Tuesday, 24 July 2018

Value statements on gouty arthritis and new disease treatments

I was recently asked to produce some value statements on gouty arthritis and new disease treatments for a 'project' that unfortunately did not materialise the way I so wished. Because I believe the research I produced under very restricted availability (in terms of time and resources) can actually be extremely helpful for all those affected by gout, or the relatives/carers of patients battling with gout, I decided to paste hereby my findings on the topic. The compiled information is divided into two main fields, a short value statement and then a brief summary developing the previously stated idea. I honestly hope this can be helpful to any readers who are looking to know more on the subject of gout, the current disease state and the pharmaceutical approaches that are being developed or presently exist in the market. All information can be verified with the scientific literature referred in the bibliography attached. Any questions, be my guest and let me know. I will do my best to help you within my present knowledge on the topic. For medical advice, please seek the help of your healthcare professional (medical doctor, pharmacist, physiotherapist and the like).

Gout, a common arthritis disease defined by inflammatory symptoms as a consequence of the crystallization of uric acid within the joints, is presently a major increasing public health issue. The fundamental anomaly in gout is chronic hyperuricemia, usually resulting from reduced renal uric acid elimination and upsurge of monosodium urate crystals deposition in the joints (Lawrence, 2008). The underlying mechanisms responsible for hyperuricemia in gout patients can be divided into two main origins: a) renal underexcretion of uric acid or b) problems that result in increased secretion of systemic uric acid (Lawrence, 2008). If not treated gout can progress through four phases: a) asymptomatic hyperuricemia, b) acute gout, c) intercritical gout, d) chronic tophaceous gout (Croft, 2008). On the origin of the disease there is a behavioural/societal pattern, such as: accentuated increase in obesity (St-Onge et al., 2003) an aging population (Mikuls et al., 2005), the growing incidence of hypertension and renal failure (Johnson et al., 1999), the generalised use of antihypertensives, e.g., thiazide diuretics and acetylsalicylic acid (Caspi et al., 2000), and a growing intake of beer (Choi et al., 2004). Refractory hyperuricemia and acute flares of gout are a reality for patients and demand early treatment based on previous medication, possible adverse events associated to medication, level of flare onset and site of inflammation (Richette et al., 2016).

An accurate clinically consistent profiling code is deemed crucial for the primary (general medicine) and secondary (specialty) diagnosis and treatment of gout. Gout is usually clinically diagnosed by reassessing past symptoms described by patients in response to an applied treatment (Annemans et al., 2008), however this coding system does not distinguish between different clinical traits (e.g., signs and symptoms of the disease). Health-related quality of life (HRQOL) measurements in gout are difficult to apply due to the sporadic, recurrent and progressive chronic nature of the disease, but after several meetings the American College of Rheumatology (ACR) declared it now as a core area for application in chronic gout clinical trials (Lawrence, 2008) (Kim and Choi, 2009), thus replacing the old 1987 ACR gout classification criteria that missed the identification of cases where very early onset of arthritis later progressed to rheumatic arthritis (Kim and Choi, 2009). In 2010, the ACR provided new classification criteria suggested to clinicians, nevertheless there are still reports that these still make epidemiological counts complicated, lack uniformity (recruitment-wise) across studies and prevent clear comparison of results (Péntek et al., 2014). A recent collaboration between the ACR and the European League against Rheumatism (EULAR) resulted in the new 2015 coding criteria for gout (Tuhina et al., 2015). In addition to considering clinical features, signs, and symptoms, this new coding system also takes into account radiographic and computed tomography imaging, ultrasound, and a biochemical profiling.

Gout is the most common form of inflammatory joint disease in men aged 40 years and older, although postmenopausal women (due to declining oestrogen levels are also at increased risk of developing the disease) at around the age of 45 years. Even though the incidence of gout is quite similar between genders, it is however more prevalent in males, as reported by the Framingham Heart Study as of 1.4 in women and 4.0 in men per each 1000 individuals/year (Roddy and Doherty, 2010) (Weaver, 2008). The aforementioned difference is a natural result of the human physiology where males usually display greater serum uric acid (SUA) levels. This tendency for higher SUA values also intensifies the putative development of hyperuricaemia at a later stage in the lives of these individuals (Weaver, 2008). In fact, age is directly related to the onset of gout for both males and females, although, for males typically reaching a maximum point within the age interval of 75 to 84 years (Doherty, 2009). On the other side of the spectrum, as women approach the age of 45 years old, recognised for the triggering of their endocrine decline (e.g., oestrogen levels decline/menopause) a greater risk of developing hyperuricemia also appears, increasing as women go deeper towards the postmenopausal phase (e.g., ≥60 years old). The recommended age for a patient to initiate uratelowering therapy (ULT) is usually after the first diagnosis in patients respecting certain establishes clinical conditions: a) of age 40 years or younger, b) with an ‘aberrant’ SUA level (>8.0 mg/dL; 480 mmol/L) and/or signs of renal impairment, hypertension, ischaemic heart disease or heart failure (typical comorbidities in gout patients (Richette et al., 2016).

