Glucocorticoids

Mechanism of action:

• Effects are mediated through genomic nuclear glucocorticoid receptors and nongenomic cell surface receptors.

• Affects both cell mediated and antibody mediated autoimmunity.

• Affects T cell function, induces T-cell apoptosis and suppresses transcription of proinflammatory cytokines. It impairs dendritic cell maturation. It causes suppression of T-cell proliferation and downregulation of of proinflammatory cytokine production such as nuclear factor-kappa B (NF-κB), and the concurrent suppression of the humoral immune response through decreased clonal expansion and antibody production of B cells.

• Corticosteroid therapy is frequently effective in a majority of immune-mediated neuromuscular disorders, with GBS being a notable exception. Although randomized, controlled trial data do not exist to support the use of corticosteroids for MG, CIDP, peripheral nerve vasculitis, and idiopathic inflammatory myopathies, broad consensus exists that corticosteroids are effective. In this era, placebo-controlled studies of corticosteroids cannot be performed due to ethical considerations.

Uses:

• 75% of MG patients improve with CS use. 30% achieve remission, and 45% have marked improvement.

• The treatment induction regimen is used when a pressing need for disease control justifies the exposure to high-dose corticosteroids. An initial dose of 1 to 1.5 mg/kg/d is used with a total daily dose rarely exceeding 100 mg/d. Tapering begins in 4 to 8 weeks, either when the patient starts to show signs of disease stabilization or if it appears the patient is not improving. Typically, daily prednisone is tapered by 10 mg every month and more slowly at doses below 10 mg/d.

• Prednisone may also be converted to every-other-day dosing. If the patient has been on daily prednisone for over 1 month, the every other-day dose can be tapered slowly down to zero (eg, 60 mg alternating with 50 mg for 1 month; 60 mg alternating with 40 mg for 1 month, etc). If the patient has been on high-dose daily prednisone for less than 1 month, then the dose can be abruptly converted to every-other-day dosing prior to gradual tapering (eg, 60 mg/d converted to 60 or 80 mg every other day). This high-dose regimen has been shown in generalized MG to lead to pharmacological remission in 28% and marked improvement in an additional 53%.

• "Start low, and go slow" approach: 10 mg (1 tab) of prednisone daily for 2 weeks., then increased to a total of 15 mg (1 1/2 tabs) daily on 3rd and 4th week, then increase it to a total of 20 mg (2 tabs) daily from 4th week.

• The transient exacerbation of myasthenic weakness is well documented after the initiation of corticosteroids. It occurs, on average, about 5 days after corticosteroid initiation, lasts 1 to 7 days, and weakness can vary from mild to sufficient to tip the patient into respiratory failure. Hence: (1) pulse high-dose methylprednisolone should only rarely be considered in MG; and (2) treatment induction with high-dose prednisone should be initiated in the inpatient setting in patients with bulbar or respiratory weakness. If steroid-associated worsening occurs in this setting, it is usually transient, and the dose of prednisone can be maintained until the patient improves. The mechanism behind transient myasthenic weakness with corticosteroids is not fully understood. Studies of repetitive nerve stimulation in MG patients have shown worsening of decrement within 1 to 3 hours of an oral dose followed by resolution 6 to 18 hours later. These data suggest a direct physiochemical effect at the neuromuscular junction or skeletal myofiber, as opposed to glucocorticoid receptor-mediated changes in gene expression.

• For OMG. A double-blind, placebo-controlled, randomized study showed that prednisone is also effective in pyridostigmine resistant ocular MG. In this study, patients were assigned either to placebo or to 10 mg of prednisone every other day with a titration up to 40 mg/d as needed to treat diplopia. At 16 weeks, the study showed that treatment failure with persistent diplopia was 100% in the placebo group vs 17% in the prednisone group (P = .02). That study, although small, provided strong evidence that low-dose gradual escalation corticosteroid therapy can be well tolerated and should be the standard of care for cholinesterase inhibitor–resistant diplopia in ocular MG.

• Steroids are not good and may be bad to use in GBS, MMN, DADS associated with IgM monoclonal proteins, and MGUS.

• For GBS, the evidence is clear: corticosteroids are ineffective and should not be used. For CIDP, however, corticosteroids are accepted as one of the three core therapies along with IVIG and PLEX on the basis of retrospective data and clinical experience.

