurology clinic 8 weeks later following 2 rounds of IVIG posthospitalization and reported that his muscle strength was returning, and he was able to slowly reintroduce exercise into his daily routine. During a follow-up appointment about 11 months after the initial hospitalization, the patient’s primary care clinical pharmacist provided education of effective management of cholesterol without statins, including use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors as recommended by the Neurology service. At this time, the patient’s calculated low-density lipoprotein (LDL) was 110 mg/dL (reference range, 0-99 mg/dL). The patient preferred to work on a healthy diet and positive lifestyle choices before trialing any lipid lowering therapies.

The patient appeared to tolerate this treatment regimen following 7 rounds of IVIG. He noted fatigue for about 24 hours after his infusion sessions but otherwise reported no additional AEs. He has continued to attend weekly physical therapy sessions and is able to walk without the assistance of a cane. He can now walk a mile before he begins to feel fatigued or experience bilateral lower leg pain. The pain appears neuropathic in nature, as the patient reports ongoing “pins and needles” sensation in his legs and feet. The patient has noticed a major improvement in his overall function, strength, and exercise tolerance since starting IVIG treatments and although he is not yet back to his baseline, he is motivated to continue his recovery. Neurology is considering ongoing treatment with IVIG monthly infusions given his continued clinical improvement.

DISCUSSION

There is limited evidence on the use of IVIG monotherapy for SINAM, although it may be a viable option for patients deemed poor candidates for glucocorticoid or methotrexate therapy. This particularly applies to patients with DM for which there may be concerns for managing blood glucose levels with steroid use. The Johns Hopkins Myositis Center evaluated 3 patients with SINAM who declined glucocorticoid therapy and had documented DM and weakness in the proximal arms and legs. Following 2 to 3 monthly rounds of IVIG 2 g/kg monotherapy, these patients had reduced CPK levels and had improvement in both arm and hip-flexion strength. Two patients reported no muscle-related symptoms after completing IVIG monotherapy treatment for 9 and 19 months.³

The optimal treatment duration for IVIG monotherapy for SINAM is still uncertain given the limited available data. The patient in this case report showed clinically significant muscle-related improvement following 7 monthly rounds of 2 g/kg IVIG treatments. The mechanism of action for IVIG in this setting is still unknown, although the medication may allow muscle regeneration to surpass muscle destruction, thus leading to resolution of the muscle-related symptoms.³

There are numerous concerns with IVIG use to consider prior to initiating treatment, including expense, AEs, patient response, and comorbidities. IVIG is considerably more expensive than glucocorticoid and methotrexate alternatives. Systemic reactions have been shown to occur in 5% to 15% of patients receiving IVIG infusion.⁴ The majority of these infusion reactions occur early during infusion or within a few hours after administration is complete.⁵ Early AEs to monitor for include injection site reactions, flu-like symptoms, dermatologic reactions, anaphylaxis, transfusion-related acute lung injury, and transfusion-associated circulatory overload. Additional AEs may be delayed, including thromboembolic events, acute kidney injury, aseptic meningitis, hemolysis, neutropenia, and blood-borne infection.⁶ IVIG has a boxed warning for thrombosis, renal dysfunction, and acute renal failure risk.⁷ There are multiple strategies documented to reduce the risk of IVIG reactions including slowing the infusion rate, ensuring adequate hydration, and/or giving analgesics, antihistamines, or steroids prior to infusion.⁶ The patient in this case had monthly IVIG infusions without the need of any pretreatment medications and only reported fatigue for about 24 hours following the infusion.

An essential question is how to provide safe cholesterol management for patients with SINAM. Some evidence has suggested that other lipid-lowering medications that avoid the mevalonate pathway, such as fenofibrate or ezetimibe, may be used cautiously initially at lower doses.¹ Due to the severity of SINAM, it is crucial to closely monitor and ensure tolerability as new lipid-lowering agents are introduced. More evidence suggests that PCSK9 inhibitors are a safer option.⁸ PCSK9 inhibitors avoid the mevalonate pathway and block PCSK9 from binding to LDL receptors, allowing LDL to be removed from circulation.

Tiniakou et al followed 8 individuals for a mean 1.5 years who had anti-HMGCR immune-mediated myopathy at high cardiovascular risk. Muscle strength, CPK levels, and serum anti-HMGCR antibody titers were assessed at baseline and again after initiation of PCSK9 inhibitor. None of the patients experienced a decline in their muscle strength. CPK, anti-HMGCR antibody levels, and LDL trended down in all participants and 2 patients were able to reduce their immunosuppression treatment while still achieving clinical improvement. Tiniakou et al suggest that PCSK9 inhibitors are a safe and effective option to lower cholesterol in patients with SINAM.⁸

Alirocumab is the preferred PCSK9 inhibitor for patients at the US Department of Veterans Affairs (VA). The VA Pharmacy Benefits Management (PBM) Service guidance recommends alirocumab for patients with a history of atherosclerotic cardiovascular disease (ASCVD) or severe hypercholesterolemia.⁹ PBM guidance suggests alirocumab use for patients with a contraindication, intolerance, or insufficient LDL reduction with a maximally tolerated dose of statin and ezetimibe with a desire to reduce ASCVD risk by lowering LDL. Per the PBM Criteria for Use guidance, patients should follow the stepwise approach and trial ezetimibe prior to being considered for PCSK9 inhibitor therapy. Given the patient’s contraindication to future statin use and severity of myopathy, in this case the Neurology Service felt that the safest option to reach goal LDL reduction would be a PCSK9 inhibitor. Consideration can be made for alirocumab use when considering an alternative lipid lowering therapy.

CONCLUSIONS

This report demonstrates a case of SINAM caused by atorvastatin therapy. Patients presenting with proximal muscle weakness and elevated CPK even after statin discontinuation should be considered for a full workup to determine whether SINAM may be involved. This uncommon form of myopathy can be diagnosed based on the detection of anti-HMGCR antibodies and/or presence of necrosis on muscle biopsy. A combination of glucocorticoid, methotrexate, and IVIG is recommended for a patient’s best chance of muscle symptom improvement. IVIG monotherapy should be considered for patients with glycemic control concerns.