There is a positive correlation between prevalence of comorbidities and increased SUA levels; and the latter is also directly related to the occurrence of gout flares. Hence the importance of periodic monitoring of these indicators. Considering a study focused on two of the major European and Global economies, UK and Germany, distinct scenarios can be drawn in terms of prevalence of comorbidities: in the UK, obesity was the commonest comorbidity observed (27.7%); whereas in Germany a different scenario was verified with diabetes accounting for 25.9% of the reported comorbidities (Annemans et al., 2008). However, for the studied time frames (2000–2005), the tendency indicators concerning gout flares reveal different propensities (when analysing subjects in whom SUA was inferior to 360 mmol/l (less than 6 mg/dl), i.e., odds ratios of 1.33 (UK) and 1.37 (Germany) [SUA between 360–420 mmol/l (6–7 mg/dl)], and 2.15 (UK)and 2.48 (Germany) [SUA over 530 mmol/l ( over 9 mg/dl) (Annemans et al., 2008). Overall, for both markets the results in terms of prevalence of the disease was 1.4%, consequently in agreement with the tendency registered back in the 90s (1990–1999). This study showed that the implementations that led to a stable numerical prevalence, above all reveal the worth and significance of regular monitoring of SUA to address adequate and specific treatments to patients with a range of underlying symptoms. As observed in the analysed subjects, patients with SUA levels over 360 mmol/l (>6 mg/dl) had an increased risk of flaring up (Annemans et al., 2008) and it was projected that for the US adult population, up to 3.0 million would already have had selfreported gout in 2007, against a previous 2.1 million estimate predicted for the year of 1995 (Lawrence, 2008).

Several epidemiological studies originating from multiple geographical areas propose that gout is still increasing in prevalence and incidence over the past decades, however there is still a general lack of data on difficult-to-treat diseases. Based on the NHANES III age/sex prevalence and the 2005 US Census Bureau population estimates, it is expected that up to 6.1 million adults over the age of 20 years old have ever had gout (Kim and Choi, 2009). Additionally, a recent American study from a US managed care population, established that the total prevalence of gout or hyperuricemia where need for gout-directed treatment was observed, grew by 80% in approximately 10 years (from 1990 to 1999) (Wallace et al., 2004). Nevertheless, increased clinical awareness and better treatment approach can be behind this growth (Lawrence, 2008). Studies are still lacking for an adequate evaluation of the frequency and prevalence of occurring difficult-to-treat diseases (Schlesinger, 2010).

The prevalence of gout is highest in rich developed countries and lowest in countries with weaker economies, but the reported prevalence scores lack uniformity between studies, likely due to varying analytical methodologies. In Europe the lowest prevalence of gout was registered in Czech Republic (0.3 %) in opposition to the highest score registered by UK and Germany (1.4%), according to the analytical review of European epidemiological data (Smith et al., 2010). However, these numbers clash with those published by yet another study that consider the overall UK prevalence of gout to be 2.49 % (Kuo et al., 2014). Placed amid both extremes sits Portugal with 1.3%; a country marked by a weak though more buffered economy in comparison to Eastern European countries. However, prevalence scores are affected by differing analytical models (different reporting methods and different definitions) as is suggested by a study that considers that about twothirds of self-reported gout cases lack validity by clinicians (Chen and Schumacher, 2008).

Gouty arthritis is a painful arthritic disorder marked by the likelihood of patients developing comorbidities and/or intolerance/unresponsiveness to treatments. This outcome can substantially impact on the quality of life of the affected individuals. Consequently, it has driven the pharmaceutical industry to reinvest on researching novel molecules has means to take control of what was considered to be a ‘forgotten disease’. Allopurinol (a xanthine oxidase inhibitor), is still the most regularly prescribed ULT pharmaceutical to counteract hyperuricaemia back to standardised levels of 6 mg/dL on the basis of its efficacy, availability, and low cost (Sattui and Gaffo, 2016). Unfortunately, the number of comorbid/uncompliant patients reporting lack of efficacy (no target SUA levels attained) is still relevant, ergo the reporting of recurrent acute flaring (Schlesinger, 2010) (Sattui and Gaffo, 2016). Since the main focus of treatment in chronic gout is to avert crystal formation and stimulate crystal dissolution (Annemans et al., 2008) physicians invest in approaches that address management of hyperuricemia values and related symptoms (Lawrence, 2008). However, many of the affected individuals develop comorbidities to which non-steroidal antiinflammatories respond inefficiently (due to associated NSAIDs and proton pump inhibitors being limited by a considerable number of adverse effects) that have enticed new investments from big pharma (Schlesinger, 2010) (Khanna, 2012) (Jordan et al., 2007) (Zhang et al., 2006). In summary, the new therapies in development (Table 1) that, due to clinical trial results, deserve further attention are:

But above all, it is the approval of febuxostat (a xanthine oxidase inhibitor capable of overcoming the limitations of allopurinol) that finally promises to respond successfully to the biochemical control of gout whilst representing an enticing share-market niche, as it is presented in part 2 of this report.

