Webcast CME

Major Glucocorticoid Toxicity



Case Report

A 67-year-old female presents to your clinic with a 4-month history of progressive “aches and pains.” She says she feels old when she gets out of bed in the morning. Both her shoulders and upper thighs have deep aches that last for several hours before improving in the late morning. Overall, she feels better if she keeps moving. She denies headaches, jaw pain with chewing, or vision changes. She has no other joint pain or joint swelling. She has tried nonsteroidal anti-inflammatory medications and acetaminophen, but neither provides substantial relief.

A laboratory workup reveals elevated inflammatory markers.

The diagnosis of polymyalgia rheumatica is suspected, and glucocorticoids are prescribed, which provide the patient rapid relief of her symptoms.

Which of the following side effects of glucocorticoids can occur during the first day of taking the medication?

  1. Elevated glucose levels
  2. Elevated blood pressure
  3. Mood changes
  4. Difficulty sleeping
  5. All of the above

Correct! Answer:



Rationale

Glucocorticoids have a long list of side effects, but some happen more rapidly than others. Patients should be counseled on the potential for rapid elevations in blood glucose levels (usually only mild with low-dose glucocorticoids), elevations in blood pressure (also more pronounced with higher doses), mood changes, and sleeping difficulties.1 Many patients have no changes in mood or sleeping difficulties with low-dose glucocorticoids but others are sensitive to glucocorticoids and experience these side effects even with low doses.



Case continued

Three months later, the patient is taking prednisone 8 mg/day and has minimal symptoms and normal inflammatory markers. She has tried several times to reduce the dose, going down by 1 mg every 4 weeks, but her symptoms recur if she takes less than 8 mg/day.

Which of the following statements is correct regarding prednisone and her risk of developing osteoporosis?

  1. She should only be started on bisphosphonate therapy if her DXA scan shows a T score below −2.5.
  2. If her prednisone dose is projected to be more than 7.5 mg/day for more than 3 months, she should be started on bisphosphonate therapy.
  3. The patient should be started on bisphosphonate therapy if she has been taking prednisone 10 mg/day for 1 month.
  4. All patients on prednisone for more than 1 week should be on bisphosphonate medication

Correct! Answer:



Rationale

Prolonged glucocorticoid use is a clear risk factor for the development of osteoporosis. The duration and amount of glucocorticoids appear to be correlated with the risk, with longer duration and higher doses conferring a greater risk of osteoporosis development. Guidelines have established recommendations for reducing the risk of developing osteoporosis and subsequent fractures in patients on prolonged glucocorticoids. Most guidelines use the long-term threshold of 3 months at a dose between 5 and 7 mg/day of prednisone or glucocorticoid equivalent as the level to initiate antiresorptive therapy.2

Case continued

While attempting to reduce her glucocorticoid dose, she develops a headache in her left temporal area, which is worsened by palpation as well as jaw claudication. Giant cell arteritis is suspected, and the patient is started on prednisone 60 mg/day while a temporal artery biopsy is scheduled. The prednisone alleviates her headache and jaw pain, but 1 week later she develops severe pain in her left groin. She has difficulty bearing weight on her left leg and has severe pain getting in and out of a car.

On examination, the patient has difficulty getting onto the exam table. When lying prone, she has severe pain with external rotation of the left hip. She has no tenderness to palpation of the femur.

An x-ray is taken but shows no fractures.

Which of the following is the most likely diagnosis?

  1. Trochanteric bursitis
  2. Left labral tear
  3. Avascular necrosis
  4. Femoral fracture

Which of the following imaging modalities would be best to confirm the most likely diagnosis?

  1. Magnetic resonance imaging
  2. Exploratory surgery
  3. Bone scan
  4. Computer tomography scan

Correct! Answer:



Rationale

For unclear reasons, glucocorticoid use is a clear risk factor for the development of avascular necrosis, usually at higher doses and prolonged courses. Avascular necrosis of the femoral head is likely caused by decreased vascular perfusion, leading to necrosis of the area. Why does this happen with prolonged glucocorticoid use? Like many mysteries of glucocorticoid toxicity, it is not clear, but it often presents with sudden onset of hip or groin pain making it difficult to walk.

X-ray results may be normal, especially early in the course of the disease process.

Magnetic resonance imaging (MRI) is the most sensitive and specific imaging modality for the diagnosis of avascular necrosis. Unlike other imaging modalities, MRI can pick up early changes such as bone marrow edema along with more advanced changed that plain radiographs can miss. A CT scan can help make the diagnosis, but the sensitivity is estimated to be only 55%, and it may miss the early vascular and bone marrow abnormalities that an MRI will demonstrate.3,4

Case continued

A 23-year-old female with no significant past medical history presents to the emergency department with joint swelling and pain, facial rash, and lower extremity edema. Laboratory values are notable for a creatinine of 3.2 with 2-plus protein in the blood. Autoimmune serology results reveal high titer positive results for antinuclear antibodies, ribonucleoprotein, chromatin, and double-stranded DNA antibodies. A renal biopsy is performed that shows evidence of lupus nephritis. The patient is started on cyclophosphamide and high-dose IV glucocorticoids with a plan of tapering glucocorticoids over 3 months.