Prosthetic joint infection (PJI) occurs in about 1% to 2% of joint replacements. ¹ Risk factors include immunosuppression, diabetes, chronic illnesses, and prolonged operative time.² Bacterial infections constitute most of these infections, while fungal pathogens account for about 1%. Candida (C.) species, predominantly C. albicans, are responsible for most PJIs.^1,3 In contrast, C. glabrata is a rare cause of fungal PJI, with only 18 PJI cases currently reported in the literature.⁴ C. glabrata PJI occurs more frequently among immunosuppressed patients and is associated with a higher treatment failure rate despite antifungal therapy.⁵ Treatment of fungal PJI is often complicated, involving multiple surgical debridements, prolonged antifungal therapy, and in some cases, prosthesis removal.⁶ However, given the rarity of C. glabrata as a PJI pathogen, no standardized treatment guidelines exist, leading to potential delays in diagnosis and tailored treatment.^7,8

CASE PRESENTATION

A male Vietnam veteran aged 75 years presented to the emergency department in July 2023 with a fluid collection over his left hip surgical incision site. The patient had a complex medical history that included chronic kidney disease, well-controlled type 2 diabetes, hypertension, and osteoarthritis. His history was further complicated by nonalcoholic steatohepatitis with hepatocellular carcinoma that was treated with transarterial radioembolization and yttrium-90. The patient had undergone a left total hip arthroplasty in 1996 and subsequent open reduction and internal fixation about 9 months prior to his presentation. The patient reported the fluid had been present for about 6 weeks, while he received outpatient monitoring by the orthopedic surgery service. He sought emergency care after noting a moderate amount of purulent discharge on his clothing originating from his hip. In the week prior to admission, the patient observed progressive erythema, warmth, and tenderness over the incision site. Despite these symptoms, the patient remained ambulatory and able to walk long distances with the use of an assistive device.

Upon presentation, the patient was afebrile and normotensive. Laboratory testing revealed an elevated erythrocyte sedimentation rate of 77 mm/h (reference range, 0-20 mm/h) and a C-reactive protein of 9.8 mg/L (reference range, 0-2.5 mg/L), suggesting an underlying infectious process. A physical examination revealed a well-healed incision over the left hip with a poorly defined area of fluctuance and evidence of wound dehiscence. The left lower extremity was swollen with 2+ pitting edema, but tenderness was localized to the incision site. Magnetic resonance imaging of the left hip revealed a multiloculated fluid collection abutting the left greater trochanter with extension to the skin surface and inferior extension along the entire length of the surgical fixation hardware (Figure).

Upon admission, orthopedic surgery performed a bedside aspiration of the fluid collection. Samples were sent for analysis, including cell count and bacterial and fungal cultures. Initial blood cultures were sterile. Due to concerns for a bacterial infection, the patient was started on empiric intravenous (IV) ceftriaxone 2 g/day and IV vancomycin 1250 mg/day. Synovial fluid analysis revealed an elevated white blood cell count of 45,000/ìL, but bacterial cultures were negative. Five days after admission, the fungal culture from the left hip wound was notable for presence of C. glabrata, prompting an infectious diseases (ID) consultation. IV micafungin 100 mg/day was initiated as empiric antifungal therapy.

ID and orthopedic surgery teams determined that a combined medical and surgical approach would be best suited for infection control. They proposed 2 main approaches: complete hardware replacement with washout, which carried a higher morbidity risk but a better chance of infection resolution, or partial hardware replacement with washout, which was associated with a lower morbidity risk but a higher risk of infection persistence and recurrence. This decision was particularly challenging for the patient, who prioritized maintaining his functional status, including his ability to continue dancing for pleasure. The patient opted for a more conservative approach, electing to proceed with antifungal therapy and debridement while retaining the prosthetic joint.

After 11 days of hospitalization, the patient was discharged with a peripherally inserted central catheter for long-term antifungal infusions of micafungin 150 mg/day at home. Fungal sensitivity test results several days after discharge confirmed susceptibility to micafungin.

About 2 weeks after discharge, the patient underwent debridement and implant retention (DAIR). Wound cultures were positive for C. glabrata, Enterococcus faecalis, Staphylococcus epidermidis, and Corynebacterium tuberculostearicum. Based on susceptibilities, he completed a 2-month course of IV micafungin 150 mg daily and daptomycin 750 mg daily, followed by an oral suppressive regimen consisting of doxycycline 100 mg twice daily, amoxicillin-clavulanate 2 g twice daily, and fluconazole initially 800 mg daily adjusted to 400 mg daily. The patient continued wound management with twice-daily dressing changes.

Nine months after DAIR, the patient remained on suppressive antifungal and antibacterial therapy. He continued to experience serous drainage from the wound, which greatly affected his quality of life. After discussion with his family and the orthopedic surgery team, he agreed to proceed with a 2-staged revision arthroplasty involving prosthetic explant and antibiotic spacer placement. However, the surgery was postponed due to findings of anemia (hemoglobin, 8.9 g/dL) and thrombocytopenia (platelet count, 73 x 10³/λL). At the time of this report, the patient was being monitored closely with his multidisciplinary care team for the planned orthopedic procedure.

DISCUSSION

PJI is the most common cause of primary hip arthroplasty failure; however, fungal species only make up about 1% of PJIs.^3,9-11 Patients are typically immunocompromised, undergoing antineoplastic therapies for malignancy, or have other comorbid conditions such as diabetes.^12,13 C. glabrata presents a unique diagnostic and therapeutic challenge as it is not only rare but also notorious for its resistance to common antifungal agents. C. glabrata is known to develop multidrug resistance through the rapid accumulation of genomic mutations.¹⁴ Its propensity towards forming protective biofilm also arms it with intrinsic resistance to agents like fluconazole.¹⁵ Furthermore, based on a review of the available reports in the literature, C. glabrata PJIs are often insidious and present with symptoms closely mimicking those of bacterial PJIs, as it did in the patient in this case.¹⁶

Synovial fluid analysis, fungal cultures, and sensitivity testing are paramount for ensuring proper diagnosis for fungal PJI. The patient in this case was empirically treated with micafungin based on recommendations from the ID team. When the sensitivities results were reviewed, the same antifungal therapy was continued. Echinocandins have a favorable toxicity profile in long-term use, as well as efficacy against biofilm-producing organisms like C. glabrata.^17,18

While there are a few cases citing DAIR as a feasible surgical strategy for treating fungal PJI, more recent studies have reported greater success with a 2-staged revision arthroplasty involving some combination of debridement, placement of antibiotic-loaded bone cement spacers, and partial or total exchange of the infected prosthetic joint.^4,19-23 In this case, complete hardware replacement would have offered the patient the most favorable outlook for eliminating this fungal infection. However, given the patient’s advanced age, significant underlying comorbidities, and functional status, medical management with antifungal therapy and DAIR was favored.

