Evidence-based management of gout-A systematic search and review

Gout is the most common form of inflammatory arthritis. Hyperuricaemia is the pre-requisite for gout and is influenced by variable modifiable and non-modifiable risk factors. Clinical features unique for gout are due to deposition of monosodium urate (MSU) crystal in articular and extraarticular tissues. Among various treating agents, anti-inflammatory drugs and urate lowering therapies (ULT) are used widely and successfully, however, non-medicinal means are also effective in the disorder. In their updated guidelines, ACR (2012) and EULAR (2016) recommended both medicinal and non-medicinal approaches that could be used in treating gout, though some of the recommendations are based on lower level of evidence. Moreover, researchers’ continued effort in finding new gout managing agents appear promising, for example, role of Lesinurad in gout management (CLEAR1, CLEAR2). In this new synthesis the author is aimed to provide updated information on gout management based on a systematic review including published work within last ten years between 2008 and 2018 and for this purpose, using ‘clinical trials in gout management’ string, published worked searched in PubMed database from 1 September 2018 to 30 October 2018. Besides the recent ACR and EULARevidence based management guidelines, the author reviewed another 91 (total 93) articles to make this new draft – 39 articles describe role of pharmacological agents and 54 describe different gout risks, pharmacokinetics/pharmacodynamics of ULT, association between raised sUA level and renal impairment, efficacy of non-pharmacological agents in reducing sUA. According to published work, anti-inflammatory agent is the most appropriate drug group in mitigating inflammatory symptoms of gout, though they often adversely affect over other vital Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 7 December 2020 doi:10.20944/preprints202012.0156.v1 © 2020 by the author(s). Distributed under a Creative Commons CC BY license. 2 organs with impaired function. Besides ULT, uricase analogues are also found useful in nonrefractory gout. Since anti-inflammatory agents and ULT contraindicate in some clinical conditions, intra-articular steroid and or adrenocorticotropic hormone (ACTH) are appropriate alternatives instead. However, head-to-head comparison between different NSAIDs, NSAID and prednisolone, NSAID and colchicine are yet to perform. Use of combined anti-inflammatory preparations in gout is also based on lower level of evidence. Regarding effective maximum dose and long-standing impact of ULT on vital organs we are yet to reach a conclusion. Likewise, non-medicinal approaches are widely using in achieving target sUA level, though some of them are based on biased study outcomes and or study with inadequate power, requiring further analysis. Among non-pharmacological approaches, life-style modification, restriction of purine rich diets, avoidance of gout inciting agents are important, but inconclusive. Educating patients’ about diseases, risk factors, available treatment options and side effects from them are also important in terms of achieving sUA level, nevertheless too much counseling sometimes could be worthless.


Introduction
Gout is a form of acute inflammatory arthritis of metabolic origin that causes severe pain and swelling in peripheral joints and soft tissues. It most commonly affects the big toe, but heel, ankle, hand, wrist, or elbow are also involved. Hyperuricaemia is the pre-requisite of gout and resultant clinical manifestation is due to urate crystal deposition in articular and non-articular soft tissues. Uric acid is the end product of purine metabolism and hyperuricaemia signifies serum urate (sUA) level beyond normal level, greater than either 5.0 or 6.0 mg/dl (Richette et al., 2017) or 6.8 or 7.0 mg/dl .
When sUA level past the normal level of saturation, urate crystal starts to form and deposit in both intra-articular and or extra-articular soft tissues, with resultant detrimental clinical manifestations, called gout and is of two types: podagra (acute) and tophous (chronic) . Hyperuricaemia (HU) is the result of either increased uric acid production or decreased excretion of uric acid; in case of increased uric acid production some intrinsic (for example, myelo-proliferative disorders, psoriasis) and extrinsic (like, consumption of red meat, seafood, purine-rich vegetables) factors contribute, however, in the millieu of renal impairment and concomitant ingestion of gout triggering diet and drugs could result in secondary HU, due to decreased excretion of uric acid .
Hyperuricaemia (HU) doesn't always require drug management and sometimes nonpharmacological approaches appear sufficient. Persistent asymptomatic HU could lead to renal impairment and could develop unwanted cardiovascular events, for example atherosclerosis, requires timely judicial pharmacological interventions Mallat, Kattar, Tanios & Jurjus 2016). Furthermore, as incidental HU is a 4 component of metabolic syndrome, further screening for other components of metabolic syndrome in asymptomatic HU could be a great help for both patients and treating physicians as well.

