Injection Site Irritation - an overview

Chapters and Articles

You might find these chapters and articles relevant to this topic.

Side Effects

▪

Injection site irritation

▪

Acute inflammatory reaction: Because of the ability of TNF to influence the immune system, extensive inflammatory reactions can occur within 24 hours (usually within 6 hours) after administration. They are characterized by fever, hypotension, tachycardia, itching, chest pain, and shortness of breath. These reactions are relatively common (10% of the time), but only rarely are they severe enough to discontinue treatment.

▪

Delayed inflammatory reaction: Signs and symptoms that occur within 2 weeks after the injection are probably mediated by antibodies to the drug. Symptoms of these reactions include fever, rash, urticaria (itching), myalgia (muscle pain), arthralgia (joint pain), jaw tightness, and edema.

▪

Infection: Because of the immune suppression, common bacterial and also opportunistic infections are more common in patients receiving TNF suppression:

▴

Bacterial sepsis (widespread inflammatory response caused by bacterial infection in the blood)

▴

Fungal infections

▴

Latent TB (previous TB can be reactivated); patients must be screened for previous TB infections before starting anti-TNF therapy

▴

Herpes zoster

▪

Severe but rare side effects include heart failure, liver failure, and demyelinating disorders of the central nervous system (CNS).

▪

Cancer: Another function of the immune system is to provide surveillance of early cancer cells and to destroy them early. A blunted immune system therefore can increase the potential for development of cancer.

Read full chapter

URL: https://www.sciencedirect.com/science/article/pii/B9781437703108000178

Adverse reactions and side effects

The animal safety studies have produced few serious adverse reactions. In dogs and cats, vomiting and diarrhea have been observed in a dose-related manner. With approved doses, mild gastrointestinal upset may be observed for 2-3 days. Injection-site irritation and transient edema occurred with increasing frequency in a dose-related manner and with repeat injections. The long half-life indicates that drug concentrations will persist in animals for at least 60 days after an injection, but at this time, this has not produced adverse reactions attributed to a long persistence of drug in tissues. Allergic reactions are possible with any cephalosporin, but cross-reactivity between penicillin allergy and cephalosporin allergy is low.

Read full chapter

URL: https://www.sciencedirect.com/science/article/pii/B9780323244855001418

19.2.1 Intravenous injection

Drugs administered into the venous circulation return to the heart, where they are available for distribution to all parts of the body. This route of administration guarantees complete bioavailability, meaning that the entire dose of the drug reaches the systemic circulation (see Chapter 18). In the tissues, the capillary endothelium allows passage of small molecules, such as water and low molecular weight drugs and proteins, to the interstitial fluid, which fills the spaces between the cells based on membrane transport processes described in Chapter 16. The movement of fluids between the capillaries and the interstitial fluids is controlled by the balance between the hydrostatic pressure in the capillaries, which favor moving water from the capillaries to the tissues, and the osmotic pressure of the solutes in the capillaries, which favor water movement from the tissues to the capillaries. Distribution of drugs from the blood in the capillaries to the tissues occurs through membrane transport processes and usually results in initial net drug transfer from the blood to the tissues. Eventually, a distribution equilibrium is established between the drug in the circulation and the drug in tissues. The extent of drug distribution to tissues depends on the affinity of the drug to different tissues and can be different from one tissue to the other (see Chapter 17) [1].

Drugs are administered via the IV route when rapid drug effect is desired, such as in cases of emergency, when the drug has limited or unpredictable absorption, or in patients who cannot receive the drug by other routes. However, IV drug administration must be carried out by trained individuals, and special precautions must be considered. IV drug products must be sterile, nonimmunogenic, and pyrogen free. The formulations should also be generally solutions free of suspended particles that could obstruct small capillaries, have physiologically compatible pH values near 7.4, be isotonic with the blood, and be formulated in physiologically compatible solvents. Large- and small-volume IV drug products are usually formulated to comply with these requirements. However, some IV drug products cause administration site reactions because the formulations are irritating to the vascular epithelium, often due to high or low pH values; hypertonic or hypotonic solutions; or irritating drug, solvents, or excipients. These irritating formulations can cause phlebitis (inflammation of the vascular epithelium) and potentially severe damage in the tissues surrounding the site of administration after a single or repeated injections. It is more common and severe especially when the injection is inadvertently delivered extravascularly or when extravasation of the administered drug occurs. However, these formulations should be administered slowly to allow the drug solution to be diluted in and buffered with the blood to prevent injection-site reactions. For example, vancomycin is an intravenously administered antibiotic that is associated with inflammatory responses if it is administered too quickly. It is usually administered slowly over a period of at least 60 min to avoid these reactions.

Drug administration via the IV route can either be by IV bolus administration or by IV infusion. IV bolus administration involves the delivery of the entire drug dose over a short period of time (usually seconds to minutes), which achieves the highest observed drug concentration immediately following drug administration. IV infusion is the administration of an IV drug solution at a constant rate over a period of time. Usually, the rate of drug administration by IV infusions (i.e., the infusion rate) is controlled by a mechanical pump that delivers a preset constant volume per unit time. The period of infusion can be long (hours to days) or short (minutes to hours) times. Long IV infusions will cause the drug concentration in the plasma to gradually increase until a constant drug concentration is achieved. These long infusions are typically referred to as continuous infusions and usually involve large fluid volumes. Continuous IV infusions are typically used in hospitalized patients, and the infusion rate can be increased or decreased to achieve a desired drug concentration, desired drug effect, or until the patient condition is stabilized.

Some drugs are administered by repeated short infusions of relatively small fluid volumes referred to as intermittent IV infusions. Drugs administered by intermittent IV infusions are infused at a constant rate over a short period of time, usually 30 min to 2 h. Repeated infusions are then administered after a period of time referred to as the dosing interval. Intermittent infusions are used for drugs that might produce injection-site irritation or produce high toxic drug concentrations if administered as a bolus dose. Drug administration by intermittent IV infusion allows the drug to distribute to the tissues during the infusion, and the maximum drug concentration achieved in blood at the end of the infusion is usually lower than the blood concentration achieved if an equivalent dose were administered by IV bolus.

Read full chapter

URL: https://www.sciencedirect.com/science/article/pii/B9780323997966000060

Polyclonal Antibody Production

To produce polyclonal antibodies against an antigen of interest an experimental animal is administered the antigen, generally with a stimulant (an adjuvant), and the resultant activated antibodies are then collected from the blood. Adverse effects in test animals depend on the dose and the frequency of injections and/or use of adjuvants, which can lead to injection site irritation or abscess formation (Leenaars et al., 1999). Immunization can also occasionally lead to a severe allergic reaction (anaphylaxis), which can be fatal.

Because of the unavoidable stress of the polyclonal (or monoclonal) procedures, it is strongly encouraged that investigators look for and optimize all husbandry and veterinary interventions including group housing, environmental enrichment, and elimination of all procedures (e.g. castration) deemed nonessential by the IACUC or attending veterinarian. Dietary impact on immunosuppression has been noted for these animals, and the welfare impact of diet modifications should also be considered as part of the review considerations. The dominant species utilized in this research are mammals including rabbits, sheep, goats, and mice (Lipman et al., 2005; Clark et al., 2002), however increased use of chickens and their eggs has been advocated as a partial replacement (Narat, 2003; Hau and Hendriksen, 2005). The rare use of nonhuman primates has been justified in specific research contexts (Bettauer, 2011). Welfare and enrichment concerns are often raised for animals used in antibody production due to housing recommendations that often suggest animals must live singly in a specific pathogen-free environment.

Immune reaction to the antigen is often enhanced by the use of an adjuvant. Some adjuvants such as the traditional Freunds Adjuvant (FA) can be painful, and alternative adjuvants should be used whenever possible, although others challenge the true level of stress induced by these procedures (Stills, 2005). Booster doses of antigen often do not require FA after the initial injection.