Based on the discussion from the 6-month follow-up visit, the patient was experiencing progressive and persistent wound drainage and frequent dressing changes, highlighting the limitations of medical management for PJI in the setting of retained prosthesis. If the patient ultimately proceeds with a more invasive surgical intervention, another important consideration will be the likelihood of fungal PJI recurrence. At present, fungal PJI recurrence rates following antifungal and surgical treatment have been reported to range between 0% to 50%, which is too imprecise to be considered clinically useful.^22-24

Given the ambiguity surrounding management guidelines and limited treatment options, it is crucial to emphasize the timeline of this patient’s clinical presentation and subsequent course of treatment. Upon presentation to the ED in late July, fungal PJI was considered less likely. Initial blood cultures from presentation were negative, which is common with PJIs. It was not until 5 days later that the left hip wound culture showed moderate growth of C. glabrata. Identifying a PJI is clinically challenging due to the lack of standardized diagnostic criteria. However, timely identification and diagnosis of fungal PJI with appropriate antifungal therapy, in patients with limited curative options due to comorbidities, can significantly improve quality of life and overall outcomes.²⁵ Routine fungal and mycobacterial cultures are not currently recommended in PJI guidelines, but this case illustrates it is imperative in immunocompromised hosts.²⁶

This case and the current paucity of similar cases in the literature stress the importance of clinicians publishing their experience in the management of fungal PJI. We strongly recommend that clinicians approach each suspected PJI with careful consideration of the patient’s unique risk factors, comorbidities, and goals of care, when deciding on a curative vs suppressive approach to therapy.

CONCLUSIONS

This case report highlights the importance of considering fungal pathogens for PJIs, especially in high-risk patients, the value of obtaining fungal cultures, the necessity of a multidisciplinary approach, the role of antifungal susceptibility testing, and consideration for the feasibility of a surgical intervention. It underscores the challenges in diagnosis and treatment of C. glabrata-associated PJI, emphasizing the importance of clinician experience-sharing in developing evidence-based management strategies. As the understanding of fungal PJI evolves, continued research and clinical data collection remain crucial for improving patient outcomes in the management of these complex cases.

Prosthetic joint infection (PJI) occurs in about 1% to 2% of joint replacements. ¹ Risk factors include immunosuppression, diabetes, chronic illnesses, and prolonged operative time.² Bacterial infections constitute most of these infections, while fungal pathogens account for about 1%. Candida (C.) species, predominantly C. albicans, are responsible for most PJIs.^1,3 In contrast, C. glabrata is a rare cause of fungal PJI, with only 18 PJI cases currently reported in the literature.⁴ C. glabrata PJI occurs more frequently among immunosuppressed patients and is associated with a higher treatment failure rate despite antifungal therapy.⁵ Treatment of fungal PJI is often complicated, involving multiple surgical debridements, prolonged antifungal therapy, and in some cases, prosthesis removal.⁶ However, given the rarity of C. glabrata as a PJI pathogen, no standardized treatment guidelines exist, leading to potential delays in diagnosis and tailored treatment.^7,8

CASE PRESENTATION

A male Vietnam veteran aged 75 years presented to the emergency department in July 2023 with a fluid collection over his left hip surgical incision site. The patient had a complex medical history that included chronic kidney disease, well-controlled type 2 diabetes, hypertension, and osteoarthritis. His history was further complicated by nonalcoholic steatohepatitis with hepatocellular carcinoma that was treated with transarterial radioembolization and yttrium-90. The patient had undergone a left total hip arthroplasty in 1996 and subsequent open reduction and internal fixation about 9 months prior to his presentation. The patient reported the fluid had been present for about 6 weeks, while he received outpatient monitoring by the orthopedic surgery service. He sought emergency care after noting a moderate amount of purulent discharge on his clothing originating from his hip. In the week prior to admission, the patient observed progressive erythema, warmth, and tenderness over the incision site. Despite these symptoms, the patient remained ambulatory and able to walk long distances with the use of an assistive device.

Upon presentation, the patient was afebrile and normotensive. Laboratory testing revealed an elevated erythrocyte sedimentation rate of 77 mm/h (reference range, 0-20 mm/h) and a C-reactive protein of 9.8 mg/L (reference range, 0-2.5 mg/L), suggesting an underlying infectious process. A physical examination revealed a well-healed incision over the left hip with a poorly defined area of fluctuance and evidence of wound dehiscence. The left lower extremity was swollen with 2+ pitting edema, but tenderness was localized to the incision site. Magnetic resonance imaging of the left hip revealed a multiloculated fluid collection abutting the left greater trochanter with extension to the skin surface and inferior extension along the entire length of the surgical fixation hardware (Figure).

Upon admission, orthopedic surgery performed a bedside aspiration of the fluid collection. Samples were sent for analysis, including cell count and bacterial and fungal cultures. Initial blood cultures were sterile. Due to concerns for a bacterial infection, the patient was started on empiric intravenous (IV) ceftriaxone 2 g/day and IV vancomycin 1250 mg/day. Synovial fluid analysis revealed an elevated white blood cell count of 45,000/ìL, but bacterial cultures were negative. Five days after admission, the fungal culture from the left hip wound was notable for presence of C. glabrata, prompting an infectious diseases (ID) consultation. IV micafungin 100 mg/day was initiated as empiric antifungal therapy.

ID and orthopedic surgery teams determined that a combined medical and surgical approach would be best suited for infection control. They proposed 2 main approaches: complete hardware replacement with washout, which carried a higher morbidity risk but a better chance of infection resolution, or partial hardware replacement with washout, which was associated with a lower morbidity risk but a higher risk of infection persistence and recurrence. This decision was particularly challenging for the patient, who prioritized maintaining his functional status, including his ability to continue dancing for pleasure. The patient opted for a more conservative approach, electing to proceed with antifungal therapy and debridement while retaining the prosthetic joint.

After 11 days of hospitalization, the patient was discharged with a peripherally inserted central catheter for long-term antifungal infusions of micafungin 150 mg/day at home. Fungal sensitivity test results several days after discharge confirmed susceptibility to micafungin.

About 2 weeks after discharge, the patient underwent debridement and implant retention (DAIR). Wound cultures were positive for C. glabrata, Enterococcus faecalis, Staphylococcus epidermidis, and Corynebacterium tuberculostearicum. Based on susceptibilities, he completed a 2-month course of IV micafungin 150 mg daily and daptomycin 750 mg daily, followed by an oral suppressive regimen consisting of doxycycline 100 mg twice daily, amoxicillin-clavulanate 2 g twice daily, and fluconazole initially 800 mg daily adjusted to 400 mg daily. The patient continued wound management with twice-daily dressing changes.

