Chapter 17 Immune Modifiers

Systemic Steroids

Description

Steroids as used in this section refers to glucocorticoids that are administered systemically. Inhaled, topically administered, and injected steroids are described in other sections.

Prototype and Common Drugs

Prototype: prednisone

Others: cortisone, hydrocortisone, methylprednisolone, dexamethasone, triamcinolone

MOA (Mechanism of Action)

Cortisol is the endogenous glucocorticoid and is synthesized from cholesterol. The hypothalamus secretes corticotropin-releasing hormone (CRH), which stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH), which acts on the adrenal glands to produce cortisol.

Cortisol acts in the nucleus of the cell; therefore it must first diffuse through the cell membrane. It is bound in the cytoplasm with heat shock protein and other proteins and transported into the nucleus.

Steroid receptors located in the nucleus are called glucocorticoid receptor elements. They regulate transcription of DNA by acting on promoters, which are specific DNA sites where RNA polymerase binds and starts transcription.

Steroids exert their actions in a broad range of tissues, and therefore there are many effects of glucocorticoids:

Catabolism

• Increased serum glucose: increased gluconeogenesis, increased lipolysis, decreased uptake of glucose into tissues, and direct inhibition of insulin via cortisone (breakdown of cortisol)

• Mobilization of calcium from bones

• Increased breakdown of muscle to liberate amino acids

Inflammatory effects

• Increased blood neutrophil counts: increased marrow release and decreased tissue margination

• Decreasing numbers of other white blood cells: lymphocytes, eosinophils, macrophages

• Reduced function of lymphocytes and macrophages

• Reduced function of phospholipase A₂, resulting in reduced mediators of inflammation: prostaglandins and leukotrienes

Antimitotic effects (decreased cell division)

Water retention (because of mineralocorticoid effect)

Pharmacokinetics

Cortisol is largely bound to corticosteroid-binding globulin (CBG); it is also bound to albumin but with only low affinity (Table 17-1).

TABLE 17-1 Steroid Potencies

Side Effects

Hyperglycemia and steroid induced diabetes

Weight gain and severe swelling, particularly in the face; caused, in part, by the mineralocorticoid effects

Psychiatric symptoms including depression, mania, and psychosis; other types of cognitive dysfunction can also occur, including euphoria, insomnia, mental confusion

Gastric and duodenal bleeding secondary to inflammation or ulceration

Infections resulting from immunosuppression

Skin effects: thin skin, violaceous striae (stretch marks), acne

Eyes: cataracts and glaucoma

Muscular effects: muscle wasting, myopathy

Adipose distribution: buffalo hump, central obesity

Skeletal effects:

Adults and children: Osteoporosis may occur.

Children: Short stature results from interference with growth plates.

Avascular necrosis (AVN) of the hips: The femoral head loses its blood supply, resulting in a devastating destruction of bone and joint. The lack of blood supply means that healing cannot occur and could necessitate joint replacement.

Cushing’s syndrome is a collection of signs from endogenous overproduction of cortisol. A cushingoid appearance can be produced from iatrogenic exogenous steroid:

Moon facies, buffalo hump (cervical fat pad), central obesity, supraclavicular fat collection, acne

Adrenal suppression: Because of negative feedback loops, exogenous glucocorticoids will suppress CRH and ACTH. Rapidly terminating exogenous glucocorticoids after prolonged exposure will result in hypoadrenalism. Steroids must therefore be tapered (administration of smaller and smaller doses) before being stopped if they have been administered for more than about 1 or 2 weeks.

Important Notes

The baseline secretion of cortisol in the body is 10 to 20 mg. In periods of stress (illness, trauma, inflammation, infection), the secretion increases.

Glucocorticoids must be differentiated from mineralocorticoids; the prototype mineralocorticoid is aldosterone, also a steroid, which acts primarily on the kidney to regulate water and electrolyte homeostasis.

One significant side effect of glucocorticoids is an increased white blood count (driven by an increase in neutrophils). Increased neutrophil counts are more commonly caused by infection; because steroids increase the risk of infection, it is sometimes clinically difficult to differentiate whether the increased white count is the result of a new infection (which would make the steroids relatively contraindicated) or the result of a direct effect of the steroid. The rise in white cell count can be quite dramatic when caused by steroid effect alone.

Steroids and nonsteroidal antiinflammatory drugs (NSAIDs) are commonly coadministered for inflammatory conditions that result in pain (e.g., RA). The risk of gastrointestinal (GI) bleeding with steroids or NSAIDs alone is 2 times and 4 times (respectively) higher than baseline, but when these agents are taken together, the risk is 12 times higher than baseline.

Because of the long list of side effects, steroids are not ideal for long-term high-dose administration. In diseases in which prolonged and substantial immunosuppression is required, steroid-sparing immunosuppressants are administered so that doses of steroids can be reduced or the steroids can be completely discontinued.

Advanced

Prophylactic antibiotics against Pneumocystis pneumonia (also called Pneumocystis jiroveci pneumonia or Pneumocystis carinii pneumonia [PCP]) are administrated to patients on long-term moderate- to high-dose steroids because of the risk of acquiring this infection when immunosuppressed. Human immunodeficiency virus (HIV) infection is the most common risk factor for PCP

In addition to being a risk factor for PCP, steroids are also coadministered to patients being treated for PCP because the antibiotic-mediated destruction of the pathogen generates a strong inflammatory response in the lungs, making the respiratory condition much worse. Steroids blunt this response.

Evidence

The range of diseases treated with systemic steroids is too large to be summarized, but some of the more common uses of systemic steroids are presented here.