Read full chapter

URL: https://www.sciencedirect.com/science/article/pii/B9780123851031000099

Arthritis

TABLE 5-12. Primary Features of Osteoarthritis and Rheumatoid Arthritis

Feature	Osteoarthritis	Rheumatoid Arthritis
Prevalence	Affects 27 million Americans	Affects 1.3 million Americans
Peak incidence	Increases with age, <50 yr more common in males and >50 yr more common in females	Ages 40-60, 3:1 female-to-male ratio
Onset	Usually develops slowly, over years	Usually develops suddenly, within weeks or months
Systemic features	None	Fever, fatigue, malaise, extraarticular manifestations
Disease process	Noninflammatory, characterized by cartilage destruction	Inflammatory, characterized by synovitis
Joint involvement	Individual	Polyarticular, symmetrical
Joints commonly affected	Neck, spine, hips, knees, MTPs, DIPs, PIPs, thumb CMCs	Neck, jaw, hips, knees, ankles, MTPs, shoulders, elbows, wrists, PIPs, MPs, thumb joints
Morning stiffness	<30 min	At least 1 hr, often >2 hr

CMC, Carpometacarpal; DIP, distal interphalangeal; MTP, metatarsophalangeal; PIP, proximal interphalangeal.

TABLE 5-13. Common Arthritis Medications and Side Effects

Class	Name	Possible Side Effects
Analgesics
Non-narcotic	Excedrin, Tylenol	Usually none if taken as prescribed
Narcotic	Darvon, Tylenol with codeine, Vicodin	Dizziness or lightheadedness, drowsiness, nausea, vomiting, drug tolerance, and physical dependence with long-term use
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Traditional	Advil, Aleve, Motrin, Naprosyn	Abdominal pain, dizziness, drowsiness, gastric ulcers and bleeding, greater susceptibility to bruising or bleeding, heartburn, indigestion, lightheadedness, nausea, tinnitus, kidney and liver effects
COX-2 inhibitors	Celebrex	Same as traditional NSAIDs except less likely to cause gastric ulcers and susceptibility to bruising or bleeding; increased risk of heart attack and stroke
Salicylates	Anacin, Bayer, Bufferin	Abdominal cramps, gastric ulcers, increased bleeding tendency, confusion, dizziness, tinnitus, nausea, vomiting, deafness
Corticosteroids	Cortisone, methylprednisone, prednisone	Cushing’s syndrome (weight gain, moon face, thin skin, muscle weakness, osteoporosis), cataracts, hypertension, elevated blood sugar, insomnia, mood changes, nervousness or restlessness
Disease-Modifying Antirheumatic Drugs (DMARDs)
	Gold salts	Sun sensitivity, blood and kidney effects
	Imuran	Immunosuppression
	Methotrexate	Liver and blood effects, decreased fertility
	Penicillamine	Blood and kidney effects
	Plaquenil	Vision damage with long-term use
Biologic Response Modifiers (subset of DMARDs)
	Enbrel	Headache, injection site irritation
	Humira	Injection site irritation, upper respiratory infection
	Remicade	Infusion reaction, injection site irritation, upper respiratory infection

Evaluation for arthritis

Onal therapy evaluation

It is important to recognize that every client with arthritis has a unique presentation of clinical problems and functional impairment. A strong client-centered and occupation-based approach is helpful in determining each client’s specific needs. The evaluation process for clients with arthritis includes many of the same elements as for any physical disability. Special considerations related to arthritis include closer attention to pain, joint stiffness, joint changes or deformity, fatigue, and coping strategies, especially as they relate to activity limitations. Because clients with arthritis typically experience good days and bad days, many symptoms and problems are unpredictable. A thorough systematic assessment of the client’s functional, clinical, and psychosocial status is key to prioritizing problems and planning effective intervention.

BOX 5-4

American College of Rheumatology Criteria for Classification of Rheumatoid Arthritis

From Steinbrocker O, Traeger CH, Batterman RC: Therapeutic criteria in rheumatoid arthritis. JAMA 140:659-662, 1949.

Stage I: early1.

No destructive changes on roentgenographic examination*

2.

Possible presence of radiographic evidence of osteoporosis

Stage II: moderate1.

Radiographic evidence of osteoporosis, with or without slight subchondral bone destruction; possible presence of slight cartilage destruction*

2.

No joint deformities, although possible limitation of joint mobility*

3.

Adjacent muscle atrophy

4.

Possible presence of extra-articular soft tissue lesions, such as nodules and tenosynovitis

Stage III: severe1.

Radiographic evidence of cartilage and bone destruction, in addition to osteoporosis*

2.

Joint deformity, such as subluxation, ulnar deviation, or hyperextension, without fibrous or bony ankylosis*

3.

Extensive muscle atrophy

4.

Possible presence of extra-articular soft tissue lesions, such as nodules and tenosynovitis

Stage IV: terminal1.

Fibrous or bony ankylosis*

2.

Criteria of stage III

*These criteria must be present to permit classification in any particular stage or grade.

TABLE 5-14. Treatment Objectives by Stage of Inflammatory Disease

Stage	Symptoms	Objectives	Treatment Considerations
I. Acute	Pain, inflammation, hot, red joints, tenderness, overall stiffness, limited motion	Decrease pain and inflammation.	Splinting for localized rest day and night, increased bed rest, joint protection, assistive devices, physical agent modalities
		Maintain ROM.
		Maintain strength and endurance.	Gentle active ROM and/or passive ROM to point of pain (no stretch), proper positioning
			Functional activities to tolerance, isometric exercises
II. Subacute	Inflammation subsiding, warm, pink joints, decreased pain and tenderness, stiffness limited to morning	Decrease pain and inflammation.	Less restrictive splinting for day, splinting continued at night, joint protection, assistive devices, physical agent modalities
		Maintain ROM.
		Maintain strength and endurance.	Active ROM and/or passive ROM with gentle stretch, proper positioning
			Increased functional activities to tolerance, isometric exercises
III. Chronic active	Minimal inflammation, less pain and tenderness, increased activity tolerance, low endurance	Decrease pain and inflammation.	Joint protection, splinting as needed, assistive devices as needed, physical agent modalities as needed
		Increase ROM.	Active ROM and/or passive ROM with stretch at end range
		Increase strength and endurance.	Resistive exercises (isometric or isotonic if no risk of overstressing joints), cardiovascular exercises, increased functional activities
IV. Chronic inactive	No inflammation, pain and stiffness from disuse, low endurance	Decrease pain.	Joint protection, splinting as needed, assistive devices as needed, physical agent modalities as needed
		Increase or maintain ROM.
		Increase strength and endurance.	Active ROM and/or passive ROM with stretch at end range
			Resistive exercises (isometric or isotonic if no risk of overstressing joints), cardiovascular exercises, increased functional activities

BOX 5-5

Treatment Precautions Related to Arthritis

•

Respect pain.

•

Avoid fatigue.

•

Avoid placing stress on inflamed or unstable joints.

•

Use resistive exercise or activity with caution.

•

Be aware of sensory impairments.

•

Be cautious with fragile skin caused by systemic disease or pharmacologic side effects.

