Drugs in Context

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Authors: Vincenzo Accurso MD, Marco Santoro MD, Salvatrice Mancuso MD, Marisante Napolitano MD, Florinda Di Piazza MD, Antonio Russo MD, Sergio Mario Siragusa MD

Accurso V, Santoro M, Mancuso S, Napolitano M, Di Piazza F, Russo A, Siragusa SM. Efficacy of ruxolitinib retreatment in a patient with high-risk myelofibrosis using the international prognostic scoring system. Drugs in Context 2019; 8: 212569. DOI: 10.7573/dic.212569

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Authors: Jean G Bustamante Alvarez MD, MS, Gregory A Otterson MD

BRAF mutations are seen in up to 3.5–4% of the non-small cell lung cancer (NSCLC) patients. BRAF V600E mutations account for 50% of these cases, and the remaining BRAF mutations are non-V600E. The biologic behavior of BRAF-mutated lung tumors tends to be more aggressive and resistant to chemotherapy, but responses to tyrosine kinase inhibitors such as BRAF inhibitors with or without MEK inhibitors have provided another effective tool to attain better response rates when compared to cytotoxic chemotherapy. New strategies such as immunotherapy are becoming as well another option to treat in the second-line setting patients with BRAF-mutated NSCLC.

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Authors: Natasha A Jain MD, Gregory A Otterson MD

The leading cause of cancer-related deaths in the United States continues to be lung cancer. Approximately 25–30% of patients are diagnosed with locally advanced nonsmall cell lung cancer (NSCLC). Concurrent chemoradiation with a platinum-based doublet is the current standard of care for patients with inoperable stage III NSCLC. Unfortunately, only 15–20% of patients treated with definitive chemoradiation are alive at 5 years. Thus, there has been a major unmet need in this area. In this article, we summarize the current status and ongoing clinical trials incorporating immunotherapy into the management of inoperable stage III NSCLC, and we also present our perspective on the future directions.

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Authors: Daniele Orsucci MD, Laura Maria Raglione MD, Monica Mazzoni MD, Marco Vista MD

Episodic ataxias (EAs) are characterized by recurrent, discrete episodes of vertigo and ataxia. EA1 and EA2 are the two most common forms. In the interictal interval, myokymia is typically present in EA1, whereas EA2 patients present with interictal nystagmus. Specific pharmacological therapies are available for EA1 and especially EA2. We briefly discuss the case of an Italian young man with EA2, with a novel de novo CACNA1A mutation, who in our opinion is particularly illustrative for introducing the therapeutic approach. Acetazolamide could fully suppress EA episodes in our patient. We also provide a perspective review of the topic. 4-Aminopyridine is another valid treatment option. For EA1 (and for rarer EAs), the therapeutic possibilities are more limited. Carbamazepine is probably the treatment of choice for EA1, but the optimal treatment plan is unknown. A better understanding of the molecular processes involved in the mediation of EAs will lead to more specific and efficacious therapies for this still elusive group of disorders.

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Authors: Cristina P Alcañiz Escandell MD, José A Román Ivorra PhD

Background: This article presents a descriptive analysis of our Clinical Research Unit (CRU) at the Rheumatology Department in the University and Polytechnic Hospital La Fe (RD-UPH La Fe), Valencia (Spain), as well as an estimation of the economic impact of conducting clinical trials for the Spanish Health System in terms of avoided costs. Methods: During the period 2011–2015, a retrospective observational study was conducted based on the trials performed in our CRU, along with a cost analysis from the health authority perspective. Results: Most of the trials conducted during this period were phase III studies in patients with rheumatic disorders, particularly rheumatoid arthritis. An economic evaluation study showed that the implementation of these studies in our CRU resulted in an annual saving of €13,935.30 per patient. Conclusion: Our CRU is an efficacy and efficiency tool for cost saving in the healthcare system.