Systemic steroids and adult asthma: A systematic review in 2009 concluded that the available studies were frequently underpowered. However, some general conclusions and recommendations were made: steroids administered in the emergency department reduce hospitalizations; steroids accelerate improvements in lung function; there was no benefit in using doses larger than 50 to 100 mg prednisone equivalent; and no benefit was seen when steroids were administered for longer than 5 to 10 days total.

Systemic steroids and RA: A Cochrane review in 2007 (15 studies, N = 1414 patients) examined radiological progression of disease and concluded that the proportion of benefit gained by glucocorticoids in reducing the progression of erosions from an average of all the studies over 1 year was 67.2% (confidence interval [CI] 48.9%, 85.4%) and over 2 years was 61.3% (CI 46.5%, 76.1%). Furthermore, this benefit was achieved in patients who were (mostly) already receiving disease-modifying antirheumatic drug (DMARD) treatment. It therefore represents a gain over and above any benefits from DMARDs alone.

FYI

Memory tip: the effects of elevated cortisol in starvation would predict the metabolic effects: releasing and making available carbohydrate, fats, and proteins from body stores to be used by the body.

Introduction to Monoclonal Antibodies

Monoclonal antibodies (mAbs) belong to a broad category of agents (often called simply biologics) with a very large number of effects and clinical indications. The common denominator among all these drugs is the use of engineered proteins that are antibodies. There are two main categories of biologic drugs: mAbs and dimeric fusion proteins.

mAbs are produced by the body’s immune system (by B lymphocytes) for the function of recognizing, binding, and subsequently destroying infectious agents that display foreign antigens. By creating antibodies that target antigens that are part of a disease process, the disease process can potentially be inhibited or completely destroyed.

To produce large quantities of an antibody, an animal first needs to be exposed to an antigen so that the B cells are able to produce the specific antibody. Second, a method of collecting the antibody-producing cell and enabling it to produce massive quantities is required. This is accomplished by fusing two cells together into a hybridoma. Antibody-producing cells (which have a limited life span) are then fused with cells that have an unlimited life span (a cancer cell, specifically a B-lymphoma cancer cell called a myeloma), which creates cells that can indefinitely produce antibodies. In a batch of these cells, there are many different cells, giving rise to many different clones of future generations (polyclonal). The isolation and growth of single cells that produce the desired antibody results in a monoclonal production of antibodies. These monoclonal hybridomas can be grown in cultures or in mice.

Newer technologies are enabling the animal (usually mouse) portion of the antibody to be less and less, so that the resulting antibody is mostly human and therefore not destroyed by the patient’s own immune system for being a foreign antibody by human antimurine antibodies (HAMAs). Chimeric (human-mouse combination) antibodies contain fewer mouse regions than full mouse antibodies. Humanization involves replacing most of the mouse antibody with equivalent human regions while keeping only the variable, antigen-specific regions intact. Humanized mAbs have more human regions than chimeric mAbs do. Finally, fully human mAbs that contain no mouse regions are now being created (Figure 17-1).

Figure 17-1

Fusion Proteins

Fusion proteins are antibodies but are engineered differently than mAbs. The antigen portion is fused to the Fc fragment. The dimeric molecule can then bind to the specific cell surface binding protein and allow the activity of the Fc portion of the antibody to be directed to the cell. For example, etanercept is a combination of tumor necrosis factor (TNF) receptor bound to the antibody Fc fragment. The drug binds TNF, and the Fc fragment results in inactivation and removal of circulating TNF.

Table 17-2 will not be fully inclusive by the time it is published because of the rapid growth of this area of medicine. Some drugs listed may not yet be approved for use.

Table 17-2 Monoclonal Antibodies

Name	Type	Target
Rituximab	Chimeric	CD20 on B lymphocytes
Ocrelizumab	Humanized	CD20 on B lymphocytes
Ofatumumab	Human	CD20 on B lymphocytes
Tositumomab	Mouse	CD20, bound to ¹³¹I
Ibritumomab	Mouse	CD20, bound to ⁹⁰Y or ¹¹¹In
Epratuzumab	Humanized	CD22 on B lymphocytes
Alemtuzumab	Humanized	CD52 on B and T lymphocytes
Muromonab	Mouse	CD3 on T lymphocytes
Efalizumab	Humanized	CD11a on T lymphocytes
Inolimomab	Mouse	CD25 (IL-2) on T lymphocytes
Basiliximab	Chimeric	CD25 (IL-2) on T lymphocytes
Daclizumab	Humanized	CD25 (IL-2) on T lymphocytes
Gemtuzumab	Humanized	CD33 on hematopoietic cells
Bevacizumab	Humanized	Vascular-endothelial growth factor (VEGF)
Ranibizumab	Humanized	Vascular-endothelial growth factor (VEGF)
Cetuximab	Chimeric	Epidermal growth factor receptor (EGFR)
Satumomab	Mouse	Tumor-associated glycoprotein TAG-72
Capromab	Mouse	PSA (prostate), bound to ¹¹¹In
Omalizumab	Humanized	IgE (increased in asthma)
Eculizumab	Humanized	C5 (complement)
Palivizumab	Humanized	Fusion protein of RSV
Trastuzumab	Humanized	HER2 (EGF)
Infliximab	Chimeric	TNF-α
Adalimumab	Human	TNF-α
Certolizumab pegol	Humanized	TNF-α, bound to polyethylene glycol
Denosumab	Human	Receptor activator for nuclear factor κ B ligand (RANKL) in bone

EGF, epidermal growth factor; HER2, human epidermal growth factor receptor 2; ¹³¹I, iodine-131; IgE, immunoglobulin E; IL, interleukin; ¹¹¹In, indium-111; PSA, prostate-specific antigen; TNF, tumor necrosis factor; ⁹⁰Y, yttrium-90.