TABLE 5-15. Splinting Indications by Classification of Progression of Rheumatoid Arthritis

Stage	Symptoms and Radiographic Changes	Splinting Indications
Stage I: Early	No destructive changes, possible osteoporosis	Resting splints to decrease acute inflammation, decrease pain, protect joints
Stage II: Moderate	Osteoporosis with or without slight subchondral bone destruction, slight cartilage destruction, no joint deformities, limited joint mobility possible, muscle atrophy, extraarticular soft tissue lesions possible	Day splints to provide comfort
		Night splints to relieve pain and/or protect joints against potential deformity
		Splints to increase ROM
Stage III: Severe	Cartilage and bone destruction, joint deformity, extensive muscle atrophy, extraarticular soft tissue lesions possible	Day splints to improve function (decrease pain, provide stability, limit undesired motion, properly position joints)
		Night splints to provide positioning and comfort
Stage IV: Terminal	Criteria of stage III, with fibrous and bony ankylosis	Day splints to improve function (decrease pain, provide stability, limit undesired motion, properly position joints)
		Night splints to provide positioning and comfort

BOX 5-6

Principles of Fatigue Management

Attitudes and emotions

Remove yourself from stressful situations.

Refrain from concentrating on things that make you tense.

Close your eyes, and visualize pleasant places and thoughts.

Body mechanics

When lifting something that is low, bend your knees and lift by straightening your legs. Try to keep your back straight.

Avoid reaching (use reachers). Avoid stretching, bending, carrying, and climbing. If you have to bend, keep your back straight.

Incorporate good posture into your activities.

Whenever possible, sit when working.

To get up from a chair, slide forward to the edge of the chair. With your feet flat on the floor, lean forward and push with your palms on the arms or seat of the chair. Stand by straightening your legs.

Before you get tired, stop and rest.

Work pace

Plan on getting 10 to 12 hours of rest daily (naps and at night).

Work at your own pace.

Spread tedious tasks throughout the week.

Do the tasks that require the most energy at the times when you have the most energy.

Alternate easy and difficult activities, and take a 10- to 15-minute rest break each hour.

Leisure time

Devote a portion of your day to an activity that you enjoy and find relaxing.

Check out what’s available in the community.

Work methods

Keep items within easy reach.

Use good light and proper ventilation and room temperature.

Use joint protection techniques.

Work surfaces should be at a correct height.

Organization

Plan ahead; don’t rush or push yourself.

Decide which jobs are absolutely necessary.

Share the workload with family and friends.

How to begin

Plan ahead by charting your daily routine.

Make a list of tasks, and spread them out in your schedule.

Include daily rest periods and rest breaks during energy-consuming times.

Time	Sun.	Mon.	Tues.	Wed.	Thur.	Fri.	Sat.
7:00 am
8:00 am
9:00 am
10:00 am
11:00 am
12:00 am
1:00 pm
2:00 pm
3:00 pm
4:00 pm
5:00 pm
6:00 pm
7:00 pm
8:00 pm
9:00 pm
10:00 pm

Check your schedule for the following factors:

•

Is there one day in the week that is longer than the others?

•

Are heavier tasks distributed through the week?

•

Is there a long task that could be done in several steps?

•

Will your plan allow for flexibility?

•

Have you devoted part of your day to a relaxing activity?

•

Does your plan use the principles of energy conservation?

Read full chapter

URL: https://www.sciencedirect.com/science/article/pii/B9780323067676000147

Combination Treatment with Teriperatide and Risedronate

29 adult male patients with osteoporosis (idiopathic, steroid-induced or secondary to hypogonadism) were randomised to receive oral risedronate (25 mg weekly) plus placebo injection (n = 10), subcutaneous teriparatide (20 μg daily) plus oral placebo (n = 9), or oral risedronate plus subcutaneous teriparatide (n = 10). All strategies were effective at increasing bone mineral density at several points (total hip, femoral neck, lumbar spine); combination treatment was actually more effective than either monotherapy at increasing total hip bone density. Adverse events were not significantly different across the three groups. In the teriperatide-only group, these included injection site irritation (n = 2) and leg cramps (n = 1) [79c].

Read full chapter

URL: https://www.sciencedirect.com/science/article/pii/S0378608015000288

International Brand Names

Log on to ExpertConsult.com for a list of all international brand names.

Desferal (Argentina, Brazil, Canada, Chile, China, Hong Kong, India, Indonesia, Korea, Taiwan, Thailand, Venezuela); Desferin (Spain)

Drug Class	Antidotes; Chelators
Indications	Iron toxicity
Mechanism	Chelation
Dosage With Qualifiers	Acute iron intoxication—1 g IM × 1, then 500 mg IM q4h × 2, may repeat; do not exceed 6 g/24 h Chronic iron overload—500–1000 mg IM qd, plus 2000 mg IV (not to exceed 15 mg/kg/h) with each transfused unit of PRBCs • Contraindications—hypersensitivity to drug or class, severe renal disease or anuria • Cautions—IV route should be used only in instances of CV collapse or with blood transfusion
Maternal Considerations	There are no adequate reports or well-controlled studies of deferoxamine in pregnant women. There are case reports of its use during pregnancy and lactation in women with transfusion-dependent homozygous β-thalassemia. Side effects include ocular disturbances such as blurred vision, cataracts, decreased acuity, color perception, and night vision; injection site irritation; pruritus; tachycardia; hypotension; shock; N/V; diarrhea; and abdominal pain.
Fetal Considerations	There are no adequate reports or well-controlled studies in human fetuses. It is unknown whether deferoxamine crosses the human placenta. However, there are more than 50 published cases without evidence of adverse fetal effects. One case suggested decreased fetal iron. Rodent studies reveal an increased incidence of delayed ossification and skeletal anomalies when administered at multiples of the MRHD.
Breastfeeding Safety	There are no adequate reports or well-controlled studies in nursing women. It is unknown whether deferoxamine enters human breast milk. Case reports suggest deferoxamine therapy does not alter the iron content of human breast milk.
Drug Interactions	Treatment in combination with prochlorperazine may lead to temporary impairment of consciousness. Imaging results may be distorted by the rapid urinary excretion of deferoxamine-bound gallium-67. Deferoxamine should be discontinued 48 h prior to scintigraphy. Ascorbic acid may enhance toxicity of deferoxamine.
References	Diamantidis MD, Neokleous N, Agapidou A, et al. Int J Hematol 2016; 103:537-44. Pafumi C, Zizza G, Caruso S, et al. Ann Hematol 2000; 79:571-3. Pearson HA. J Pediatr Hematol Oncol 2007; 29:160-2. Perniola R, Magliari F, Rosatelli MC, De Marzi CA. Gynecol Obstet Invest 2000; 49:137-9. Singer ST, Vichinsky EP. Am J Hematol 1999; 60:24-6. Surbek DV, Glanzmann R, Nars PW, Holzgreve W. J Perinat Med 1998; 26:240-3.
Summary	Pregnancy Category: C Lactation Category: U • Deferoxamine should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

Read full chapter

URL: https://www.sciencedirect.com/science/article/pii/B9780323428743000045

Absorption

Erythromycin is available for oral administration as enteric-coated erythromycin base, erythromycin esters (ethylsuccinate or estolate), and erythromycin salts (phosphate or stearate). Because of expense, many practitioners administer the drug as crushed enteric-coated tablets of erythromycin base. However, erythromycin base is degraded in the stomach by gastric acid. The esterified formulations are absorbed intact and must be hydrolyzed to the active erythromycin A. The erythromycin salts are absorbed unchanged.260 The oral bioavailability of erythromycin base is 17% in fasted foals, with most of the drug being degraded and absorbed as the microbiologically inactive anhydroerythromycin A.264 Microencapsulation of the base improves the oral bioavailability of erythromycin base to 26% in fasted foals, but it remains only 7.7% in fed foals.265 The oral bioavailability of erythromycin estolate in fasted foals is 36% but only 16% for erythromycin phosphate.266 The estolate formulation appears to have the best pharmacokinetic profile in foals. Because of injection site irritation, IM administration of erythromycin is not recommended in horses. The reported oral bioavailability of azithromycin in foals ranges between 39% and 56%.267,268 The oral bioavailability of clarithromycin in foals is similar (57%).269 Telithromycin, an oral ketolide antibiotic used for treatment of macrolide-resistant R. equi in humans, has also been studied in foals. Bioavailability has not been determined; however, although absorption was adequate for treatment of susceptible R. equi isolates, it was not high enough for treatment of most macrolide-resistant R. equi isolates in foals.270 The bioavailability of tulathromycin has not been determined; however, after IM administration the drug is rapidly detected in the plasma of foals, with maximum concentrations of 0.41 μg/mL 4 hours after administration.271 Gamithromycin has maximum concentrations of 0.33 μg/mL 1 hour after IM administration in foals.272

Read full chapter

URL: https://www.sciencedirect.com/science/article/pii/B9780323443296000024

Immunotherapy to Allergens

The term “allergy” was first introduced by Clemens Freiherr von Pirquet, an Australian pediatrician, who believed that it was a pathological state of altered immune reactivity. However in 1911 Leonard Noon and John Freeman proposed the concept of allergen immunotherapy (IT). They hypothesized that toxins from grass pollen somehow accounted for symptoms seen in patients suffering from hay fever. By inoculating the patients with gradually increasing doses of the toxin itself to stimulate the immune system against the toxin, the symptoms could be reduced or even abolished.