Which of the following antibiotics can be given prophylactically to reduce the risk of opportunistic infections?

  1. Vancomycin
  2. Amoxicillin
  3. Trimethoprim/sulfamethoxazole
  4. Ertapenem

Correct! Answer:



Rationale

Opportunistic infections are a major concern in patients on chronic glucocorticoid therapy. This is especially a concern in patients concurrently on additional immunosuppression therapy, such as this patient who is taking cyclophosphamide, an aggressive immunosuppressive agent. Patients on high-dose glucocorticoids in combination with a secondary immunosuppressive agent are at high risk for developing opportunistic infections such as Pneumocystis jirovecii pneumonia.

Generally, if a patient is on prednisone 20 mg/day or more in combination with an immunosuppressive agent such as methotrexate, azathioprine, mycophenolate mofetil, or rituximab, trimethoprim/sulfamethoxazole is added to reduce the risk of developing P jirovecii pneumonia.5

Case continued

A 65-year-old female with a long history of rheumatoid arthritis treated with methotrexate and low-dose glucocorticoids presents with progressive changes in vision. She says her vision is blurrier, and she experiences more difficulty driving at night because lights appear to have a halo around them. She has no redness or pain associated with the vision changes.

What is the most likely cause of the patient's vision changes?

  1. Cataracts
  2. Uveitis
  3. Keratitis
  4. Scleritis

Correct! Answer:



Rationale

The eye does not escape the wrath of long-term systemic steroids. The two most common ocular complications of long-term systemic steroids are cataracts and glaucoma.6 Patients on long-term systemic steroids should be asked about visual changes and counseled on the complications of cataracts and glaucoma. Clinicians should have a low threshold for referral to an ophthalmologist for evaluation.

The other options listed are inflammatory eye conditions that can be associated with underlying rheumatoid arthritis (particularly scleritis), which typically causes eye redness and a dull pain.

Case continued

A 65-year-old male with a long history of psoriatic arthritis presents with weakness in his upper and lower extremities that developed over several months. The patient reports experiencing some difficulty with holding his arms above his head for any extended periods of time along with difficulty standing up from a seated position. He has no breathing or swallowing problems. He feels his psoriatic arthritis has been well controlled on sulfasalazine and prednisone 12.5 mg/day for the past 7 years.

A physical exam finds the patient has 4/5 muscle weakness with shoulder abduction and hip flexors bilateral. The distal muscles in his upper and lower extremity are normal. Laboratory results are notable for an elevated creatine kinase of 180 U/L (reference range 22-200 U/L).

Which of the following is the most reasonable next step in managing this patient?

  1. MRI of the upper arm or thigh
  2. Electromyogram of the lower extremities
  3. Check for inflammatory myopathy or anti-synthetase serologies
  4. Taper the prednisone dose

Correct! Answer:



Rationale

Steroid-induced myopathy is a toxic, non-inflammatory myopathy induced by glucocorticoid use. Typically, steroid-induced myopathy requires doses greater than prednisone 10 mg/day or glucocorticoid equivalent daily for at least 4 weeks, but often longer.

Clinically, steroid-induced myopathy can look like an inflammatory myopathy, predominately affecting the proximal muscles with painless weakness usually coming on gradually. A diagnostic clue is long-term steroid use. The creatine kinase level is another clue. A patient with steroid-induced myopathy typically has a creatine kinase result in the normal range or mildly elevated. In contrast, the creatine kinase levels in a patient with an autoimmune inflammatory myopathy is typically very elevated.7  

The other workup options would be reasonable if an underling inflammatory myopathy was being considered. This patient is already on immunosuppression therapy that includes moderately high doses of glucocorticoids for a prolonged period, putting him at risk for developing steroid-induced myopathy. The normal creatine kinase result helps as well. The first goal would be to begin tapering his prednisone. In this case, another agent besides sulfasalazine may need to be added to keep the psoriatic arthritis under control.

Case continued

A 65-year-old female with a history of systemic lupus erythematosus controlled by daily azathioprine and 7.5 mg of prednisone comes to your office to ask about adding a nonsteroidal anti-inflammatory (NSAID) medication to help with the osteoarthritis of her hands.