• The PREDICT trial was a randomized, double-blind study in which treatment-naive CIDP patients were assigned to either prednisolone 60 mg/d for 5 weeks, followed by a forced taper, or pulsed-high-dose dexamethasone 40 mg/d for 4 days, followed by placebo tablets for the remainder of the month for 12 months, which was the duration of the study. At the conclusion of the study, the primary outcome of CIDP remission was comparable in both treatment groups, as was overall safety. However, difficulty with quality of sleep and a cushingoid facial appearance were more common in the prednisolone group.

• Corticosteroids have also had a significant role in the treatment of idiopathic inflammatory myopathies since the early 1960s. Despite the absence of placebo-controlled trials demonstrating effectiveness in dermatomyositis and polymyositis, corticosteroids are considered by consensus the foundation of modern therapy. In general, corticosteroids are initiated in the presence of functionally limiting weakness or other rheumatic manifestations, such as a rash in dermatomyositis. A dose of 1 mg/kg/d can be used, with a dose not to exceed 80 to 100 mg/d. For patients with a severe inflammatory myopathy phenotype, corticosteroid therapy can be initiated with pulsed-dose intravenous methylprednisolone at 1000 mg/d for 3 to 5 days. A steroid sparing immunosuppressive, typically azathioprine or methotrexate, can be started at the same time, in anticipation of a slow steroid taper over 6 months to 1 year to the lowest tolerated dose with or without IVIG.

• Corticosteroids such as prednisone and deflazacort are unique in that, unlike other immunosuppressive and immunomodulatory treatments, they have also been shown to improve strength and pulmonary function, delay functional impairment and cardiomyopathy, and reduce the need for scoliosis surgery in boys with DMD. The mechanism behind the beneficial effect of corticosteroids in DMD remains uncertain, but negative clinical studies with azathioprine indicate it is not immunosuppression. Currently, corticosteroids remain the mainstay of pharmacotherapy in DMD patients, despite the advent of promising exon-skipping genetic therapies. For Becker muscular dystrophy, the role of corticosteroids remains undefined. This is likely due to the broad spectrum of clinical severity that has rendered clinical trials harder to perform in this dystrophinopathy.

Tapering Regimens:

• Prednisone 60 mg even day, 50 mg odd day > taper 60 - 40 > 60 -30 > 60-20> 60-18> 60-16>.....60-0. Reduce by 10 mg q2 weeks, when at 20 mg further reduction by 1-2.5 mg every 3 months (single morning dose).

Monitoring while on CS:

• BP, cataracts IOP, BS, lipids, DEXA.

• In patients receiving CS for > 3 months:

  • Bone density scan - DEXA

  • Vitamin D2, 2000 IU daily

  • Calcium 1000 mg daily

  • Exercise - aerobic: steroid myopathy is increased by immobility

  • No more than modest alcohol consumption.

  • Men >50, women who are postmenopausal:

    • Biphosphonate (alendronate 10 mg daily or 70 mg weekly or 35 mg thrice a week

  • GI prophylaxis: PPI, misoprostol

  • Augment CS dosing perioperatively to avoid risk of AI in patients receiving CS > 1 month

  • Low sodium, low -CHO, high protein diet (reduce risk of steroid myopathy).

• Pneumocystis jerovici prophylaxis: prednisone 20 mg qd x 4 weeks.

AE:

• CS facilitates osteopenia and enhances bone resorption. It interferes with bone formation through apoptosis of osteocytes. it inhibits osteoprotegerin an endogenous antiresorptive cytokine.

Prednisone:

Rapid induction: 1.5 mg/kg/d for 2-4 weeks (dose rarely exceeds 100 mg/d), followed by taper and every other day dosing if desired;

Start-low, go-slow regimen: 10 mg/d, increase dose to 60-100 mg/d over 4-8 wk; Initiate and maintain regimen: 20 mg/d;

Taper: every 4 weeks by 10 mg until 10 mg/d, then taper by 1-2.5 mg every 3 months (single morning dose)

2-4 wk, effect may build over time (mo)

SE: Fluid and weight gain, insomnia, mood elevation, hyperglycemia, hypokalemia, hypertension, gastric irritation, bone thinning; long-term use: infection, cataracts, glaucoma, osteonecrosis, adrenal insufficiency, and growth suppression in pediatric use.

Weight, BP; glucose and potassium; yearly bone density for chronic use

Methylprednisolone:

gm/d IV for 3-5 doses

2-4 wk

Arrhythmia, flushing, dysgeusia and as prednisone

Same as prednisone