Nine months after DAIR, the patient remained on suppressive antifungal and antibacterial therapy. He continued to experience serous drainage from the wound, which greatly affected his quality of life. After discussion with his family and the orthopedic surgery team, he agreed to proceed with a 2-staged revision arthroplasty involving prosthetic explant and antibiotic spacer placement. However, the surgery was postponed due to findings of anemia (hemoglobin, 8.9 g/dL) and thrombocytopenia (platelet count, 73 x 10³/λL). At the time of this report, the patient was being monitored closely with his multidisciplinary care team for the planned orthopedic procedure.

DISCUSSION

PJI is the most common cause of primary hip arthroplasty failure; however, fungal species only make up about 1% of PJIs.^3,9-11 Patients are typically immunocompromised, undergoing antineoplastic therapies for malignancy, or have other comorbid conditions such as diabetes.^12,13 C. glabrata presents a unique diagnostic and therapeutic challenge as it is not only rare but also notorious for its resistance to common antifungal agents. C. glabrata is known to develop multidrug resistance through the rapid accumulation of genomic mutations.¹⁴ Its propensity towards forming protective biofilm also arms it with intrinsic resistance to agents like fluconazole.¹⁵ Furthermore, based on a review of the available reports in the literature, C. glabrata PJIs are often insidious and present with symptoms closely mimicking those of bacterial PJIs, as it did in the patient in this case.¹⁶

Synovial fluid analysis, fungal cultures, and sensitivity testing are paramount for ensuring proper diagnosis for fungal PJI. The patient in this case was empirically treated with micafungin based on recommendations from the ID team. When the sensitivities results were reviewed, the same antifungal therapy was continued. Echinocandins have a favorable toxicity profile in long-term use, as well as efficacy against biofilm-producing organisms like C. glabrata.^17,18

While there are a few cases citing DAIR as a feasible surgical strategy for treating fungal PJI, more recent studies have reported greater success with a 2-staged revision arthroplasty involving some combination of debridement, placement of antibiotic-loaded bone cement spacers, and partial or total exchange of the infected prosthetic joint.^4,19-23 In this case, complete hardware replacement would have offered the patient the most favorable outlook for eliminating this fungal infection. However, given the patient’s advanced age, significant underlying comorbidities, and functional status, medical management with antifungal therapy and DAIR was favored.

Based on the discussion from the 6-month follow-up visit, the patient was experiencing progressive and persistent wound drainage and frequent dressing changes, highlighting the limitations of medical management for PJI in the setting of retained prosthesis. If the patient ultimately proceeds with a more invasive surgical intervention, another important consideration will be the likelihood of fungal PJI recurrence. At present, fungal PJI recurrence rates following antifungal and surgical treatment have been reported to range between 0% to 50%, which is too imprecise to be considered clinically useful.^22-24

Given the ambiguity surrounding management guidelines and limited treatment options, it is crucial to emphasize the timeline of this patient’s clinical presentation and subsequent course of treatment. Upon presentation to the ED in late July, fungal PJI was considered less likely. Initial blood cultures from presentation were negative, which is common with PJIs. It was not until 5 days later that the left hip wound culture showed moderate growth of C. glabrata. Identifying a PJI is clinically challenging due to the lack of standardized diagnostic criteria. However, timely identification and diagnosis of fungal PJI with appropriate antifungal therapy, in patients with limited curative options due to comorbidities, can significantly improve quality of life and overall outcomes.²⁵ Routine fungal and mycobacterial cultures are not currently recommended in PJI guidelines, but this case illustrates it is imperative in immunocompromised hosts.²⁶

This case and the current paucity of similar cases in the literature stress the importance of clinicians publishing their experience in the management of fungal PJI. We strongly recommend that clinicians approach each suspected PJI with careful consideration of the patient’s unique risk factors, comorbidities, and goals of care, when deciding on a curative vs suppressive approach to therapy.

CONCLUSIONS

This case report highlights the importance of considering fungal pathogens for PJIs, especially in high-risk patients, the value of obtaining fungal cultures, the necessity of a multidisciplinary approach, the role of antifungal susceptibility testing, and consideration for the feasibility of a surgical intervention. It underscores the challenges in diagnosis and treatment of C. glabrata-associated PJI, emphasizing the importance of clinician experience-sharing in developing evidence-based management strategies. As the understanding of fungal PJI evolves, continued research and clinical data collection remain crucial for improving patient outcomes in the management of these complex cases.

Prosthetic joint infection (PJI) occurs in about 1% to 2% of joint replacements. ¹ Risk factors include immunosuppression, diabetes, chronic illnesses, and prolonged operative time.² Bacterial infections constitute most of these infections, while fungal pathogens account for about 1%. Candida (C.) species, predominantly C. albicans, are responsible for most PJIs.^1,3 In contrast, C. glabrata is a rare cause of fungal PJI, with only 18 PJI cases currently reported in the literature.⁴ C. glabrata PJI occurs more frequently among immunosuppressed patients and is associated with a higher treatment failure rate despite antifungal therapy.⁵ Treatment of fungal PJI is often complicated, involving multiple surgical debridements, prolonged antifungal therapy, and in some cases, prosthesis removal.⁶ However, given the rarity of C. glabrata as a PJI pathogen, no standardized treatment guidelines exist, leading to potential delays in diagnosis and tailored treatment.^7,8

CASE PRESENTATION

A male Vietnam veteran aged 75 years presented to the emergency department in July 2023 with a fluid collection over his left hip surgical incision site. The patient had a complex medical history that included chronic kidney disease, well-controlled type 2 diabetes, hypertension, and osteoarthritis. His history was further complicated by nonalcoholic steatohepatitis with hepatocellular carcinoma that was treated with transarterial radioembolization and yttrium-90. The patient had undergone a left total hip arthroplasty in 1996 and subsequent open reduction and internal fixation about 9 months prior to his presentation. The patient reported the fluid had been present for about 6 weeks, while he received outpatient monitoring by the orthopedic surgery service. He sought emergency care after noting a moderate amount of purulent discharge on his clothing originating from his hip. In the week prior to admission, the patient observed progressive erythema, warmth, and tenderness over the incision site. Despite these symptoms, the patient remained ambulatory and able to walk long distances with the use of an assistive device.