Since then allergen IT has become a proven approach for treating allergic rhinitis and allergic asthma and has undergone significant development in the last two decades. Current allergen-specific IT (SIT) involves administering increasing doses of the causative allergen in order to reduce the clinical signs and symptoms associated with exposure to the allergen and thereby produce tolerance. As currently practiced, IT involves subcutaneous or sublingual administration of allergens, both methods of which have been extensively investigated. In addition to allergen IT, a number of additional non-SIT approaches are being used or are in phase II/phase III clinical trials. Such therapies include anti-IgE antibodies and the soluble IL-4 receptor (sIL-4R). Other experimental IT approaches are at the preclinical research stage and may also proceed to clinical trials and the clinic within the next 5–10 years. Here in this chapter we will discuss the pros and cons of recent developments in both currently practiced and experimental IT approaches with a focus on costimulation-based IT for allergy and asthma.

The allergens are administered by two different routes: parenteral or subcutaneous IT (SCIT) and sublingual IT (SLIT), which was introduced relatively recently. The current state of the art for each of these immunotherapeutic approaches is discussed below.

Subcutaneous IT

As currently practiced, SCIT has proven effective in allergic rhinitis and asthma and is Food and Drug Administration (FDA) approved and reimbursable. SCIT has been extensively studied in double-blind trials to determine effective doses, establish duration, define the mechanisms, and to investigate the persistence of efficacy after treatment ends. However, the need for multiple visits to the clinic for shots is inconvenient, only a few allergens have been standardized for SCIT, and the potential for systemic anaphylactic reactions is a serious limitation. Although allergen IT has been around for about a century, little is known about the absorption and fate of subcutaneously administered allergen. The pharmacokinetics of SCIT has been studied using leukocytes labeled with 99mTc-HMPAO on allergic patients injected intravenously in contralateral arms. Local inflammatory activity was noted in the first hour and the increase was time-dependent. The immune system responded quickly as the activity was traced in the lymphoid tissue of the upper mediastinum and anterior region of the neck. Thoracic and bowel focalization was also noted for the subcutaneous route. Factors important in SCIT include the dose of allergen being administered, the quality of the allergen extract, and the duration over which it is given.56,57 The effects of duration of allergen dosing appear to depend on individual factors according to a review of studies performed between 1976 and 2006 in which the rate of relapse ranged from 0% to 50%.58 The immune mechanism of SCIT has been extensively studied. SIT alters allergen-specific T-cell responses from Th2-like to Th1-like and reduces inflammatory cells and mediators in the target nasal mucosa and the airways.59 For example, IT with house dust-mite extract induces antigen-specific suppressive activity by CD4+ CD25+ T cells in allergic subjects, which causes the regulatory/suppressor T cells to secrete IL-10 and transforming growth factor-β (TGF-β). This in turn increases IgG4 and IgA antibody production and suppression of IgE antibodies by B cells, thus mimicking a healthy immune response to environmental allergens.

Interestingly, a controlled study of traditional allergen vaccine IT to prevent asthma in atopic children demonstrated that more children in the nontreated group developed asthma than in the IT group. Moreover, it has been shown that IT in children sensitive to a single aeroallergen prevented new sensitization to other allergens.60 Currently, only 2–3 million people of the 55 million with allergic diseases are on SCIT. The main reasons for this are that the target populations dislike injections or cannot afford the time and expense of frequent visits to a doctor’s office. There is also a concern about the safety of SCIT, and it cannot be used for young children with allergy or asthma. In an effort to decrease the frequency of allergen administrations, intralymphatic allergen administration was attempted in a randomized (but not blinded) controlled trial.61 While the results of this study are promising, it was not a blinded study and the technology of ultrasound-guided intralymphatic injection may not be available in all clinics.

Sublingual IT

SLIT consists of placement of an aqueous allergen extract (50% glycerin and 0.4% phenol) in single allergen tablets or capsules under the tongue. It has been extensively practiced in Europe,62 and tested in clinical trials in the United States but is not yet FDA approved. Presently, SLIT is considered to have about one-tenth the risk of SCIT and has been shown to prevent new sensitization and progression from rhinitis to asthma. In addition, SLIT provides effective protection that persists for a long time after treatment is stopped. The disadvantages are that SLIT is less effective than SCIT and has not been tested for multiple allergen mixes. The pharmacokinetics of local IT by SLIT has been studied in allergic volunteers using radiolabeled allergen given in the form of soluble tablets. Plasma radioactivity was measured at different intervals using early and late sequential scintigraphic acquisition. No absorption through the oral mucosa was observed, and the plasma radioactivity, which peaks at 2 h, was increased only after swallowing. No allergen was detected in the blood stream.63 Another study, in which the biodistribution of 123I-radiolabeled Der p2 was assessed in allergic volunteers, confirmed these findings. Plasma radioactivity was only noted after the tablets were swallowed and the effect peaked at 1–2 h.64 It was noted that in order for the IT to be successful, the allergen had to be swallowed after the tablet had dissolved sublingually. This confirms that the contact with oral mucosa is an important factor, although no allergen was absorbed through the oral mucosa. It was also found that duodenal enzymes were necessary for hydrolyzing the allergen.65 Treatment with SLIT is initiated with a build-up phase lasting 4–6 weeks starting with the lowest concentration. The dosage is then gradually increased up to a maintenance dose. The recommended duration of the treatment is 3–4 years for optimal results.66 SLIT can be administered coseasonally, preseasonally, or continuously.67 The majority of SLIT studies have shown clinical efficacy in the form of improvement in symptom scores or medication scores, or both for allergic rhinitis and allergic asthma. A meta-analysis of five randomized double-blind, placebo-controlled studies on patients with allergic asthma showed significantly improved symptom scores and decreased use of rescue medication.68

Experimental IT Approaches

The availability of recombinant allergens makes it possible to treat allergic patients with identical, consistent vaccines. Recombinant allergens have other advantages which include (1) administration of allergens in optimal doses; (2) immunization with vaccines tailored to the major allergens to which the patient is allergic; (3) more accurate dosing; and (4) the possibility of modifying the structure of IgE-binding allergen epitopes, thereby increasing the safety of allergen IT. Recombinant allergens are not yet used in medicine since like other recombinant proteins; they must undergo rigorous clinical trials before they are available for clinical use.