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Authors: Jan Kestřánek MD

Hemorrhoids are commonly reported in women. However, despite the high prevalence of hemorrhoids in women and the major impact of this condition on quality of life, specific evidence and recommendations on the treatment of hemorrhoids in women are scant. This paper reviews various options in current therapy for hemorrhoids in women—namely, medical intervention (topical and systemic drug therapy)—and discusses the available clinical evidence for an appropriate use of over-the-counter topical formulations for the symptomatic treatment of hemorrhoids. Its focus is on a medical preparation containing tribenoside + lidocaine, available as a rectal cream (tribenoside 5%/lidocaine 2%) and a suppository (tribenoside 400 mg/lidocaine 40 mg) and marketed under the brand Procto-Glyvenol® (Recordati, SpA, Italy). Given its rapid comprehensive efficacy on all the different symptoms of hemorrhoids, the tribenoside + lidocaine combination can find a place in the treatment of this hemorrhoidal disease. Importantly, its efficacy and tolerability have been formally evaluated in several well-conducted studies, some of which were specifically conducted in women. In particular, tribenoside + lidocaine can be safely administered in postpartum women and in pregnant women after the first trimester of pregnancy. In pregnant women, the tribenoside/lidocaine combination significantly improved both subjective and objective symptoms of hemorrhoids. Fast onset of symptom relief was reported from 10 minutes after administration, lasting up to 10–12 hours. On these bases, tribenoside + lidocaine can represent a fast, effective, and safe option to treat hemorrhoids when conservative therapy is indicated, and it deserves consideration as a first-line treatment of this disease in clinical practice.

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Authors: Brian Ford MD, Alex McDonald MD, Shilpa Srinivasan MD, DFAPA

Anti-N-methyl D-aspartate (NMDA) receptor (anti-NMDAR) encephalitis is among one of the most common autoimmune encephalitides. However, variations in clinical presentation and nonsequential multiphasic course often lead to delays in diagnosis. The mild encephalitis (ME) hypothesis suggests a pathogenetic mechanism of low-level neuroinflammation sharing symptom overlap between anti-NMDAR encephalitis and other psychiatric disorders including schizophrenia. Clinical symptoms of anti-NMDAR encephalitis may mimic schizophrenia and psychotic spectrum disorders or substanceinduced psychosis. Although initially described in association with ovarian teratomas in women, anti-NMDAR encephalitis has been reported in individuals without paraneoplastic association, as well as in males. It can affect all age groups but is usually lower in prevalence in individuals greater than 50 years old, and it affects females more than males. Clinical evaluation is supported by laboratory workup, which includes cerebrospinal fluid (CSF) assays. The latter often reveals lymphocytic pleocytosis or oligoclonal bands with normal to elevated CSF protein. CSF testing for anti-NMDAR antibodies facilitates diagnostic confirmation. Serum anti-NMDAR antibody assays are not as sensitive as CSF assays. Management includes symptomatic treatment and immunotherapy.

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Authors: Federico Lavorini MD, PhD

Inhalation therapy is likely to continue to dominate asthma and chronic obstructive pulmonary disease (COPD) treatment. The pressurised metered-dose inhaler (pMDI) accounts for most of the global inhaler market, but this kind of device is difficult to use properly. Dry powder inhalers (DPIs) have several advantages over pMDIs: they are breath-activated, easy and convenient to use, and environmentally friendly. The Easyhaler® (Orion; Finland) is a multidose reservoir-type DPI developed to efficiently deliver a wide range of medications, including fixed-dose combinations of bronchodilators and corticosteroids. Easyhaler shares a similar shape with the pMDI, and its performance is unaffected by moisture, dropping, vibration, and freezing/thawing. For these reasons, Easyhaler may be considered one of the most convenient inhalers for daily use in patients with asthma or COPD.

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Authors: Antonio Ruggiero MD, Anna Ariano MD, Silvia Triarico MD, Michele Antonio Capozza MD, Pietro Ferrara MD, Giorgio Attinà MD

During the neonatal period, there is physiological immaturity of organs, systems and metabolic pathways that influences the pharmacokinetics and pharmacodynamics of administered drugs, the dosage of which should be constantly amended, considering the progressive increase in weight and the maturation of the elimination pathways. In this article, we analyse the main pharmacokinetic aspects (absorption, distribution, metabolism and excretion) that exist during the neonatal period, to offer a description of the physiological background for variability in pharmacological dosing.

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Authors: Tomas Fait MD, PhD

Menopause hormone therapy (MHT) is the most efficient treatment for symptoms of acute climacteric syndrome and for efficient prevention of long-term estrogen deficiency. Vaginal administration of low doses of estrogen is a therapy of choice for treatment and prevention of urogenital atrophy and its consequences. Systemic treatment may include estrogen, but an equally efficient alternative is tibolone. Nonhormonal therapy relies on phytoestrogens, black cohosh extract, and serotonin reuptake inhibitors.