Upon presentation, the patient was afebrile and normotensive. Laboratory testing revealed an elevated erythrocyte sedimentation rate of 77 mm/h (reference range, 0-20 mm/h) and a C-reactive protein of 9.8 mg/L (reference range, 0-2.5 mg/L), suggesting an underlying infectious process. A physical examination revealed a well-healed incision over the left hip with a poorly defined area of fluctuance and evidence of wound dehiscence. The left lower extremity was swollen with 2+ pitting edema, but tenderness was localized to the incision site. Magnetic resonance imaging of the left hip revealed a multiloculated fluid collection abutting the left greater trochanter with extension to the skin surface and inferior extension along the entire length of the surgical fixation hardware (Figure).

Upon admission, orthopedic surgery performed a bedside aspiration of the fluid collection. Samples were sent for analysis, including cell count and bacterial and fungal cultures. Initial blood cultures were sterile. Due to concerns for a bacterial infection, the patient was started on empiric intravenous (IV) ceftriaxone 2 g/day and IV vancomycin 1250 mg/day. Synovial fluid analysis revealed an elevated white blood cell count of 45,000/ìL, but bacterial cultures were negative. Five days after admission, the fungal culture from the left hip wound was notable for presence of C. glabrata, prompting an infectious diseases (ID) consultation. IV micafungin 100 mg/day was initiated as empiric antifungal therapy.

ID and orthopedic surgery teams determined that a combined medical and surgical approach would be best suited for infection control. They proposed 2 main approaches: complete hardware replacement with washout, which carried a higher morbidity risk but a better chance of infection resolution, or partial hardware replacement with washout, which was associated with a lower morbidity risk but a higher risk of infection persistence and recurrence. This decision was particularly challenging for the patient, who prioritized maintaining his functional status, including his ability to continue dancing for pleasure. The patient opted for a more conservative approach, electing to proceed with antifungal therapy and debridement while retaining the prosthetic joint.

After 11 days of hospitalization, the patient was discharged with a peripherally inserted central catheter for long-term antifungal infusions of micafungin 150 mg/day at home. Fungal sensitivity test results several days after discharge confirmed susceptibility to micafungin.

About 2 weeks after discharge, the patient underwent debridement and implant retention (DAIR). Wound cultures were positive for C. glabrata, Enterococcus faecalis, Staphylococcus epidermidis, and Corynebacterium tuberculostearicum. Based on susceptibilities, he completed a 2-month course of IV micafungin 150 mg daily and daptomycin 750 mg daily, followed by an oral suppressive regimen consisting of doxycycline 100 mg twice daily, amoxicillin-clavulanate 2 g twice daily, and fluconazole initially 800 mg daily adjusted to 400 mg daily. The patient continued wound management with twice-daily dressing changes.

Nine months after DAIR, the patient remained on suppressive antifungal and antibacterial therapy. He continued to experience serous drainage from the wound, which greatly affected his quality of life. After discussion with his family and the orthopedic surgery team, he agreed to proceed with a 2-staged revision arthroplasty involving prosthetic explant and antibiotic spacer placement. However, the surgery was postponed due to findings of anemia (hemoglobin, 8.9 g/dL) and thrombocytopenia (platelet count, 73 x 10³/λL). At the time of this report, the patient was being monitored closely with his multidisciplinary care team for the planned orthopedic procedure.

DISCUSSION

PJI is the most common cause of primary hip arthroplasty failure; however, fungal species only make up about 1% of PJIs.^3,9-11 Patients are typically immunocompromised, undergoing antineoplastic therapies for malignancy, or have other comorbid conditions such as diabetes.^12,13 C. glabrata presents a unique diagnostic and therapeutic challenge as it is not only rare but also notorious for its resistance to common antifungal agents. C. glabrata is known to develop multidrug resistance through the rapid accumulation of genomic mutations.¹⁴ Its propensity towards forming protective biofilm also arms it with intrinsic resistance to agents like fluconazole.¹⁵ Furthermore, based on a review of the available reports in the literature, C. glabrata PJIs are often insidious and present with symptoms closely mimicking those of bacterial PJIs, as it did in the patient in this case.¹⁶

Synovial fluid analysis, fungal cultures, and sensitivity testing are paramount for ensuring proper diagnosis for fungal PJI. The patient in this case was empirically treated with micafungin based on recommendations from the ID team. When the sensitivities results were reviewed, the same antifungal therapy was continued. Echinocandins have a favorable toxicity profile in long-term use, as well as efficacy against biofilm-producing organisms like C. glabrata.^17,18

While there are a few cases citing DAIR as a feasible surgical strategy for treating fungal PJI, more recent studies have reported greater success with a 2-staged revision arthroplasty involving some combination of debridement, placement of antibiotic-loaded bone cement spacers, and partial or total exchange of the infected prosthetic joint.^4,19-23 In this case, complete hardware replacement would have offered the patient the most favorable outlook for eliminating this fungal infection. However, given the patient’s advanced age, significant underlying comorbidities, and functional status, medical management with antifungal therapy and DAIR was favored.

Based on the discussion from the 6-month follow-up visit, the patient was experiencing progressive and persistent wound drainage and frequent dressing changes, highlighting the limitations of medical management for PJI in the setting of retained prosthesis. If the patient ultimately proceeds with a more invasive surgical intervention, another important consideration will be the likelihood of fungal PJI recurrence. At present, fungal PJI recurrence rates following antifungal and surgical treatment have been reported to range between 0% to 50%, which is too imprecise to be considered clinically useful.^22-24

Given the ambiguity surrounding management guidelines and limited treatment options, it is crucial to emphasize the timeline of this patient’s clinical presentation and subsequent course of treatment. Upon presentation to the ED in late July, fungal PJI was considered less likely. Initial blood cultures from presentation were negative, which is common with PJIs. It was not until 5 days later that the left hip wound culture showed moderate growth of C. glabrata. Identifying a PJI is clinically challenging due to the lack of standardized diagnostic criteria. However, timely identification and diagnosis of fungal PJI with appropriate antifungal therapy, in patients with limited curative options due to comorbidities, can significantly improve quality of life and overall outcomes.²⁵ Routine fungal and mycobacterial cultures are not currently recommended in PJI guidelines, but this case illustrates it is imperative in immunocompromised hosts.²⁶

This case and the current paucity of similar cases in the literature stress the importance of clinicians publishing their experience in the management of fungal PJI. We strongly recommend that clinicians approach each suspected PJI with careful consideration of the patient’s unique risk factors, comorbidities, and goals of care, when deciding on a curative vs suppressive approach to therapy.

CONCLUSIONS

This case report highlights the importance of considering fungal pathogens for PJIs, especially in high-risk patients, the value of obtaining fungal cultures, the necessity of a multidisciplinary approach, the role of antifungal susceptibility testing, and consideration for the feasibility of a surgical intervention. It underscores the challenges in diagnosis and treatment of C. glabrata-associated PJI, emphasizing the importance of clinician experience-sharing in developing evidence-based management strategies. As the understanding of fungal PJI evolves, continued research and clinical data collection remain crucial for improving patient outcomes in the management of these complex cases.