Vaccination with a recombinant allergen before sensitization resulted in a state of immune deviation—a shift from a Th2, IgE response to a Th1, IgG2a response in a murine model.69 Because the immune system of neonates and adult mice is similar in terms of their ability to develop immune deviation, and because allergic sensitization occurs predominantly in the first 2 years of human life,70,71 using recombinant allergens for IT holds promise and needs further investigation. The recombinant allergens for IT may be used as aqueous, enteric-coated, or liposome-packaged vaccines or polymerized as recombinant allergoids using formaldehyde. Polymerized recombinant allergens are antigenic but nonallergenic and therefore may improve allergen-SIT. The problem with the available polymerized allergen vaccines is that they are not standardized and considerable batch-to-batch variation exists, making it uncertain whether all allergens have been uniformly polymerized or if some have been denatured. Recombinant allergens may also be conjugated with n-formyl-methionyl-leucyl-phenylalanine before being used to treat allergic patients.72 These chemically modified recombinant allergen vaccines should provide a safer and more effective vaccine with fewer injections than are needed with current allergen vaccines. Furthermore, once the epitopes have been identified, an allergen-cDNA can be altered specifically to reduce the IgE-binding ability of the corresponding recombinant allergen without compromising its capacity to stimulate T cells. Genetically modified allergens not only appear to be safe, but also may prove to be effective agents for patient-tailored IT.

Allergen genes expressed in an appropriate host may be used as live vaccines while recombinant allergens and their corresponding cDNAs can be used to prevent allergen-specific IgE responses. Genes can be introduced via live bacteria, or viruses, or using plasmid vectors. Two models are noteworthy. First is oral immunization with Salmonella typhimurium expressing the cDNA coding for the major birch tree allergen, Bet v 1. This live vaccine promoted IgG2a instead of the default IgE antibody response in mice;73 however, the Bet v 1-specific IgG2a response could be detected in only 10% of the immunized mice. Second, a live vaccine to treat allergic diseases using recombinant Bacillus Calmette-Guerin-expressing allergens has been proposed.74 These experimental approaches appear promising and may lead to effective prophylactic allergy vaccines. About one-quarter of the population is genetically predisposed to develop allergic disease. With advances in the identification of genes associated with asthma, it may be possible to develop methods for predicting atopic predisposition, which may then allow for the vaccination of predisposed individuals against the dominant allergens in their environments.

Alternatively, plasmids expressing allergens can be used for therapeutic vaccination. The immunization of mice with an allergen-cDNA cloned in a plasmid vehicle resulted in an allergen-specific IgG2a and Th1-like response, with no detectable IgE. Furthermore, the gene immunization induced a Th1-like response by reversing the ongoing allergen-specific Th2-like response. These studies suggest that immunization with allergen-cDNAs may provide a novel type of IT for allergic diseases; however, the application of DNA vaccines as a prophylactic may be more feasible because of the possibility of inducing anti-DNA antibodies and autoimmunity.

Peptide-Based Therapies

Because T cells play a dominant role in IgE synthesis, T-cell peptides may be useful as immunotherapeutic vaccines. T-cell peptide vaccines induce anergy in allergen-specific T cells or interfere with the formation of the trimolecular complexes involving the interaction of MHC–peptide duplexes with the appropriate TCR.75,76 Peptide vaccines have several advantages: a defined chemical structure, simplicity of preparation, and prolonged shelf life. They also appear to be safe because, at least in mice, T-cell peptides do not bind to IgE;77 however, human immune responses to allergens are more complex than murine immune responses. Various theoretical constraints are predictable: (1) some major allergens, particularly pollen allergens, contain several T-cell epitopes that are recognized by allergic individuals; (2) certain major allergens appear to have various isoforms containing crossreacting and noncrossreacting epitopes, which increase the repertoire of allergenic epitopes;78 (3) allergic individuals differ with respect to their recognition of these epitopes; (4) B-cell and T-cell epitopes may be present on the same peptide, which increases the risk of systemic reactions; and (5) excessive doses of some peptides may induce autoimmune reactions. Thus, in individuals allergic to certain complex aeroallergens, treatment with peptides may not be effective or appropriate. In experimental animals, synthetic Fel d1 (cat major allergen) or Der p1 (house dust-mite major allergen) T-cell peptides induced peripheral T-cell tolerance.79,80 The activation of allergen-specific T cells and IgE antibody synthesis was inhibited by in vivo administration of peptides by intranasal, oral, and subcutaneous routes.

The largest clinical study with allergen peptides was conducted using a total of four injections of 750 μg each of two peptides from the cat-allergen Fel d1 (ALLERVAX-CAT; ImmuLogic, Boston, MA) at 2-week intervals. In a multicenter, randomized, double-blind, placebo-controlled study, 133 cat-allergic patients chronically exposed to cats or who had failed previous conventional cat IT, were given ALLERVAX-CAT as a 750 μg dose, and patients with reduced baseline forced expiratory volume in 1 s (FEV1) showed improved pulmonary function. Side effects of the treatment were considered to be of mild-to-moderate severity and were reported by 77 patients who had at least one respiratory system event including chest tightness, dyspnea, coughing, throat irritation, wheezing, and asthma aggravation. The most common dermatologic reaction presented was pruritus. Although severe adverse effects (AEs) did occur, there was no statistical difference in the frequency of their appearance between the treated and placebo group.81 Therefore, although peptide therapy in severely cat-allergic patients was associated with some adverse effects, the therapy was found to be effective.

Allergen-Specific Therapy with Th1-Stimulating Adjuvants

Immune deviation from a Th2-like to Th1-like response may be achieved by designing vaccines with allergens or recombinant allergens in conjunction with adjuvants. The adjuvants may be cytokines or synthetic compounds, such as immunostimulatory DNA sequences containing a cytosine-phospho-guanosine (CpG) motif that induces a Th1-like cytokine response.82,83 The adjuvant may be injected with natural allergens or genetically linked with allergen-cDNA. Among the cytokines, IFN-α and IL-12 both induce a strong Th1-like cytokine profile and therefore have the potential to convert allergen-specific Th2-like responses to Th1-like responses. IL-12 has also been suggested as an adjuvant for vaccination against diseases in which the Th2 profile predominates. IFN-τ, a type I IFN that lacks the toxicity associated with type I IFNs, inhibited IgE production in a murine allergy model and in an IgE-producing human myeloma cell line. Administration of a recombinant allergen (ovalbumin) vaccine with the IL-12 (subunit p40) fusion protein downregulated ovalbumin-specific IgE responses in vivo;84 however, IL-12 may cause side effects, and its effectiveness requires IFN-α production by the target cells. Because IL-12’s ability to convert an established Th2 to a Th1 response remains uncertain, the use of IL-12 as an adjuvant for allergen vaccines is unproven. Also of note are the studies involving TLR antagonists, which are based on the observation that LPS, the ligand of TLR-4, inhibits Th2 cytokine production in nasal explants of children.85 MPL, a chemically modified derivative of LPS, was still a TLR-4 agonist and decreased combined symptom and medication scores compared to placebo in clinical trials.86 A ragweed-TLR-9 agonist vaccine for IT was also tested in clinical trials in allergic rhinitis patients. While the results for the primary endpoint were not statistically significant, the secondary endpoints were significantly reduced. A similar study with this TLR-9 ligand in asthmatics showed a clear reduction of FEV1 and sputum eosinophils after allergen challenge.87 Another potential form of IT involves the Fcγ1-linker-major cat-allergen, Fel d1, fusion protein, which was effective in inhibiting allergic responses in mice in vivo and human cells in vitro.88 Gamma Fel D inhibits cat-allergen-induced degranulation of human basophils and cord blood mast cells in culture. Since results of mouse studies may not be translatable to humans, the proof-of-concept needs to be obtained in humans and the potential adverse effects need to be examined. Also, IT with mite allergen Der p1 on virus-like particles was reported to be safe and highly immunogenic in healthy adults.89 The IgG response to dust mite allergens, particularly IgG1 and IgG3, but not IgG2 and IgG4, was significantly induced by these particles. However, this study was limited by lack of comparisons between Der p1 on virus and Der p1 without virus, lack of cellular studies and appropriate clinical endpoints relevant to human allergy and asthma.