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Authors: Pilar I Beato-Víbora PhD, Francisco J Arroyo-Díez PhD

Hypoglycaemia is the more frequent complication of insulin therapy and the main barrier to tight glycaemic control. Injectable glucagon and oral intake of carbohydrates are the recommended treatments for severe and non-severe hypoglycaemia episodes, respectively. Nasal glucagon is currently being developed as a ready-to-use device, to simplify severe hypoglycaemia rescue. Stable forms of liquid glucagon could open the field for different approaches for mild to moderate hypoglycaemia treatment, such as mini-doses of glucagon or continuous subcutaneous glucagon infusion as a part of dual-hormone closed-loop systems. Pharmaceutical companies are developing stable forms of native glucagon or glucagon analogues for that purpose.

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Authors: Michael E Røder

Glucagon-like receptor agonists (GLP-1RAs) are included in current national and international guidelines as second-line treatment especially in patients with type 2 diabetes and concomitant cardiovascular disease (CVD). First-generation GLP-1RAs were two- or once-daily injectables, but longeracting GLP-1RAs have now been developed for onceweekly administration – e.g., exenatide ER, dulaglutide and semaglutide. With semaglutide, the same prolongation principle as designed in liraglutide is used (spacer and fatty acid chain). However, the similarity to endogenous human GLP-1 is well preserved, sharing 94% homology. It is administered with a simple device and without resuspension before use. The efficacy and safety of semaglutide have been investigated in an extensive clinical development program including more than 9,000 patients with type 2 diabetes. Semaglutide has been compared head-to-head with a dipeptidyl peptidase-4 (DPP4)-inhibitor, GLP-1RAs and basal insulin. Further head-to-head studies are awaiting that compare semaglutide against a sodium-dependent-glucose transporter-2 (SGLT2)-inhibitor. In these studies, semaglutide was found to provide significant and clinically relevant reductions in HbA1c, fasting plasma glucose (FPG), glucose excursions, body weight and blood pressure. The reduction in glycaemic parameters was more pronounced than that in the comparator GLP-1RAs. The rate of hypoglycemia is very low during treatment with semaglutide if not combined with sulphonylureas or insulin. A cardiovascular outcome trial (CVOT) was performed before the approval of semaglutide, at the request of legal authorities. Not only non-inferiority was confirmed, but also superiority compared with placebo used in a population of patients with type 2 diabetes and CVD treated with oral antihyperglycaemic drugs (OADs) and/ or insulin with regard to the primary composite endpoint: death from cardiovascular (CV) causes, nonfatal myocardial infarction or nonfatal stroke. The safety of treatment with semaglutide in patients with type 2 diabetes has been extensively investigated. Overall, gastrointestinal side effects dominate, as observed with other GLP-1RAs, and was observed in the same range as for comparator GLP-1RAs. As observed with other GLP-1RAs, side effects such as nausea and vomiting diminished over time during continuous treatment. Regarding microvascular complications, an unexpected increase in diabetes-related retinopathy was observed in the CVOT; Semaglutide Unabated Sustainability in Treatment of Type 2 diabetes’ [SUSTAIN 6]), but not in other studies. The reason for this increase is not finally elucidated, but may be due to a nonspecific effect of a rapid decrease in glycaemic parameters in patients with preexisting retinopathy with high HbA1c at the start of the treatment. There is currently a warning in the Summary of Product Characteristics (SmPC) for semaglutide concerning treatment in patients with preexisting retinopathy. Further studies are needed to clarify this.

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Authors: Stefania Nicola MD, Giovanni Rolla MD, Luisa Brussino MD

Hereditary angioedema (HAE) is a rare genetic disorder, characterized by recurrent and unexpected potentially life-threatening mucosal swelling. The impairment underlying HAE could be a defect in C1-inhibitor activity, or in its serum concentration. Patients affected by HAE should be treated with on-demand or prophylactic drugs. Lifelong C1-inhibitor supplementation is sometimes required. In this review, we review the currently approved drugs for HAE due to C1-inhibitor defect and to describe those under research. In particular, we focused on the mechanisms of action, routes of administration, and efficacy of these therapies. A systematic review of the literature was performed using the PubMed database for original articles and clinical trials of HAE treatments from 2005 to 2019. The approved HAE treatments can minimize the risk of death, but they are not effective in complete healing from the disease. The new gene therapies seem to provide promising opportunities for the treatment of hereditary angioedema. However, there are still many unmet needs, including efficacy, route, and timing of administration.