Pemphigoid gestationis (PG), which manifests in the second or third trimester of pregnancy, is thought to result from an excessive type 2 inflammatory response that leads to the formation of antibodies primarily targeting BP180 antigens with resultant damage to the skin basement membrane.¹ Maternal antibodies can be transferred to the fetus, resulting in neonatal pemphigoid with the development of widespread vesicles and bullae.² Maternal morbidity from placental insufficiency, intrauterine growth restriction, and premature labor are common comorbidities of PG, underscoring the critical need for safe and effective treatments for this condition.³

Systemic corticosteroids currently are the first-line treatment for moderate to severe PG but carry considerable risks to both the mother and fetus, including preterm labor and intrauterine growth restriction.^4,5 Dupilumab is approved by the US Food and Drug Administration for moderate to severe atopic dermatitis in children aged 6 months and older. Dupilumab inhibits downstream signaling of IL-4Rα, reducing IL-4 and IL-13. Use of dupilumab to target the type 2 inflammatory response has shown significant promise in the treatment of BP, where it met primary and secondary endpoints in adults with moderate to severe disease, but studies in PG are limited.^6-8 There are multiple reports in the literature demonstrating the safety of dupilumab in pregnancy and postpartum,^9-27 including a pharmacovigilance report that found no adverse drug reactions from dupilumab reported during pregnancy.⁹ There also are 4 reports of pregnant patients who were diagnosed with PG and treated with dupilumab, all of whom were initially started on prednisone prior to treatment initiation.^9-12 In this article, we report 2 additional cases of dupilumab treatment in patients with PG.

Case Reports

Patient 1—A 39-year-old G5P1 woman presented to the dermatology department at 27.5 weeks’ gestation with a widespread eruption of erythematous, annular, urticarial, edematous papules and plaques on the abdomen of 4 weeks’ duration (Figure 1A). Direct immunofluorescence was positive, indirect immunofluorescence confirmed an IgG-positive epidermal pattern, and serum BP180 levels were elevated, supporting a diagnosis of PG. The patient was prescribed prednisone (60 mg/d) but developed type 1 diabetes mellitus after 1 week of treatment. Following insurance approval, dupilumab therapy was initiated 3 weeks later at a dose of 300 mg subcutaneously every 2 weeks. Rapid and complete resolution of papules and plaques as well as symptomatic relief from pruritus was noted within 2 weeks of treatment (Figure 1B). The prednisone dose was tapered to 2.5 mg every other day at 6 weeks prior to induction of labor; the diabetes resolved 7 weeks after initiation of dupilumab.

At the recommendation of the patient’s high-risk maternal-fetal medicine team, 100 mg of stress-dose hydrocortisone was administered intravenously just prior to delivery to prevent flaring of PG. She delivered a healthy infant at 37 weeks and 3 days’ gestation without bullous disease and was discharged from the hospital the day after delivery on a prednisone dose of 2.5 mg every other day.

The patient subsequently developed localized pruritic papules on the hands and feet at 2 weeks postpartum. Based on shared decision-making and the patient’s concern for the severity of the previous pruritic eruption, prednisone was increased to 10 mg daily for 5 days and then was tapered over 2 weeks without flaring. Dupilumab was continued until 12 weeks postpartum with complete resolution of PG and no further sequelae.

Patient 2—A 30-year-old G1P0 woman presented to the dermatology department at 25 weeks’ gestation with a widespread eruption of 1 week’s duration on the abdomen, hands, thighs, legs, buttocks, and feet that was clinically consistent with PG (Figure 2A). Direct immunofluorescence was positive, indirect immunofluorescence showed an IgG-positive epidermal pattern, and an enzyme-linked immunosorbent assay for BP180 was elevated, confirming a diagnosis of PG. The patient was started on 40 mg of prednisone and topical steroids daily, with improvement of the pruritus but persistence of the eruption after 3 to 4 days. Five days after the initial presentation following expedited insurance approval, dupilumab 300 mg was initiated subcutaneously every 2 weeks along with a slow taper of prednisone to 5 mg, with complete clearance of the eruption within 4 weeks (Figure 2B). She delivered a healthy infant at 38 weeks’ gestation without bullous disease.

In contrast to patient 1, this patient did not receive corticosteroids at the time of delivery and did not experience flaring of her disease. The patient remained on dupilumab 5 weeks postpartum without subsequent recurrence after treatment discontinuation.

Comment

Although a myriad of effective treatments exist for bullous pemphigoid, there are very few options for PG due to the need for treatment during pregnancy. Systemic corticosteroids—the treatment of choice in severe PG disease—are not without risk in pregnancy and complicate assessment of morbidity, as both PG and chronic steroid exposure are associated with preterm labor and intrauterine growth restriction.³

Dupilumab currently is undergoing phase III trials (Clinicaltrials.gov identifiers NCT02277743 and NCT02277769) for the treatment of bullous pemphigoid, with interim reports suggesting efficacy across all primary and key secondary endpoints in moderate to severe disease, including notable steroid-sparing effects.⁸ In our patients, treatment with dupilumab resulted in resolution of cutaneous disease and was well tolerated, facilitating the tapering of corticosteroids and resolution of type 1 diabetes in patient 1. Although the response to dupilumab in both cases may have been confounded by concomitant steroid administration, which was started due to the severity of symptoms and uncertainty regarding insurance approval, the dose was tapered in both patients after initiation of dupilumab. Patient 1 was given a stress dose of hydrocortisone during delivery and developed a mild flare following delivery, consistent with previous literature.^{28, 29} Because the flare was localized to the hands and feet, she might have responded to clobetasol in addition to dupilumab, but given the severity of disease at presentation and her concern that it might worsen, low-dose prednisone was added with resolution of the flare within 2 weeks.

Dupilumab dosing regimens have not been studied in a controlled prospective manner for PG. We acknowledge that dupilumab (at least using the conventional atopic dermatitis dosing regimen) may be insufficient as monotherapy to control PG, as both patients received steroids prior to initiation of dupilumab, in part due to concern that the insurance might delay or deny approval. Previous World Health Organization vigilance reporting has suggested that dupilumab appears safe during pregnancy although it lacks pregnancy categorization in the United States due to limited studies in this population.^9-28 This observation supports the conclusion that, like bullous pemphigoid, PG also is driven by Th2–mediated inflammation. Treatment with dupilumab may be safe and effective in pregnancy, reducing maternal complications from long-term corticosteroids. Additional studies are needed to confirm these hypotheses.