Novel Approaches to Allergen-SIT

Although excellent drugs to control the symptoms of allergy and asthma are available, the only treatment able to cure allergy remains allergen-SIT. SIT is, however, rarely chosen as a therapeutic option by allergic patients mainly because it requires a treatment period lasting between 3 and 5 years to reach protection against the offending allergen. This unsatisfactory situation has strongly stimulated innovative research activities within the allergy field aimed at making SIT faster and safer in order to augment patient’s compliance. Two main problems need to be reduced or eliminated to render SIT more attractive, and these are side effects and treatment time. Several exciting approaches to solve these issues are currently under clinical investigation. Therapy-related SIT side effects derive from the intrinsic property of allergens to crosslink high-affinity receptors for IgE on effector cells resulting in their degranulation and release of premade toxic substances, like histamine and leukotrienes, leading to local or generalized anaphylactic reactions. Allergoids, hypoallergens, and immunodominant allergen peptides are allergen surrogates with markedly reduced IgE-binding capacity, while conserving the whole and/or the immunodominant T-cell epitopes required for eliciting protective (IgG-mediated) immune responses. SIT with allergoids reached the market some time ago and has yielded results comparable to those obtained with allergen extracts with a reduced side effect profile, but it still requires a long treatment time. Peptide IT showed promising results in clinical trials with bee venom allergic and cat-allergic individuals.

Many genetically engineered hypoallergens have shown promising results in mouse models of allergy. Perhaps the more advanced form of IT with allergens showing a favorable safety profile is SLIT. SLIT still suffers from a long treatment time comparable to those of classical SCIT but is increasingly used as a therapeutic option, especially in Europe. These approaches have significant potential for improvement, particularly in combination with novel adjuvants and modified treatment regimens. Obviously, a long treatment time strongly reduces patient’s compliance, and therefore many efforts have been undertaken to reduce the number of injections (currently 50–80 are required) in order to achieve protection. Four different strategies have entered phase I/IIA clinical trials and yielded promising results: peptides covalently coupled to virus-like particles,89 A-type CpG oligodeoxynucleotides as an adjuvant,90 direct injection of allergens into lymph nodes,61 and modular antigen translocating vaccines, which directly target the MHC class II antigen presentation pathway.91,92 All these therapeutic innovations have, if confirmed in larger multicenter clinical trials, the potential to turn IT into a true vaccination approach because only a few injections are required to achieve long-lasting protection. These approaches indicate that the problems related to the long treatment time of classical IT, which is mechanistically based on immunomodulation, which requires a long time to establish, can be reduced using strong adjuvants, by changing the route of application, or by direct targeting of the antigen presentation pathways. We conclude that the limited efficacy associated with classical SIT is not closely related to the potential of the immune system to mount protective responses against allergens. There is clear evidence that low amounts of antigen, such as those encountered during natural exposure to most of the environmental allergens, favor the switch of B cells toward IgE production in predisposed individuals, whereas higher doses of antigen favor the development of protective IgE antibody responses. Therefore, the most promising approaches to faster and more successful SIT treatment regimens will most likely derive from strategies aimed at increasing the therapeutic dose of the allergen in lymph nodes, while avoiding effector cell degranulation.

Current Immunomodulatory Strategies for Asthma Under Investigation

A number of anti-cytokine therapies are currently being examined. Daclizumab (an IL-2 receptor antagonist) has been examined in a phase II study in patients with moderate-to-severe asthma. Patients treated with daclizumab showed improved pulmonary function; reduced asthma symptoms and medication use; increased interval between severe exacerbations; and reduced blood eosinophils and serum eosinophil cationic protein levels.93,94 Two humanized IL-5 monoclonal antibodies (mAbs)—reslizumab and mepolizumab—have been studied in humans. Mepolizumab decreased blood and airway eosinophils, but no significant sustained changes in FEV1, asthma symptom scores, sputum eosinophils, or physician-evaluated overall condition were noted with mepolizumab or reslizumab compared with placebo.95,96 In order to neutralize the activity of IL-4, recombinant human sIL-4R has been examined.97 Patients with moderate, persistent asthma had significant improvement in asthma symptom scores, rescue β-agonist use, and exhaled nitric oxide levels compared with those receiving placebo.63 However, a follow-up study revealed that only asthma patients receiving the highest dose of sIL-4R maintained their lung function.98 Blocking TNF-α using neutralizing antibodies improved lung function and quality of life and reduced exacerbation frequency in patients with asthma in some studies but not in all studies.99–101 It is likely that additional cytokines (e.g., chemokines) will also be targeted in the near future for patients with allergy and asthma. Several humanized mAb that bind to the Fc portion of the IgE molecule have been used in clinical studies, and one (omalizumab) is currently available for treatment of allergic asthma. Anti-IgE in combination with allergen-SIT resulted in a greater reduction in seasonal allergic rhinitis symptoms and rescue medication scores compared to allergen-SIT alone.102 Importantly, the addition of omalizumab to a rush SIT protocol significantly reduced the risk of anaphylaxis.103

Anti-histamine compounds that target the histamine receptor 1 (H1R) have been used for some time. However, the discovery of a new histamine receptor, H4R, has provided a new target for drug development. Thus far, only animal model data are available that demonstrate proof of the efficacy for H4R antagonists in models of asthma, allergic rhinitis, and pruritis.104 Candidate molecules have been identified, which are expected to enter clinical trials shortly.

Monoclonal Anti-IgE Antibody Therapy

The development of an allergic state is a gradual process, and as a genetically predisposed individual undergoes the “allergic march,” he or she may develop allergies to several antigens.105 Because IgE crosslinking on the mast cell membrane by allergens is an important first step in an allergic reaction, IgE has been an attractive therapeutic target. Although the idea of anti-IgE as a therapeutic agent was conceived during the 1970s, the use of anti-IgE as a therapeutic strategy failed because the antibodies initially employed caused mast cell degranulation. With the advances in recombinant DNA technology, it has become possible to engineer mAbs that reduce unbound IgE levels in the serum by binding to circulating serum IgE antibodies but not to IgE antibodies bound to FcεRI or to FcεRII.106

Two mouse monoclonal anti-IgE antibodies, TES-C21 and MAE11, have been humanized107 and MAE11 (rhuMAb E25) has been evaluated in clinical studies. In humanizing MAE11, a framework derived from consensus sequences of human VL and VH chains was used, and the critical amino acids responsible for binding IgE were engrafted onto a consensus human IgG1 framework.89 Several clinical studies have been conducted to evaluate the safety and effectiveness of using anti-human IgE antibodies to treat allergic asthma and allergic rhinitis. The results of these studies show that anti-IgE therapy reduces allergic symptoms, is well tolerated by patients, and does not cause any severe AEs.107 The two monoclonal anti-IgE antibodies, rhuMAb E25 and CGP51901, have been shown in a number of clinical trials including subjects with asthma or allergic rhinitis to be safe and effective in generating tolerance. The anti-IgE antibody CGP51901, which is a chimeric version of the mouse monoclonal anti-IgE TES-C21, has been evaluated in patients with seasonal allergic rhinitis.108 These studies have shown a decrease in free serum IgE but an increase in total IgE levels. The slow clearance of IgE–anti-IgE complexes explains the increase, with complexed IgE having a half-life of 11–13 days. The reduction in free serum IgE levels was dependent upon anti-IgE doses and was reversible. It was necessary to sustain 85% or greater reduction in free serum IgE levels to achieve improved clinical symptoms, and an 85% reduction in IgE required a serum CGP51901 concentration of 5000 ng/mL. The treatment was safe, with no serum sickness and only one case of urticarial among 153 evaluated patients.109