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Authors: Miguel Nogueira MD, Tiago Torres MD, PhD

Psoriasis is a chronic, immune-mediated, inflammatory, and debilitating skin disease with significant impact on patients’ quality of life. Its pathogenesis is complex and not yet fully understood. However, the IL-23/IL-17 axis is currently considered the main pathogenic pathway in psoriasis. Guselkumab is a fully human immunoglobulin G1 λ (IgG1λ) monoclonal antibody (mAb) that binds to the p19 subunit of IL-23. It is the first of its class, already approved by the US Food and Drug Administration (FDA), as well as the European Medicines Agency (EMA) for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for either systemic therapy or phototherapy. Several clinical trials have demonstrated potential benefits of guselkumab over other already approved immunomodulators in terms of safety and efficacy. The results of the head-to-head trial ECLIPSE were recently released and are addressed in this review. They contribute to the increasing confidence in guselkumab, demonstrating great potential for long-term treatment of psoriasis. However, further long-term data and additional comparative studies will be essential for positioning guselkumab in the therapeutic armamentarium for psoriasis.

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Authors: Francesco Menzella MD, Mirella Biava Msc, Diego Bagnasco MD, PhD, Carla Galeone Msc, Anna Simonazzi MD, Patrizia Ruggiero Msc, Nicola Facciolongo MD

Severe refractory asthma is characterized by a higher risk of asthma-related symptoms, morbidities, and exacerbations. This disease also determines much greater healthcare costs and deterioration in health-related quality of life (HR-QoL). Another concern, which is currently much discussed, is the high percentage of patients needing regular use of oral corticosteroids (OCS), which can lead to several systemic side effects. Airway eosinophilia is present in the majority of asthmatic patients, and elevated levels of blood and sputum eosinophils are associated with worse control of asthma. Regarding severe refractory eosinophilic asthma, interleukin-5 (IL-5) plays a fundamental role in the inflammatory response, due to the profound effect on eosinophils biology. The advent of the biological therapies provided an effective strategy, even if the increased number of molecules with different targets raised the challenge of choosing the right therapy and avoid overlapping. When considering severe refractory eosinophilic asthma and anti-IL-5 treatments, it is not easy to define which drug to choose between mepolizumab, reslizumab, and benralizumab. In this article, we carried out an indirect comparison among literature data, especially between OCS reduction studies (ZONDA-SIRIUS) and pivotal studies (SIROCCO-MENSA), evaluating whether the clinical efficacy and the steroid-sparing effect of benralizumab may represent an advantage over other compounds. This data could help the clinician in the decision process of treatment choice, within the different available therapeutic options for eosinophilic refractory severe asthma.

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Authors: Mohammed Awais Hameed MB, ChB, Indranil Dasgupta DM

Nonadherence is a common reason for treatment failure and treatment resistance. No matter how it is defined, it is a major issue in the management of chronic illnesses. There are numerous methods to assess adherence, each with its own strengths and weaknesses; however, no single method is considered the best. Nonadherence is common in patients with hypertension, and it is present in a large proportion of patients with uncontrolled blood pressure taking three or more antihypertensive agents. Availability of procedure-based treatment options for these patients has shed further light on this important issue with development of new methods to assess adherence. There is, however, no consensus on the management of nonadherence, which reflects the complex interplay of factors responsible for it.

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Authors: Martina Biggioggero MD, Andrea Becciolini MD, Chiara Crotti MD, Elena Agape MD, Ennio Giulio Favalli MD