A gout patient seeking healthcare sustains an incremental annual cost of over $3000 when compared to a healthy individual in the United States, and the associated healthcare investment is similar to major chronic debilitating disorders like migraine or even Parkinson’s disease. Yearly, the bill on gout amounts to more than $3000/patient in the USA where, overall, patients pay tens of billions of dollars per annum regardless of affected gender (Smolen et al., 2016) in associated healthcare. A study concentrating on population costs, analysed the usage of emergency services across the United States of America to draw conclusions on the total bill gout entails to the population (Rohini et al., 2013): a) the burden of gout emergency care is increasing through the many societal layers; b) gout was responsible for 168,410 visits just in 2006, with an overall cost of US$128 million that two years later met an increase by $16 million (due to 174,823 visits that year). Another study evaluated the direct link between gout related costs and achieving the recommended target SUA (represented 58% higher costs for patients with SUA 6–9 mg/dl when compared to patients with SUA inferior to 6 mg/dl) indicating that the financial weight of this disease varies accordingly to SUA levels (Shields and Beard, 2015). 

Since allopurinol was introduced to the markets back in 1964, no developments on low toxicity/high efficacy medication to reduce SUA levels were accomplished; ergo the emergence of febuxostat, represents a new pharmaceutical vision to the rheumatoid arthritis market. Considering the medical approaches available for treating gout, three main options are applied: 1) focusing on the acute flare; 2) focusing on urate-lowering strategies (usually based on uricosuric agents); and, 3) prophylaxis to prevent acute flares (Lawrence, 2008). Febuxostat, developed by Takeda Pharmaceuticals and approved by the Food and Drug Administration (FDA) is a pioneer urate-lowering drug (ULD) since 1964. Contrarily to other rather unsuccessful drugs that only inhibit the oxidation of xanthine to uric acid, long-term studies on Febuxostat show that the drug lowers the SUA levels by increasing the excretion of uric acid, towards the clinical target value of 6 mg/dl (360 mmol/l), more steadily. In many patients, Febuxostat has also efficiently managed tophi. Other clear disadvantage of the uricosuric drugs is its inefficacy on impaired patients (over 60 years of age and/or dealing with renal insufficiency issues) since with this class of drugs creatinine clearance is usually less than 50 ml/min/1.73 m of body surface area) (Bisht and Bist, 2011), thus forcing dose adjustments that affect drug efficacy.

Compared to allopurinol, Febuxostat is a more selective and potent inhibitor of xanthine. Febuxostat research conducted on animals have shown many biochemical advantages when compared to allopurinol: a) Potency: 10 to 30 times more potent (Horiuchi et al., 1999) as revealed by the IC50 for bovine milk xanthine oxidase (20 nmol/l), i.e., 10-fold stronger than allopurinol within the same assay (Takano et al., 2005). b) Action onset: “ADENURIC works sufficiently quickly to allow retesting of the serum uric acid after 2 weeks” (emc, 2018). c) Absorption: only 1 hour from oral administration to peak concentration, bounding to albumin in blood with an efficacy of approximately 99%, and low to medium apparent volume of distribution of about 0.7 l/ kg (Becker et al., 2004). d) Interactions: no know effect on enzymes involved in purine or pyrimidine metabolism (Lawrence, 2008).

The U.S. FDA issued a public safety alert, in November 2017, on a putative link between febuxostat and signs of increased risk of cardiovascular and all-cause mortality (FDA, 2017). Data on the incidence of adverse reactions (e.g., dizziness, nausea, diarrhoea and cephalalgia), available up to 2009, considered risks associated to the use of febuxostat at the same level as with allopurinol (Becker et al., 2004) (Schumacher et al., 2008). Nonetheless, the incidence of cardiovascular side-effects (defined by events of composite of myocardial infarction, stroke death associated to cardiovascular origins) was greater when using febuxostat than with when using allopurinol, even though no significant difference between treatments was observed. Moreover, guidelines febuxostat dosing was not immediately and directly related to cardiovascular distress incidence (Lawrence, 2008). However, febuxostat safety warnings emerged mainly from observations concerning cardiovascular adverse events in two specific studies: the APEX (Febuxostat, Allopurinol and Placebo-Controlled Study in Gout Subjects) (Schumacher et al., 2008) and the FACT study (Febuxostat versus Allopurinol Controlled Trial) (Reza et al., 2008). Presently, there are two major studies being developed in Europe and Japan concerning febuxostat hypothetic relation with cardiovascular events that have the potential to confirm or reject the link the FDA considered to be worth analysing further.

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