The anti-IgE antibody rhuMAb E25 has been evaluated in both allergic rhinitis and asthma. It decreased free serum IgE in a dose-dependent fashion in patients with seasonal allergic rhinitis;232,233 however, in this study, it was not possible to evaluate its clinical efficacy because only 11 subjects had undetectable IgE levels. To achieve undetectable IgE concentrations, the dose of rhuMAb E25 was 0.005 mg/kg/week for each international unit per milliliter of baseline IgE. There were no AEs related to this treatment. The rhuMAb E25 antibody has also been studied in asthma, but asthma symptoms, rescue medication use, or FEV1 did not improve; however, there was improvement in the allergen early- and late-asthmatic response, methacholine reactivity, and some inflammatory parameters in induced sputum. The evaluated patients had mild asthma, which may have limited the potential for improvement. The administration of rhuMAb E25 significantly increased the allergen doses required to cause a 15% decrease in FEV1, with a correlation between the decrease in free serum IgE and the protection against inhaled allergen.110,111 The same study also showed that a higher dose of methacholine was necessary to reduce FEV1 by 20% after administration of rhuMAb E25. Another study showed rhuMAb E25 reduced maximal bronchoconstriction by 60% during the late asthmatic response following allergen challenge. Reduction of the early response after bronchial allergen challenge was less affected.71 The late asthmatic response following allergen challenge correlates with airway hyperresponsiveness, airway inflammation, and improvement of asthma symptoms, suggesting rhuMAb E25 may have a clinical benefit. Additional studies support this possibility with rhuMAb E25 administration reducing the number of asthmatic exacerbations and facilitating a 50% dose reduction in use of inhaled and oral steroids.112,113

Among all of these reports, only minimal toxicity was observed with one case of urticaria. Recently, however, more side effects have been noted including local injection site irritation, upper respiratory infection, headache, and urticaria.114 Among the total of 118 cases of anaphylaxis found by the FDA AE reporting system, 19 had anaphylaxis within the first hour, 32 had reaction after receiving the first dose, while 14 reacted after the second dose, and 77 patients required hospitalization. These patients were treated with epinephrine or corticosteroids, and had anti-IgE withheld or discontinued. The vaccine was given subcutaneously every 2 or 4 weeks and the dose was determined by body weight and total pretreatment serum IgE levels. Absorption is slow from the inoculation site and the mean half-life of the drug is 26 days,115 while the evidence shows that anti-IgE is a safe and effective immunotherapeutic treatment for asthma, it is noteworthy that anti-IgE antibodies also aid with allergen IT and reduce the risk of adverse reactions. Casale et al.103 reported that anti-IgE reduces acute allergic reactions with SCIT rush IT, which reduces the frequency of hospital visits inherent with classical SCIT. In addition to the new treatments described above, several other potential approaches are being explored. Most of these are aimed at modulating the allergic immune response and inflammation in murine models using either soluble receptors or antibodies that alter cytokines, immunocyte coreceptors, IgE receptor binding, and cellular adhesion.

IgE-Binding Receptors

The IgE antibody binds to the FcεRI and CD23 on mast cells and basophils and to CD23 on monocytes and eosinophils. Both receptor and ligand are potential therapeutic targets. Antibodies attached to CD23 may be able to facilitate antigen presentation to T cells, but IgE regulation was not affected. Transgenic mice that overexpress CD23 on T and B cells exhibit decreased IgE production,116 which suggests that enhancing CD23 expression on B cells before activation can effectively inhibit IgE production. Conversely, a decrease in CD23 levels with a metalloprotease resulted in an increase in IgE.117 The administration of anti-CD23 antibodies inhibits eosinophil airway recruitment and reduces airway hyperresponsiveness.118,119 This observation suggests that anti-CD23 antibodies may be used to block the interaction between IgE and CD23, reducing eosinophil recruitment and inflammation. More studies are necessary before IgE receptors can be viewed as important therapeutic targets for allergic disease.

Anti-IgE Monoclonal Antibodies

The anti-IgE antibody omalizumab has so far only been studied as a treatment for severe allergic asthma. There are well-documented effects on risk of asthma exacerbation.120 The drug is expensive and requires injections at monthly or biweekly intervals. A reduction in free IgE levels following the anti-IgE therapy could lead to reduction in FcεRI expression on mast cells, basophils, and DCs.121 One could speculate that treatment with anti-IgE in high-risk children could prevent allergic sensitization and delay or prevent development of allergic asthma. On this premise, an observational study has shown that after stopping prolonged treatment with omalizumab, asthma control can persist as a residual effect, possibly indicating a modifying effect on the natural history of asthma.122 The results of the XPORT trial (NTC01125748), a double-blind placebo-controlled withdrawal study of moderate-to-severe asthmatic adult patients who received omalizumab for ≥5 years, have been recently disclosed. Patients were randomized to either continue receiving omalizumab, or switch to placebo for one additional year. At the end of that period, whereas the proportion of patients receiving the active treatment who had not suffered an asthma exacerbation was 67%, this only happened in 48% of patients in the placebo group. However, this would suggest that in about half of patients the effect of omalizumab would persist at least for 1 year after it was stopped.123 Furthermore, omalizumab reduces airway remodeling by modulating bronchial reticular basement membrane thickness and eosinophil infiltration.124 New immune modulator interventions are being developed to improve the immune response to viral infections in children with impaired innate immunity, as shown by decreased levels of IFN-γ or impaired function of TLRs.125 Examples are inhaled IFN-β and a TLR agonist. They are being evaluated for treatment, but they may potentially have a preventive activity.

In summary, there are still no drugs to be used for primary prevention of asthma. There are, however, treatment possibilities for tertiary prevention of deterioration and exacerbations although effects on the long-term prognosis are still uncertain. Prevention of rhinovirus infections may provide a major step forward in primary prevention; immune modulators improve the innate immunity and response to virus infections; and there are other potential approaches.

sIL-4R Therapy

IL-4 is one of the most important cytokines in a variety of allergic diseases, including asthma.126 IL-4 is produced primarily by CD4 Th2 cells but also by CD8 T cells, eosinophils, mast cells, and basophils. The role of IL-4 in human asthma has been established in several studies. The proof of the importance of IL-4 includes the following: (1) characterization of T-cell clones producing IL-4 in allergic and nonallergic individuals;127 (2) in situ localization of IL-4-producing cells in bronchial biopsies;234 (3) expression of IL-4R mRNA and protein in epithelium, subepithelium, and endothelial cell layers in bronchial biopsies of atopic asthmatics compared with controls;128 and (4) analysis of mutations of the IL-4R and their association with asthma.129 The importance of IL-4 in the regulation of the allergic response, coupled with the identification of the soluble receptor, suggested that the sIL-4R might be effective as a therapeutic agent. Soluble IL-4R inhibited the IL-4-induced proliferation of B cells; the expression of low-affinity IgER and MHC class II; and the secretion of both IgE and IgG1 antibodies in mice.130 In a murine model of allergen sensitization, soluble murine IL-4R inhibited polyclonal and particularly antigen-specific IgE and IgG1 production following restimulation with these allergens.131 In addition to inhibiting Ig class switching and IgE production, murine sIL-4R reduces allergen-induced airway reactivity, vascular cell adhesion molecule-1 (VCAM-1) expression; allergen-induced eosinophilia in bronchoalveolar lavage (BAL); and allergen-induced pulmonary infiltration and airway occlusion by inflammatory cells. The safety of sIL-4R therapy is demonstrated by transgenic mice that produce a 100-fold greater sIL-4R concentration than nontransgenic littermates. Mice with increased sIL-4R compared with controls have similar numbers of B and T lymphocytes, lymphocyte surface marker expression, and antigen-specific antibody responses.132