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by joint involvement, extra-articular manifestations, comorbidities, and increased mortality. In the last few decades, the management of RA has been dramatically improved by the introduction of a treat-to-target approach aiming to prevent joint damage progression. Moreover, the increasing knowledge about disease pathogenesis allowed the development of a new drug class of biologic agents targeted on immune cells and proinflammatory cytokines involved in RA network. Despite the introduction of several targeted drugs, a significant proportion of RA patients still fail to achieve the clinical target; so, more recently the focus of research has been shifted toward the inhibition of kinases involved in the transduction of the inflammatory signal into immune cells. In particular, two Janus kinase (JAK) inhibitors, baricitinib and tofacitinib, have been licensed for the treatment of RA as a consequence of a very favorable profile observed in randomized controlled trials (RCTs) conducted across different RA subpopulations. Both these new compounds are active on the majority of four JAK family members (JAK1, JAK2, JAK3, and TYK2), whereas the most recent emerging approach is directed toward the development of JAK1 selective inhibitors (upadacitinib and filgotinib) with the aim to improve the safety profile by minimizing the effects on JAK3 and, especially, JAK2. In this narrative review, we discuss the rationale for JAK inhibition in RA, with a special focus on the role of JAK1 selective blockade and a detailed description of available data from the results of clinical trials on upadacitinib and filgotinib.

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Authors: Vania Phuoc MD, Jose Sandoval-Sus MD, Julio C Chavez MD, MS

Double-hit lymphoma (DHL) is a rare type of aggressive B-cell lymphoma defined as a high-grade B-cell lymphoma (HGBCL) with the presence of MYC, BCL2 and/or BCL6 rearrangements. Patients usually present with rapidly progressive and advanced stage of disease and, commonly, with extranodal involvement. Typically, patients become refractory to standard R-CHOP, and more aggressive regimens such as DA-EPOCH-R, R-hyperCVAD or CODOX-R regimens are typically needed. MYC is considered an “undruggable” mutation. Recent evidence suggests that pathogenic mechanisms associated with MYC could be potential targets. In this review, we also discuss the role of hematopoietic stem cell transplantation (HCT) and chimeric antigen receptor (CAR) T-cell therapy in DHL. We also discuss the role of potential novel agents such as BCL2 inhibitors, checkpoint inhibitors, bromodomain and extraterminal (BET) family inhibitors, Pi3K inhibitors, and others.

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Authors: Donatella Marino MD, Clizia Zichi MD, Marco Audisio MD, Elisa Sperti MD, Massimo Di Maio MD

For many years, sorafenib has been the only approved systemic treatment for advanced hepatocellular carcinoma (HCC). For over a decade, randomized controlled trials exploring the efficacy of new drugs both in first- and second-line treatment have failed to prove any survival benefit. However, in the past few years, several advances have been made especially in pretreated patients; phase III trials of regorafenib, cabozantinib, and ramucirumab in patients with elevated α-fetoprotein have demonstrated efficacy in patients progressing after or intolerant to sorafenib. In addition, early phase I and II trials have shown promising results of immunotherapy alone or in combination with tyrosine-kinase inhibitors or monoclonal antibodies in the same setting of patients. In this review, we will discuss the evidence on second-line options for HCC, focusing on the latest results that are currently refining the treatment scenario.

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Authors: Carlos Henrique Ferreira Camargo MD, MSc, PhD, Hélio Afonso Ghizoni Teive MD, MSc, PhD

The term movement disorders encompasses all disorders hypokinetic and hyperkinetic, which were previously known as extrapyramidal syndromes. With the definition of movement disorders and their diagnostic criteria and classifications, new studies for therapeutics could be performed. New drugs were launched, functional neurosurgery was developed, and the introduction of botulinum toxin (BoNT) for hyperkinesias was introduced. BoNT is an important therapy for dystonia, tics, myoclonus, and tremors. The aim of this review is to present the new and well-established uses of BoNT for movement disorders.

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Authors: Shinichi Makita MD, PhD, Katsuaki Imaizumi Ph, Saiko Kurosawa MD, Kensei Tobinai MD, PhD

B-cell non-Hodgkin lymphoma (NHL) is the most frequent hematologic malignancy. Despite the refinement of chemoimmunotherapy, a substantial number of patients experience chemorefractory disease. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is considered the most promising and effective therapy to overcome chemorefractory B-cell NHL. Based on the promising results obtained from pivotal trials, the US Food and Drug Administration and European Medicines Agency approved anti-CD19 CAR T-cell therapy for relapsed/refractory diffuse large B-cell lymphoma. Nonetheless, there remain several controversial issues and problems awaiting solutions, including optimal management of toxicities, overcoming relapsed/refractory disease after CAR T-cell therapy, and improving CAR-T manufacturing platform. Definite unmet medical needs among patients with chemorefractory B-cell NHL still exist. CAR T-cell therapy might be a game changer that can defeat chemorefractory B-cell NHL, and further clinical development is warranted. In this review, we summarize the recent clinical developments, clinical implications, and perspectives of CAR T-cell therapy, focusing on B-cell NHL.