Pemphigoid gestationis (PG), which manifests in the second or third trimester of pregnancy, is thought to result from an excessive type 2 inflammatory response that leads to the formation of antibodies primarily targeting BP180 antigens with resultant damage to the skin basement membrane.¹ Maternal antibodies can be transferred to the fetus, resulting in neonatal pemphigoid with the development of widespread vesicles and bullae.² Maternal morbidity from placental insufficiency, intrauterine growth restriction, and premature labor are common comorbidities of PG, underscoring the critical need for safe and effective treatments for this condition.³

Systemic corticosteroids currently are the first-line treatment for moderate to severe PG but carry considerable risks to both the mother and fetus, including preterm labor and intrauterine growth restriction.^4,5 Dupilumab is approved by the US Food and Drug Administration for moderate to severe atopic dermatitis in children aged 6 months and older. Dupilumab inhibits downstream signaling of IL-4Rα, reducing IL-4 and IL-13. Use of dupilumab to target the type 2 inflammatory response has shown significant promise in the treatment of BP, where it met primary and secondary endpoints in adults with moderate to severe disease, but studies in PG are limited.^6-8 There are multiple reports in the literature demonstrating the safety of dupilumab in pregnancy and postpartum,^9-27 including a pharmacovigilance report that found no adverse drug reactions from dupilumab reported during pregnancy.⁹ There also are 4 reports of pregnant patients who were diagnosed with PG and treated with dupilumab, all of whom were initially started on prednisone prior to treatment initiation.^9-12 In this article, we report 2 additional cases of dupilumab treatment in patients with PG.

Case Reports

Patient 1—A 39-year-old G5P1 woman presented to the dermatology department at 27.5 weeks’ gestation with a widespread eruption of erythematous, annular, urticarial, edematous papules and plaques on the abdomen of 4 weeks’ duration (Figure 1A). Direct immunofluorescence was positive, indirect immunofluorescence confirmed an IgG-positive epidermal pattern, and serum BP180 levels were elevated, supporting a diagnosis of PG. The patient was prescribed prednisone (60 mg/d) but developed type 1 diabetes mellitus after 1 week of treatment. Following insurance approval, dupilumab therapy was initiated 3 weeks later at a dose of 300 mg subcutaneously every 2 weeks. Rapid and complete resolution of papules and plaques as well as symptomatic relief from pruritus was noted within 2 weeks of treatment (Figure 1B). The prednisone dose was tapered to 2.5 mg every other day at 6 weeks prior to induction of labor; the diabetes resolved 7 weeks after initiation of dupilumab.

At the recommendation of the patient’s high-risk maternal-fetal medicine team, 100 mg of stress-dose hydrocortisone was administered intravenously just prior to delivery to prevent flaring of PG. She delivered a healthy infant at 37 weeks and 3 days’ gestation without bullous disease and was discharged from the hospital the day after delivery on a prednisone dose of 2.5 mg every other day.

The patient subsequently developed localized pruritic papules on the hands and feet at 2 weeks postpartum. Based on shared decision-making and the patient’s concern for the severity of the previous pruritic eruption, prednisone was increased to 10 mg daily for 5 days and then was tapered over 2 weeks without flaring. Dupilumab was continued until 12 weeks postpartum with complete resolution of PG and no further sequelae.

Patient 2—A 30-year-old G1P0 woman presented to the dermatology department at 25 weeks’ gestation with a widespread eruption of 1 week’s duration on the abdomen, hands, thighs, legs, buttocks, and feet that was clinically consistent with PG (Figure 2A). Direct immunofluorescence was positive, indirect immunofluorescence showed an IgG-positive epidermal pattern, and an enzyme-linked immunosorbent assay for BP180 was elevated, confirming a diagnosis of PG. The patient was started on 40 mg of prednisone and topical steroids daily, with improvement of the pruritus but persistence of the eruption after 3 to 4 days. Five days after the initial presentation following expedited insurance approval, dupilumab 300 mg was initiated subcutaneously every 2 weeks along with a slow taper of prednisone to 5 mg, with complete clearance of the eruption within 4 weeks (Figure 2B). She delivered a healthy infant at 38 weeks’ gestation without bullous disease.

In contrast to patient 1, this patient did not receive corticosteroids at the time of delivery and did not experience flaring of her disease. The patient remained on dupilumab 5 weeks postpartum without subsequent recurrence after treatment discontinuation.

Comment

Although a myriad of effective treatments exist for bullous pemphigoid, there are very few options for PG due to the need for treatment during pregnancy. Systemic corticosteroids—the treatment of choice in severe PG disease—are not without risk in pregnancy and complicate assessment of morbidity, as both PG and chronic steroid exposure are associated with preterm labor and intrauterine growth restriction.³

Dupilumab currently is undergoing phase III trials (Clinicaltrials.gov identifiers NCT02277743 and NCT02277769) for the treatment of bullous pemphigoid, with interim reports suggesting efficacy across all primary and key secondary endpoints in moderate to severe disease, including notable steroid-sparing effects.⁸ In our patients, treatment with dupilumab resulted in resolution of cutaneous disease and was well tolerated, facilitating the tapering of corticosteroids and resolution of type 1 diabetes in patient 1. Although the response to dupilumab in both cases may have been confounded by concomitant steroid administration, which was started due to the severity of symptoms and uncertainty regarding insurance approval, the dose was tapered in both patients after initiation of dupilumab. Patient 1 was given a stress dose of hydrocortisone during delivery and developed a mild flare following delivery, consistent with previous literature.^{28, 29} Because the flare was localized to the hands and feet, she might have responded to clobetasol in addition to dupilumab, but given the severity of disease at presentation and her concern that it might worsen, low-dose prednisone was added with resolution of the flare within 2 weeks.

Dupilumab dosing regimens have not been studied in a controlled prospective manner for PG. We acknowledge that dupilumab (at least using the conventional atopic dermatitis dosing regimen) may be insufficient as monotherapy to control PG, as both patients received steroids prior to initiation of dupilumab, in part due to concern that the insurance might delay or deny approval. Previous World Health Organization vigilance reporting has suggested that dupilumab appears safe during pregnancy although it lacks pregnancy categorization in the United States due to limited studies in this population.^9-28 This observation supports the conclusion that, like bullous pemphigoid, PG also is driven by Th2–mediated inflammation. Treatment with dupilumab may be safe and effective in pregnancy, reducing maternal complications from long-term corticosteroids. Additional studies are needed to confirm these hypotheses.