Which of the following statements is correct regarding the combination of NSAIDs and systemic glucocorticoids

  1. Increased risk for osteoporosis with combined NSAIDs and glucocorticoids versus NSAIDS or glucocorticoids alone
  2. Increased risk of gastric ulcers with combined NSAIDs and glucocorticoids versus NSAIDs or glucocorticoids alone
  3. Increased risk of acute kidney injury with combined NSAIDs and glucocorticoids versus NSAIDs or glucocorticoids alone
  4. Increased risk of diabetes with combined NSAIDs and glucocorticoids versus NSAIDs or glucocorticoids alone

Correct! Answer:



Rationale

The main risk of combining systemic glucocorticoids with NSAID medications is developing gastric ulcers. Both glucocorticoids and NSAIDs have an individual increased risk of gastric ulcers, but the combination increases the risk further. When patients are on chronic glucocorticoids or NSAIDs, adding a proton pump inhibitor can lower the risk of gastric ulcer formation.8

Regarding the other answers, long-term systemic steroid use increases the risk of osteoporosis and diabetes. NSAID use increases the risk of acute kidney injury.

Case continued

A 25-year-old male presents to the emergency department with polyarticular symmetric swelling and pain in his metacarpophalangeal joints, wrists, and ankles. The pain is worse in the morning and better with activity. The physician suspects rheumatoid arthritis, prescribes prednisone at 20 mg/day, and sets up an outpatient clinic visit. At that visit 5 days later, the patient presents with improvement in his joints of nearly 80%. Laboratory tests are ordered, and the following abnormalities are found:

White blood cell count (WBC): 18.2 × 109/L (normal range: 4.5-11.0 × 109/L)

Rheumatoid factor positive

Anti-cyclic citrullinated peptides (anti-CCP) positive

C-reactive protein: 1.4 mg/L (normal: <0.9 mg/L)

Which of the following reasons if the most likely for the elevated serum WBC?

  1. Septic joint
  2. Gouty arthritis
  3. Decreased adhesion of neutrophils to endothelial lining (demargination)
  4. Reactive arthritis

Correct! Answer:



Rationale

When glucocorticoids are prescribed, clinicians should warn the patient that the WBC count is going to be elevated, and it is not because of an underling rip-roaring infection (unless, of course, there is an underling infection). The point is that glucocorticoids often cause the serum WBC to be elevated because of the phenomenon of demargination. Demargination occurs when the adhesion tape of neutrophils (L-selectin) get shut down from the glucocorticoids. This means the neutrophils cannot stick to the walls of the blood vessel and extravasate into the tissue. Instead, the neutrophils get flung into the circulation, unable to grip onto the side of the vessel.

Having a septic joint, gouty arthritis, reactive arthritis, or an underling infection such as pneumonia can all cause an elevated serum WBC. This patient’s presentation is more consistent with rheumatoid arthritis. Plus, he has positive rheumatoid factor and anti-CCP with a clinical history consistent with the diagnosis. Active autoimmune inflammatory arthritis such as rheumatoid arthritis or reactive arthritis can cause an elevated WBC, but above a level above 15.0 × 109/L is unusual. Considering that this patient was recently started on moderate-dose prednisone, the more likely cause for the elevated WBC is demargination from glucocorticoids.9

Case continued

A 75-year-old male with a history of long-term systemic steroid use for rheumatoid arthritis presents with ecchymosis on arms. He describes it feeling “like if I just slightly bump into something, I'll get a bruise.” The patient has a history of coronary artery disease and is on chronic antiplatelet therapy. He otherwise feels well from a rheumatoid arthritis standpoint

  1. Mild hirsutism
  2. Striae
  3. Acne
  4. All of the above

Correct! Answer:



Rationale

Skin thinning is the most common side effect patients experienced on prolonged glucocorticoids, but steroids potentially cause a variety of changes that can be very stressful to the patient. Most complications occur on higher doses of glucocorticoids, but skin thinning and easy bruising can persist even at relatively low dose, especially when taken in combination with antiplatelet therapy, which is common in older populations.10

Key Points

Glucocorticoid use is associated with a long list of side effects, with longer durations and higher doses conferring a greater risk, and patients should be counseled on their potential risk.

Most guidelines use the threshold of 3 months at a dose between 5 and 7 mg/day of prednisone (or glucocorticoid equivalent) to indicate long-term use.

Among the potential glucocorticoid side effects are rapid elevations in blood glucose levels and elevations in blood pressure (both more pronounced with higher doses) along with mood changes and sleeping difficulties.

Prolonged glucocorticoid use is a clear risk factor for the development of osteoporosis, avascular necrosis, skin thinning and bruising, and ocular complications of cataracts and glaucoma.

Opportunistic infections are a major concern in patients on chronic glucocorticoid therapy, especially in those taking concurrent immunosuppression therapy.

Steroid-induced myopathy is a toxic noninflammatory myopathy induced by glucocorticoid use

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