|Q&A IN INTERNAL MEDICINE
|Year : 2014 | Volume
| Issue : 2 | Page : 93-96
Questions and guide to answers
Hoda Atya, Hoda Al-Rawi
Department of Internal Medicine, Kasr Al-Aini School of Medicine, Cairo University, Cairo, Egypt
|Date of Submission||15-Feb-2014|
|Date of Acceptance||25-Apr-2014|
|Date of Web Publication||28-Aug-2014|
MD, Department of Internal Medicine, Cairo University, Cairo
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Atya H, Al-Rawi H. Questions and guide to answers. Egypt J Intern Med 2014;26:93-6
| The Egyptian Society of Internal Medicine 2014, 26:93-96|| |
Q1: Discuss complement antagonists.
A1: The complement system is an important part of innate immunity; however, as with other parts of the immune system, the complement system can become pathologically activated and create or worsen disease .
The complement system, as a part of innate immunity, carries out a wide array of functions, including protection against foreign organisms, removal of immune complexes from the circulation, and clean-up of cellular debris that accumulates over time. The complement system also plays a significant role in the initiation and propagation of the inflammatory response. Besides its beneficial effect, the complement system can also play a detrimental role in many patients. The complement system includes a group of proteins that are recognized to be an important part of the immune response. The system can be activated by a classical (usually antibody-dependent) or alternative (usually antibody-dependent) pathway. Activation by either pathway leads to the generation of an enzyme called C5 convertase. The convertase helps to form a protein called C5b, which, among other functions, initiates what is often referred to as the terminal complement pathway. A goal of this pathway is to form a membrane attack complex within the membrane of an invading pathogen, thereby causing lysis. The membrane attack complex is generally formed by the sequential assembly of complement proteins C6, C7, C8, and (C9)n along with C5b , leading to disruption of the phospholipid bilayer of the cell membrane, loss of cellular homeostasis, and eventually cell death .
The complement system comprises several plasma and cell surface proteins, including complement regulatory proteins. When these complement regulatory proteins do not function properly, the complement system can become improperly activated and cause tissue damage. Over the last several years, work has been conducted to study complement activation in certain disease states and whether there is any role for complement inhibition in the treatment of these diseases .
As the complement system has such a potent ability to cause cellular damage, it is extensively regulated both in the fluid phase and on cell surfaces .
In the classical pathway, one of the main complement regulatory proteins is C1 inhibitor [Proteins with decay-accelerating activity that regulate the classical pathway include C4-binding protein (C4bp), complement receptor 1 (CR1), and decay-accelerating factor (DAF) or CD55. Proteins with decay-accelerating activity that regulate the alternative pathway include CR1, factor H (FH), and DAF C1-INH] .
Many inflammatory, autoimmune, neurodegenerative, and infectious diseases have been shown to be associated with excessive complement activity . Numerous attempts have been performed in recent years to inhibit or modulate complement therapeutically .
Types of complement antagonists therapeutics:
Serine protease inhibitors: The consecutive cleavage and activation of several proteases constitute the driving force behind complement function. Eight serine proteases are integral elements of the complement cascade itself (C1r, C1s, C2a, MASP-1, MASP-2, factor D, factor B, and factor I).
The only complement-associated protease inhibitor currently in the market is C1 inhibitor (C1-INH); therapeutic supplementation of this protein has proven to be an effective and safe treatment for heridetary angioedema (HAE) and helps prevent severe disease relapses and life-threatening complications .
Soluble complement regulators: As regulators of complement activation are natural modifiers of complement activities and prevent a host cell from being attacked by its own defense system, they have been considered for therapeutic use since the early stages of complement drug discovery. A first breakthrough was reached with the expression of a soluble form of complement receptor 1 (sCR1) . This molecule featured both decay accelerator and cofactor activity and had a high potency in inhibiting both the classical and alternative pathways. sCR1 showed promising results in the treatment of I/R injury .
Soluble forms of MCP, DAF, and CD59 have also been considered as a treatment option for paroxysmal noctournal haemoglobinuria (PNH). This rare, genetic, life-threatening blood disorder leads to decreased expression of membrane-anchored proteins, including CD59 and DAF, on the erythrocytes. Substitution and membrane tethering of recombinant CD59 may develop into a promising therapy for PNH .
Therapeutic antibodies: Antibody-based therapeutics appear to be the most rapidly growing drug class against complement-related diseases. Selective inhibition of C5 using monoclonal antibodies has been considered a promising therapeutic option for many years. A highly selective monoclonal antibody against mouse C5 was investigated and was later demonstrated to be effective in a mouse model of rheumatoid arthritis .
Eculizumab is currently the only complement-specific antibody in the market. Eculizumab is the first and only approved therapy for PNH. As an anti-C5 antibody that inhibits the generation of both C5b and the anaphylatoxin C5a, the potential indications for eculizumab are certainly not limited to PNH. Consequently, eculizumab has undergone several preclinical and clinical studies for a variety of conditions (e.g. psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and transplant rejection).
Pexelizumab, the short-acting sc-Fv fragment of eculizumab, has undergone several phase 3 trials to test its potential for use in coronary artery bypass graft surgery and acute myocardial infarction. Ofatumumab/HuMax-CD20 has been selected for clinical development and has recently been evaluated in terms of its effectiveness in treating acute rheumatoid arthritis .
Complement component inhibitors: Smaller molecules such as peptides, nucleotides, and synthetic molecules may also have the potential to interrupt protein functions by steric hindrance or the induction of conformational changes. Small functional inhibitors of complement activity are expected to have drug-like properties. Compstatin is the most developed candidate in this class of substances and recently entered clinical trials. It effectively prevents the cleavage of C3 to its active fragments C3a and C3b, and therefore inhibits the most central step in the complement cascade .