History of Gout
The Dominican monk, Randolphus of Bocking was the first person using the term gout, which was rooted from gutta, a Latin word meaning drop, and it was believed that the disorder was due to excessive flow of one of the four "humors" (????) that are essential for maintaining optimal health causing joint inflammation and pain as a consequence (Deshpande 2014). However, nowadays, this belief doesn't exist in reality, as researchers' continuous effort over the last few years unveil exact pathophysiology behind hyperuricaemia and gout. Now it is well established that gout is a metabolic disorder, where accumulating negatively charged birefringent needle shaped monosodium urate (MSU) crystal in and around joint is required to proliferate features characteristic for gouty arthritis (Zhang, Lee, Zhang, Furst, Fitzgerald & Ozcan 2016). Ultrasonographic appearance of 'double contour sign' over the hypoechoic aricular hyaline cartilage also favors gout diagnosis (Thiele & Schlesinger 2007). Before crystallization of soluble urate, persistent hyperuricaemia is a pre-requisite and now we are well informed about factors responsible for HU and that triggers gout and more importantly how to treat them. Hippocrates remarks about gout is ubiquitous (aphorisms of gout) and many of them are still alive today -'Eunuchs do not take gout', 'women does not take gout before their menopause', 'young men do not experience gout unless they indulge in coitus', 'an un-walkable disease', 'related to affluent community ', etc. (Deshpande 2014). However, regarding Hippocrates remark -'Eunuchs do not take gout', study is lacking. 6 Familial clustering is evident in primary gout. The SLC22A12 and SLC2A9 genes code for human urate transporter 1 (URAT1), is important in controlling reabsorption of uric acid from the proximal renal tubules, though influenced by some drugs -Lactate, Nicotinate and Pyrazinoate cause an increased reabsorption of uric acid, whereas Benzbromarone, Probenecid and Losartan cause a reduction in uric acid reabsorption and polymorphism of these genes could cause under excretion of uric acid as observed as of SLC22A12 gene among German Caucasians. Polymorphisms of glucose and fructose transporter, ABCG2 (a urate efflux transporter in proximal collecting duct cells) and SLC17A3 (encoding NPT4 -a proximal tubule sodium/phosphate co-transporter), SLC17A1 gene, which codes for NPT1, a sodium-dependent phosphate co-transporter, have also been found to associate with gout. The 64Arg variant of the β3-adrenergic receptor gene induces insulin resistance by reducing lipolysis and hence an increase in adipocytesa possible explanation for metabolic syndrome. The 677T allele of the methylene tetrahydrofolate reductase (MTHFR) gene provides substrate for de novo purine synthesis. Mutation of aldolase B (ALDOB) and hypoxanthine guanine phosphorribosylpyrophosphate genes are responsible for juvenile gout, Lesch-Nyhan syndrome.

Effective screening where strong family history of gout is identified
Screening for uric acid among family members and relatives could be interesting as revealed in Hungarians in 1992 (Mituszova et al., 1992). In the study including 105 1 st degree relatives of 22 Hungarian male gout, hyperuricaemia and gout was found more prevalent than that of general population and it could be due to involvement of several genetic and environmental factors (Mituszova et al., 1992). Before then, in 1970, uric acid 7 clearance was studied in 96 1 st degree relatives of 37 patients with primary gout and a graded correlation (closer in the case of male relatives than in female relatives) was found between clearance values for patients and mean values for their relatives. It was suggested that the concept of multifactorial influences regulating uric acid levels in the blood can be extended to the renal handling of uric acid (Scott and Pollard 1970).

Symptomatology and diagnosis of gout
Gout is a mono-articular arthritis and involvement of the first metatarsophalangeal joint is a norm at least in the first attack, however, many other peripheral joints, namely, ankle, mid-foot, knee, etc. also could be affected . Gout could also be polyarticular, especially in patients' with a history of previous multiple single attack involving small joints of hand and feet, mimicking inflammatory (rheumatoid arthritis, psoriatic arthritis) and degenerative arthritis (generalized nodal osteoarthritis) . In a published case report deposition of chalky white materials in the lumbar spinal canal reportedly proliferated features alike lumbago sciatica unveiled under MRI of lumbar spine; and further examination of the aspirated materials from the lumbar spinal canal after surgical exploration revealed MSU crystal under polarized microscopy (Jegapragasan, Calniquer, Hwang, Nguyen & Child 2014). Furthermore, soft tissue inflammation from MSU deposition, for example olecranon bursitis, retro-calcaneal bursitis, pre-patellar bursitis could also be developed over the olecranon process (olecranon bursa), posterior heel (retrocalcaneal bursa), and patella (prepatellar bursa), respectively. Joint destruction with deformity could result from longstanding, treatment failure gout with or without tophi and X-ray foot could reveal punched out bony lesion with overhanging edge. Lesch-Nyhan syndrome, a rare example of gout among pediatric Among NSAIDs, COX-1 inhibitors are widely prescribed, nevertheless, COX-2 inhibitors are also effective and require judicious selections of candidates based on their level of associated cardiac, renal, hepatic, pulmonary co-morbidities . Randomized-controlled trial (RCT) based findings revealed, single anti-inflammatory agent is effective in managing gout symptoms, however, based on expert opinion, ACR  and EULAR gout managing guidelines (Richette et al., 2017) suggested that combined anti-inflammatory agents could also be used in case of failure of single drug in the group.