In clinical studies, soluble IL-4R blocked CD8 T-cell-mediated IgE production in allergic patients, suggesting that sIL-4R may be useful for treating allergic diseases.133 Studies on the effects of recombinant humanized sIL-4R (rhusIL-4R) on IL-4/staphylococcal enterotoxin B-stimulated peripheral blood mononuclear cells from patients with eczema suggested that rhusIL-4R may be an immunomodulatory drug for atopic eczema.134 In another study of human asthmatics, rhusIL-4R, was nebulized and given to 62 patients with moderate asthma at doses of 0.75, 1.5, or 3 mg. The study was double-blinded and placebo-controlled, and corticosteroid therapy was discontinued at entry. The results showed that sIL-4R was well tolerated, and the group treated with 3 mg sIL-4R demonstrated less labile FEV1 and improved asthma symptom scores compared to the placebo group.63 In an open-label, randomized, dose-ranging study, the safety and tolerability of sIL-4R was evaluated in 16 adult patients with mild atopic asthma (FEV1 >70% of predicted). A single nebulized dose (50–100 μg) was generally well tolerated and pulmonary function improved.135 In a phase I/II randomized, placebo-controlled trial,63 25 patients with moderate, inhaled corticosteroid-dependent asthma were randomly assigned to receive a single nebulized dose of IL-4R or placebo after discontinuing inhaled corticosteroids. The results indicate that sIL-4R is effective with once-weekly inhalation. The treatment is generally well tolerated and prevents a decline in FEV1, improves asthma symptom scores, and reduces β2-agonist rescue following discontinuation of inhaled corticosteroids. Pulmonary inflammation, as assessed by exhaled nitric oxide, was significantly lower in the sIL-4R treated group compared to the placebo group. The treated group had nonstatistically decreased levels of VCAM-1, intercellular adhesion molecule-1, and EPO and increased CD23 expression compared to the placebo group. These results support the potential use of sIL-4R as a therapy for asthma and other allergic diseases, but additional studies are needed.

Targeting Tregs for IT of Allergy and Asthma

The fundamental role of Treg cells in maintaining immune tolerance has been demonstrated in a wide range of animal models, in which the adoptive transfer or deliberate expansion of Treg cells was shown to prevent or cure several T-cell-mediated diseases, which include allergy, asthmatic lung inflammation, autoimmune diseases, and allograft rejection, by restoring immune tolerance to allergens, self-antigens, or alloantigens. Multiple molecular mechanisms for Treg-mediated immunosuppression have been described with secretion of IL-10 being of particular importance.136 Absence or defective function of Treg cells has also been correlated with hyper-IgE syndrome, hypereosinophilia, and autoimmunity in humans, whereas their presence has been associated with immune tolerance.137

Studies on the mechanisms by which immune responses to nonpathogenic environmental antigens lead to either allergy or nonharmful immunity have demonstrated that allergen-specific IL-10 producing Tregs (TR1 cells) are the dominant T cell subset in healthy individuals.138,139 Repeated exposure of nonallergic healthy beekeepers to bee venom antigens during the beekeeping season represents a valuable in vivo model to ascertain mechanisms of immune tolerance to venom antigens.140 After multiple bee stings, venom antigen-specific Th1 and Th2 cells switch toward IL-10-secreting TR1 cells. This occurs in parallel to the suppression of cutaneous late-phase responses to allergens and inhibition of allergen-specific Th1 and Th2 cells. The response is observed as long as venom exposure persists and returns to initial levels within 2–3 months after the end of the beekeeping season. In the same model, the upregulation of H2R on specific Th2 cells suppressed allergen-stimulated T cells and increased IL-10 production. Various strategies, which are designed to enhance Treg function in vivo, are currently under investigation. These include the adoptive transfer of inducible or constitutive Treg cells and their induction by specific adjuvants or immunomodulators. These approaches are attractive compared to conventional treatments, as the antigen-specific suppressor capacity of Treg cells does not result in general immunosuppression and may actually lead to long-lasting antigen-specific regulation in vivo. Moreover, individual patient-specific treatments are possible with limited side effects. Many immunomodulators that have been developed or are under development, such as rapamycin, the CD80/CD86:CD28 costimulation blocker abatacept (Orencia; Bristol–Myers Squibb, Co., Uxbridge, Middlesex, UK), nonmitogenic anti-CD3 mAbs, and T-cell depletion and anti-TNF-α mAbs, display direct or indirect effects on Treg cells, which may enhance or suppress their function.141–143

There is a selective advantage to expand a population of Treg cells that can target the organ (or the lymph nodes that drain the organ) by recognition of an allergen or an autoantigen expressed in inflamed organs in mouse models.144 Thus, transfer of organ-specific Treg cells can be effective at suppressing ongoing disease, although those Treg cells do not necessarily need to recognize exactly the same autoantigen as the autoaggressive effector T cells.145 This observation has implications for therapeutic strategies aimed at targeting the Treg cell arm of immune tolerance against allergens, autoantigens, or transplantation antigens. Possibilities of adoptive transfer of Treg cells or small molecular compounds that induce Treg cells in the tissue are being investigated,144 but no double-blind, placebo-controlled studies have been reported so far. To date, allergen-SIT is the only antigen-specific approach that induces Treg cell production and activation in humans. Allergen-SIT induces Treg and IL-10-secreting TR1-like cells, and treatment with glucocorticoids and β2-adrenergic agonists seems to promote the number and activity of these cells.146–148 The essential transcriptional elements regulating expression of the Foxp3 promoter have been recently reported, and these will provide new targets for the development of novel therapeutics.149

Read full chapter

URL: https://www.sciencedirect.com/science/article/pii/B9780128025857000042

Clinical Studies

A randomized, dose-escalation trial assessed the safety and tolerability of teriperatide in 42 healthy volunteers, who were randomized to receive a single dose of teriperatide (10, 20, 30, 40, 50, or 60 μg) or a 7-day course (10 and 20 μg once daily for 7 consecutive days). No side effects were reported with 10 and 20 μg as a single dose and 10 μg in multiple doses. Injection site infection was the most common side effect, followed by nausea and vomiting [76c].

A randomized, placebo-controlled trial evaluated the efficacy and safety of low-dose teriperatide (28.2 μg/week) in fracture risk reduction in osteoporotic patients, over a median observation period of 48 weeks (n = 158 each treatment arm). This regimen was effective, resulting in a relative risk reduction for vertebral fractures of 66.4%. Adverse events were more common in the teriperatide group (n = 38 vs. 5 in the placebo group, p = 0.001). Nausea (n = 9) and vomiting (n = 6) were the most common side effects [77C].

A randomized study compared teriperatide, denosumab and combination thereof in 100 women at high risk of fractures. Study participants received 20 μg teriparatide daily (n = 36), 60 mg denosumab every 6 months (n = 34), or both (n = 30). Combination treatment was more effective at increasing bone mineral density. Mild asymptomatic hypercalcaemia was detected in one woman in the teriparatide group, one in the denosumab group, and three in the combination treatment group [78C].

Combination Treatment with Teriperatide and Risedronate

29 adult male patients with osteoporosis (idiopathic, steroid-induced or secondary to hypogonadism) were randomised to receive oral risedronate (25 mg weekly) plus placebo injection (n = 10), subcutaneous teriparatide (20 μg daily) plus oral placebo (n = 9), or oral risedronate plus subcutaneous teriparatide (n = 10). All strategies were effective at increasing bone mineral density at several points (total hip, femoral neck, lumbar spine); combination treatment was actually more effective than either monotherapy at increasing total hip bone density. Adverse events were not significantly different across the three groups. In the teriperatide-only group, these included injection site irritation (n = 2) and leg cramps (n = 1) [79c].

Read full chapter

URL: https://www.sciencedirect.com/science/article/pii/S0378608015000288