Anaphylatoxin receptor antagonists: The proinflammatory activity of the anaphylatoxin C5a is the driving force behind many complement-associated disorders. Selective inhibition of the binding of C5a to its receptors offers a very promising opportunity for dampening the inflammatory response without depleting the defensive potential of complement . The most promising candidate to emerge, the cyclic peptidomimetic PMX-53, is currently under development.
Cardiogenic shock often leads to splanchnic macrocirculatory and microcirculatory complications, and these events are linked to local and systemic inflammatory activation. Complement C5A antagonist treatment improves the acute circulatory and inflammatory consequences of experimental cardiac tamponade .
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Q2: Discuss nonerosive reflux disease (NERD).
A2: NERD has been commonly defined as the presence of classic GERD symptoms in the absence of esophageal mucosal injury during upper endoscopy .
Studies reported that about 50% of patients with heartburn were found to exhibit normal esophageal mucosa during endoscopy .
Within the spectrum of GERD, the pathophysiological relationship between NERD and erosive esophagitis remains the subject of great debate . The assumption that NERD and erosive esophagitis represent one continuous disorder has been challenged by studies demonstrating differences with respect to epidemiological features, pathophysiological characteristics, and responses to treatment .
Patients with NERD have less esophageal acid exposure but have greater esophageal sensitivity than patients with erosive esophagitis.
Current concepts in the pathophysiology of NERD involve peripheral factors (luminal, mucosal, and sensory afferents) as well as central factors (psychological, stress, sleep, etc.).
The potential explanations for the symptom generation in NERD include microscopic inflammation, visceral hypersensitivity (stress and sleep), and sustained esophageal contractions . It has been observed that acid exposure disrupts intercellular connections in the esophageal mucosa, producing dilated intercellular spaces (DIS) and increasing esophageal permeability, allowing refluxed acid to penetrate the submucosa and reach chemosensitive nociceptors . DIS has been observed in both NERD and erosive disease without a significant specificity, as it is also found in 30% of asymptomatic individuals . DIS has been found to regress with acid suppression . The development of DIS may also be potentiated by bile acids and by stress . Stress alone may increase esophageal permeability, provoking DIS that can be enhanced by acid exposure . These observations suggest a complex relationship between stress and acid exposure in the generation of reflux symptoms.
Physiological studies on patients with NERD have revealed minimal esophageal abnormalities. These patients have a slightly higher rate of primary peristalsis failure, defined by nontransmitted contractions or peristaltic contractions that do not traverse the entire esophageal body, as compared with normal controls  with Barrett's esophagus.
Distal amplitude contractions, as well as mean lower esophageal resting pressure, are mildly reduced in NERD patients as compared with normal individuals.
Hiatal hernia occurs in only the minority of NERD patients. Viazis N et al.  compared hiatal hernia rates in patients with NERD as against those with erosive esophagitis and demonstrated that 29% of the NERD patients had hiatal hernia as compared with 71% of those with erosive esophagitis. The absence of diaphragmatic hernia suggests that transient lower esophageal sphincter relaxation is likely the predominant mechanism for gastroesophageal reflux in most of the NERD.
The authors found that NERD patients had a significantly higher prevalence of functional bowel disorders such as functional dyspepsia and irritable bowel syndrome, psychological disorders, and positive acid perfusion test.
Upper endoscopy is the most sensitive diagnostic tool for assessing GERD-related esophageal mucosal injury such as erosions, ulceration, stricture, Barrett's esophagus, and others. This is particularly essential in diagnosing NERD because of the need to demonstrate normal endoscopic examination of the esophageal mucosa.
Use of high-resolution magnification endoscopy demonstrated the presence of minimal mucosal changes at the squamocolumnar junction of GERD patients with normal conventional upper endoscopy.
Recently, narrow-band imaging was introduced for better visualization of mucosal and microvascular patterns at the esophagogastric junction of NERD patients with normal endoscopy. This technique utilizes spectral narrow band filters and enables imaging of superficial tissue structures such as capillary and mucosal patterns without the use of dye. The presence of microerosions and increased vascularity at the squamocolumnar junction were the best predictors for GERD diagnosis. NERD patients with normal conventional endoscopy but with minimal changes at the squamocolumnar junction during magnification endoscopy, chromoendoscopy, or narrow-band imaging should be considered as having erosive esophagitis.
PPIs are currently considered the most effective and safe therapeutic modality for gastro-esophageal reflux (GER).
As GERD is mostly not a progressive disorder, treatment for many of these patients could be symptom driven. Thus, on-demand or intermittent therapy with a PPI is an attractive therapeutic strategy for NERD patients in clinical practice . These therapeutic approaches are convenient, allow patients to remain in control, cost effective, and decrease the likelihood of rebound of acid secretion.
Novel therapeutic modalities are currently under consideration for GERD patients and specifically for those with NERD. The main areas of interest include improving acid suppression, reducing the transient lower esophageal sphincter relaxation rate, decreasing esophageal sensitivity, and enhancing esophageal motility .
There are novel therapeutic modalities developed specifically for NERD patients. The targets for novel therapy are thought to be improving the competence of lower esophageal sphincter (LES) function such as new GABA-B agonists, better acid-suppression therapy, normalizing esophageal sensitivity, and augmenting esophageal motility. In patients with failure to respond to PPI treatment, it has been suggested that pain modulators such as tricyclics and selective serotonin reuptake inhibitors are an alternative treatment option.
The role of antireflux surgery NERD has not been well established.
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| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.