2023-06-15 15:46:51
The three common diseases asthma, rheumatism and hypertension have a common denominator: interleukins. Could they be a future therapeutic target for all three diseases?
The number of people with Asthma is estimated to rise to 400 million by 2025. Around 870 million people have a systolic blood pressure of over 140 mmHg, and the trend is rising here too. Both diseases are a great challenge in their own right – if they occur together, this is an extreme challenge for doctor and patient.
Lifestyle wants to be noticed
Management of hypertension and asthma patients requires a multifactorial approach that includes pharmacotherapy and lifestyle modification measures, according to one Study. The authors suggest controlling both diseases as a first step. Among other things, attention should be paid to lifestyle changes in relation to diet, weight, exercise and alcohol consumption. The choice of antihypertensive agent in these patients requires special consideration.
Interleukins as evil cytokines
The large family of cytokines Interleukin is the common denominator for asthma and hypertension. But also with other chronic diseases such as COPD, rheumatism, gout and Diabetes the interleukins are at the center of the pathophysiological events and partly of new therapy options.
IL-11 is after a Study by Fung et al. implicated in the pathogenesis of rheumatoid arthritis, multiple sclerosis, diabetes and systemic sclerosis, as well as other chronic inflammatory diseases such as periodontitis, asthma, chronic obstructive pulmonary disease, psoriasis and colitis. Other interleukins also play a prominent role in the pathogenesis of chronic diseases. It has been known for a long time that cytokines are involved in inflammatory diseases. The finding that hypertension is also triggered by interleukins is quite new.
In experimental models of hypertension, blockade of IL-17A to a reduction in blood pressure. The effect on the small mesenteric arteries and the regulation of sodium transport in the tubules are probably responsible for this. In addition, inhibition of IL-17A reduces end-organ damage. In the future, IL-17 inhibition may be a therapeutic target for hypertension-related diseases, the authors say Study von Rodriguez-Diez.
Antibodies as a hopeful candidate
Other interleukins and their antibodies also play a role in the development of internal diseases. Tezepelumab for example, has the potential to be a novel treatment option.
Tezepelumab is the first human monoclonal antibody in its class, which works differently than the usual biologics. It inhibits the action of Thymusstroma-Lymphopoietin (TSLP). This is an important cytokine that is critical in airway inflammation associated with severe asthma. Tezepelumab is designed to reduce asthma exacerbations and improve asthma control by acting in the asthma inflammatory cascade to block TSLP. Phase III Studies give hope that tezepelumap will not occupy a niche indication, but will be suitable for the broad masses of asthma patients.
The compound has received Breakthrough Therapy Designation and Priority Review Designation from the FDA. This confirms the high utility value and the hope that is placed in the biological.
IL-11 also at RA
Many studies have demonstrated the pathogenic role of locally produced pro-inflammatory cytokines in the inflamed joints, including TNFα, IL-1, IL-6 and IL-17; all are currently targets of biological therapies. IL-11 is also found in the synovial fluid of patients with rheumatoider Arthritis (RA), according to a study by Wang et al.
In RA, IL-11 has been shown to be expressed by fibroblasts and endothelial cells. The interleukin stimulates fibroblasts, promotes the secretion of IL-8 and stimulates angiogenesis in the joints. However, whether the IL-11 elevation is pathogenic or a natural host response to restore homeostasis is not clear for many diseases.
The authors suspect that chronically inflamed mucous membranes in the respiratory tract promote the development of rheumatoid arthritis Ford et al. At Patients with COPD or asthma should therefore pay particular attention to early signs of the autoimmune disease.
Consider interactions in a patient-centric manner
Regardless of the pathogenetic similarities between asthma, hypertension and RA, problems arise in therapy when two or three of these diseases occur together drug interactions. Corticosteroids, used in asthma and RA, can increase blood pressure. Indicated against hypertension beta blockers appear to be critical in asthma and decrease skeletal muscle tone in RA patients. ACE-Hemmer can make asthma attacks worse. The list of possible interactions is long. However, not all hypothetical interactions are relevant to practice according to recent studies.