Pemphigoid gestationis (PG), which manifests in the second or third trimester of pregnancy, is thought to result from an excessive type 2 inflammatory response that leads to the formation of antibodies primarily targeting BP180 antigens with resultant damage to the skin basement membrane.¹ Maternal antibodies can be transferred to the fetus, resulting in neonatal pemphigoid with the development of widespread vesicles and bullae.² Maternal morbidity from placental insufficiency, intrauterine growth restriction, and premature labor are common comorbidities of PG, underscoring the critical need for safe and effective treatments for this condition.³

Systemic corticosteroids currently are the first-line treatment for moderate to severe PG but carry considerable risks to both the mother and fetus, including preterm labor and intrauterine growth restriction.^4,5 Dupilumab is approved by the US Food and Drug Administration for moderate to severe atopic dermatitis in children aged 6 months and older. Dupilumab inhibits downstream signaling of IL-4Rα, reducing IL-4 and IL-13. Use of dupilumab to target the type 2 inflammatory response has shown significant promise in the treatment of BP, where it met primary and secondary endpoints in adults with moderate to severe disease, but studies in PG are limited.^6-8 There are multiple reports in the literature demonstrating the safety of dupilumab in pregnancy and postpartum,^9-27 including a pharmacovigilance report that found no adverse drug reactions from dupilumab reported during pregnancy.⁹ There also are 4 reports of pregnant patients who were diagnosed with PG and treated with dupilumab, all of whom were initially started on prednisone prior to treatment initiation.^9-12 In this article, we report 2 additional cases of dupilumab treatment in patients with PG.

Case Reports

Patient 1—A 39-year-old G5P1 woman presented to the dermatology department at 27.5 weeks’ gestation with a widespread eruption of erythematous, annular, urticarial, edematous papules and plaques on the abdomen of 4 weeks’ duration (Figure 1A). Direct immunofluorescence was positive, indirect immunofluorescence confirmed an IgG-positive epidermal pattern, and serum BP180 levels were elevated, supporting a diagnosis of PG. The patient was prescribed prednisone (60 mg/d) but developed type 1 diabetes mellitus after 1 week of treatment. Following insurance approval, dupilumab therapy was initiated 3 weeks later at a dose of 300 mg subcutaneously every 2 weeks. Rapid and complete resolution of papules and plaques as well as symptomatic relief from pruritus was noted within 2 weeks of treatment (Figure 1B). The prednisone dose was tapered to 2.5 mg every other day at 6 weeks prior to induction of labor; the diabetes resolved 7 weeks after initiation of dupilumab.

At the recommendation of the patient’s high-risk maternal-fetal medicine team, 100 mg of stress-dose hydrocortisone was administered intravenously just prior to delivery to prevent flaring of PG. She delivered a healthy infant at 37 weeks and 3 days’ gestation without bullous disease and was discharged from the hospital the day after delivery on a prednisone dose of 2.5 mg every other day.

The patient subsequently developed localized pruritic papules on the hands and feet at 2 weeks postpartum. Based on shared decision-making and the patient’s concern for the severity of the previous pruritic eruption, prednisone was increased to 10 mg daily for 5 days and then was tapered over 2 weeks without flaring. Dupilumab was continued until 12 weeks postpartum with complete resolution of PG and no further sequelae.

Patient 2—A 30-year-old G1P0 woman presented to the dermatology department at 25 weeks’ gestation with a widespread eruption of 1 week’s duration on the abdomen, hands, thighs, legs, buttocks, and feet that was clinically consistent with PG (Figure 2A). Direct immunofluorescence was positive, indirect immunofluorescence showed an IgG-positive epidermal pattern, and an enzyme-linked immunosorbent assay for BP180 was elevated, confirming a diagnosis of PG. The patient was started on 40 mg of prednisone and topical steroids daily, with improvement of the pruritus but persistence of the eruption after 3 to 4 days. Five days after the initial presentation following expedited insurance approval, dupilumab 300 mg was initiated subcutaneously every 2 weeks along with a slow taper of prednisone to 5 mg, with complete clearance of the eruption within 4 weeks (Figure 2B). She delivered a healthy infant at 38 weeks’ gestation without bullous disease.

In contrast to patient 1, this patient did not receive corticosteroids at the time of delivery and did not experience flaring of her disease. The patient remained on dupilumab 5 weeks postpartum without subsequent recurrence after treatment discontinuation.

Comment

Although a myriad of effective treatments exist for bullous pemphigoid, there are very few options for PG due to the need for treatment during pregnancy. Systemic corticosteroids—the treatment of choice in severe PG disease—are not without risk in pregnancy and complicate assessment of morbidity, as both PG and chronic steroid exposure are associated with preterm labor and intrauterine growth restriction.³

Dupilumab currently is undergoing phase III trials (Clinicaltrials.gov identifiers NCT02277743 and NCT02277769) for the treatment of bullous pemphigoid, with interim reports suggesting efficacy across all primary and key secondary endpoints in moderate to severe disease, including notable steroid-sparing effects.⁸ In our patients, treatment with dupilumab resulted in resolution of cutaneous disease and was well tolerated, facilitating the tapering of corticosteroids and resolution of type 1 diabetes in patient 1. Although the response to dupilumab in both cases may have been confounded by concomitant steroid administration, which was started due to the severity of symptoms and uncertainty regarding insurance approval, the dose was tapered in both patients after initiation of dupilumab. Patient 1 was given a stress dose of hydrocortisone during delivery and developed a mild flare following delivery, consistent with previous literature.^{28, 29} Because the flare was localized to the hands and feet, she might have responded to clobetasol in addition to dupilumab, but given the severity of disease at presentation and her concern that it might worsen, low-dose prednisone was added with resolution of the flare within 2 weeks.

Dupilumab dosing regimens have not been studied in a controlled prospective manner for PG. We acknowledge that dupilumab (at least using the conventional atopic dermatitis dosing regimen) may be insufficient as monotherapy to control PG, as both patients received steroids prior to initiation of dupilumab, in part due to concern that the insurance might delay or deny approval. Previous World Health Organization vigilance reporting has suggested that dupilumab appears safe during pregnancy although it lacks pregnancy categorization in the United States due to limited studies in this population.^9-28 This observation supports the conclusion that, like bullous pemphigoid, PG also is driven by Th2–mediated inflammation. Treatment with dupilumab may be safe and effective in pregnancy, reducing maternal complications from long-term corticosteroids. Additional studies are needed to confirm these hypotheses.