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Authors: Kanae Jennifer Nagao MBBS (Hons), FRACP, Neepa J Patel MD

Motor complications are responsible for the large burden of disability and poor quality of life in Parkinson’s disease (PD). The pulsatile nature of stimulation with oral dopaminergic therapies due to relatively short pharmacokinetic profiles and dysfunctional gastrointestinal absorption have been attributed to the development of PD motor complications. In this review, we will provide an overview of the pharmacologic and surgical therapies currently available and under investigation for the treatment of motor fluctuations and dyskinesia.

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Authors: Alessandro Giallongo MD, Giuseppe Fabio Parisi MD, Amelia Licari MD, Giulio Pulvirenti MD, Caterina Cuppari MD, Carmelo Salpietro MD, Gian Luigi Marseglia MD, Salvatore Leonardi MD

The aim of precision medicine is setting up targeted therapies for selected patients that would ideally have high effectiveness and few side effects. This is made possible by targeted therapy drugs that selectively act on a specific pathway. Precision medicine is spreading to many medical specialties, and there is increasing interest in the context of allergic airway diseases, such as allergic rhinitis, chronic rhinosinusitis, and asthma. This review is an update of new targets in the treatment of childhood allergic upper airway diseases and asthma, including the most recent biologic drugs that have already been licensed or are in the pipeline to be tested with children.

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Authors: Francesco Serra MD, Pietro Lapidari MD, Erica Quaquarini MD, Barbara Tagliaferri MD, Federico Sottotetti MD, Raffaella Palumbo MD, PhD

The purpose of this review is to summarize the background and latest evidence for the use of palbociclib, an oral, first-in-class, highly selective cyclin-dependent kinase 4/6 inhibitor, in advanced breast cancer, with a focus on some of the unanswered questions about the performance of this agent in clinical practice. The available clinical data from both controlled clinical trials and real-life experiences concerning palbociclib-based combinations in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2–) metastatic disease, including patient-reported outcomes and subgroup analyses, have been reviewed and discussed. Palbociclib significantly improved progression-free survival and clinical benefit rates when added to letrozole in postmenopausal women as initial endocrine-based therapy, and it prolonged progression-free survival and overall survival when added to fulvestrant in women who progressed on previous endocrine therapy in randomized clinical trials. Tolerability profile was manageable, with neutropenia occurring most commonly, without detrimental impact on quality of life. Available data from real-life experiences confirm the good performance of palbociclib in unselected, heavily pretreated populations. Palbociclib in combination with endocrine therapy is a valuable emerging option for patients with HR+/HER2– advanced or metastatic breast cancer. Further investigation is needed to provide solutions for palbociclib resistance and to identify the best sequence to use for the best patient benefit with a minimal toxicity.

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Authors: Rudolf Hoermann, John E M Midgley, Rolf Larisch, Johannes W Dietrich

Levothyroxine (LT4) therapy has a long history, a well-defined pharmacological profile and a favourable safety record in the alleviation of hypothyroidism. However, questions remain in defining the threshold for the requirement of treatment in patients with subclinical hypothyroidism, assessing the dose adequacy of the drug, and selecting the best treatment mode (LT4 monotherapy versus liothyronine [LT3]/LT4 combinations) for subpopulations with persisting complaints. Supplied as a prodrug, LT4 is enzymatically converted into the biologically more active thyroid hormone, triiodothyronine (T3). Importantly, tetraiodothyronine (T4) to T3 conversion efficiency may be impaired in patients receiving LT4, resulting in a loss of thyroid-stimulating hormone (TSH)-mediated feedforward control of T3, alteration of the interlocking equilibria between serum concentrations of TSH, free thyroxine (FT4), and free triiodothyonine (FT3), and a decrease in FT3 to FT4 ratios. This downgrades the value of the TSH reference system derived in thyroid health for guiding the replacement dose in the treatment situation. Individualised conditionally defined setpoints may therefore provide appropriate biochemical targets to be clinically tested, together with a stronger focus on clinical presentation and future endpoint markers of tissue thyroid state. This cautionary note encompasses the use of aggregated statistical data from clinical trials which are not safely applicable to the individual level of patient care under these circumstances.