Beta-blockers are used, albeit with more restraint, in hypertension and have a firm place in the treatment of heart failure. The therapeutic target should be the beta-1 receptors in the heart. Via a detour, the so-called adrenaline reversal, the receptor density of the alpha receptors in the vessels is reduced and the release of blood pressure-increasing catecholamines is reduced. The term “cardioselective” often suggests that these substances only attack the heart, but that is incorrect. Although they have a more potent effect on the beta-1 receptors, they also always act on the beta-2 binding sites in the lungs and on the skeletal muscles. A blocker that only attacks the heart should have the attribute specifically, but there isn’t one. Since the pulmonary vasculature is controlled by the beta-2 receptor, the technical information reads that beta-blockers should not be given in pulmonary obstructive diseases.
Blockers block both receptors
β-blockers have been considered contraindicated in patients with bronchial asthma or even chronic obstructive pulmonary disease (COPD) for many years, but without clear evidence of asthma.
Despite overwhelming evidence for the usefulness of β-blockers, particularly in heart failure with reduced left ventricular ejection fraction (HFrEF) and at ischemic heart disease there is some reluctance to use these drugs in concomitant asthma or COPD.
Beta blockers in asthma
The SmPC contraindication for beta-blockers in asthma is based on small case series published in the 1980s and late 1990s with very high starting doses in young patients with severe asthma. The guidelines of the European Society of Cardiology strongly suggest that beta-blockers are only relatively contraindicated when bronchial asthma with a documented bronchodilator response to adrenaline is certain. Therefore, bronchial asthma is not an absolute contraindication for beta-blockers. Also one Study von Verdiccia et al., emphasizes that beta-blockers can also be indicated in the case of appropriate indications and asthma as a comorbidity.
In clinical practice, starting with low doses of cardioselective beta-blockers, coupled with close monitoring for signs of airway obstruction, may allow the use of potent beta-blockers in HFrEF, particularly in the elderly where true severe asthma is rare. Therefore, according to the global strategy report GINA Asthma is not an absolute contraindication, but these drugs should only be used under close medical supervision and after weighing the risks for and against their use. At higher doses, on the other hand, the occurrence of mild or severe asthma attacks is possible.
Beta blockers in COPD
The situation is even more relaxed when it comes to the use of beta-blockers in COPD. Asthma is adrenergically coupled, COPD is cholinergic and is characterized without typical bronchospasms. On the other hand, beta-blockers can be critical in insulin-dependent diabetes as a concomitant disease. The patient may gain weight during therapy and have hypoglycaemia more quickly. But masking one is dangerous hypoglycemia. This causes tremors, sweating and tachycardia. These symptoms are triggered by adrenaline. A beta blocker masks the symptoms. An insulin-dependent diabetic falls more quickly into dangerous hypoglycaemia due to a change in gluconeogenesis and does not notice it.
Use Prile carefully
ACE inhibitors such as enalapril or captopril can sometimes aggravate asthma. This group of substances is known for the undesirable effect of a dry, dry cough. This occurs because bradykinin is produced by inhibiting the conversion of angiotensinogen to angiotensin-I. This histamine-like substance can also cause problems in asthmatics because the hypersensitivity of the bronchial system can be increased.
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A cohort study by Morales et al. pursued this question. In patients with asthma, an ACE inhibitor can make the condition worse. The frequency and severity of attacks can increase, especially in severe forms of asthma. Angiotensin II receptor blockers (sartans) could potentially be considered as first-line therapy in patients with asthma and in those with high-risk characteristics, the authors said.
From a pharmacological point of view, however, this summary is not entirely correct. Sartans are not AT-II blockers. They do not intervene in the angiotensinogen, angiotensin-I and angiotensin-II cascade. They block the AT1 receptor to which AT-II docks. So it is about AT-1-Blocker. Sartans such as candesartan or olmesartan are well tolerated in asthma.
The triad of hypertension, asthma and RA can be extended to form an octet: diabetes, COPD, gout, neurodermatitis and periodontitis are the other players in the orchestra of interleukins. A ubiquitous antibody against pathogenic interleukins would be a strong pillar of internal medicine therapy.
| Editor’s note: Unfortunately, our author Matthias Bastigkeit passed away unexpectedly. This and several other pending articles will be published posthumously. We’re happy to answer questions about the content, but we can no longer pass on feedback. Our sympathy goes to Mr. Bastigkeit’s relatives and colleagues – and we will also miss him personally and professionally. |
Image source: Yoann Donzé, Unsplash
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