Implications for use of other drugs
In cases of renal impairment, conventional NSAIDs should be avoided and situation like this, oral or intra-articular steroid are recommended . Similarly, evidence suggests that anti-IL1, such as, Anakinra, Canakinumab, etc. could also be effective in preventing flaring of gout symptoms, and they could be a suitable alternative approach where other conventional antiinflammatory agents are failed or found inappropriate. However, more study including its indications and overall safety concern in gout patients is required , Alexandre & Alexander 2015Thueringer, Doll & Gertner, 2015). Critically ill hospitalized patients with contraindications to conventional anti-inflammatory drugs, intra-muscular injection of ACTH could also be of great value (Daoussis, Antonopoulos & Andonopoulos 2014).

Urate Lowering Therapy
Urate lowering therapy (ULT) is indicated to normalize increased sUA level and for this purpose xanthine oxidase inhibitors (XOIs) and uricosuric agents are the two mostly prescribed drug classes. Among XOI, Allopurinol and Febuxostat (non-purine XOI) are being used widely and Benzbromarone and Probenecid are the two commonly used uricosuric agents and recommended by EULAR and ACR to use in combination with XOI where appropriate . More recently study result suggest, Lesinurad is a promising serum urate lowering option and appears effective when used in combination with XOI (Singh 2017).
However, little is known about the safety profile of it and we are yet to have any RCT assessing superiority of one uricosuric over another, warranting further research addressing the fact. Lesinurad is not cost effective either. Effect of Lesinurad in minimizing tophus size is also not promising (Richette et al., 2017).

Uric acid Conversion
Refractory gout, meaning that both symptoms amelioration and sUA level control are not achieved using above conventional (NSAIDs, Allopurinol) drugs and situation like this, ACR and EULAR recommends the use of pegloticase in their updated guidelines (Richette et al., 2017). Pegloticase, a recombinant pegylated (PEG) uricase, it converts uric acid into more water soluble allantoin for easy excretion through kidney -first approved to use in the United States in chronic tophaceous gout, however later has got approval to be used in several European countries. Pegloticase failure could be the result of developing anti-pegloticase antibodies and infusion related adverse events. The drug is not cost effective either and could restrict physicians from prescribing this promising gout drug even when indicated .

Non-pharmaceutical options for management of gout
Alongside medicinal agents, patients' education regarding gout pathophysiology, clinical manifestation, diseases and drugs triggering gout (metabolic syndrome, diet, drugs), available treatment options and life-style modifications could contribute in effective control of sUA level and thereby could impede appearing painful gout manifestations and because of this ACR  and EULAR (Richette et al., 2017) adopted them as recommendations to follow while managing gout in day to day clinical practice.
Moreover, limited air-flow could contribute in developing HU and gout and it is important to address this issue while managing gout as well (Fukuhara et al., 2017).  (Zhang, Peloquin, Dubreuil, Roddy, Lu, Neogi & Choi 2015).
Moreover, Fukuhara et at., reported a link between hyperuricaemia and airflow limiting disorders (AL) with respiratory symptoms among smokers in 156 patients aged over 40 (Fukuhara et al., 2017). So, elevated sUA in association with respiratory symptoms, high smoking index, and low BMI could predict the risk of developing of AL risk.
1.6.4. Metabolic syndrome -when evaluating and planning to manage gout, searching whether other components of metabolic syndrome, for example, obesity, insulin resistance, hypertension, dyslipidemia, and or cardiac failure could be of great value for effective management of gout (Doherty et al., 2016).
If we don't address all these factors while managing gout, treatment outcomes could be disappointing even following the most prudent gout managing guidelines, as described in a recent audit in a UK primary care practice (Cottrell, Crabtree, Edwards & Roddy 2013).

The challenge with managing gout
Gout is a challenging condition to treat effectively due to the varying nature of disease severity and progression, as well as the other secondary and associated conditions/symptoms which may occur. It is this author's view that few (if any) single and objective works exist for the agreed management of gout on an international scale, other than the guidelines by ACR and EULAR. Research quality and consistency is varied and may differ between clinics and on a wider healthcare front, between countries. Though, ACR  and recent EULAR (Richette et al., 2017) recommendations for gout management could help physicians regarding the issue, some of their recommendations were not based on RCT, rather adapted in line with expert opinion.

Study aims and objectives: The research question asked by the author 'what
evidence is available for 'pharmacological' and 'non-pharmacological' treatment options for gout?' Through critical synthesis of current and widely acknowledge treatment strategies for managing gout, this author aims to create an up-to-date evidence-based gout management review. It is plausible that making available updated information about gout treatment could assist practicing physicians' efficiency in treating gout. Here in this new synthesis, the author will present both pharmacological and non-pharmacological approaches for managing gout based on past ten years published works.
Peer-reviewed literature were searched and screened systematically. Preferred Reporting Items for Systematic Meta-Analysis (PRISMA) (Larissa et al., 2015) guidelines were consulted for this study. Using the PubMed database, keywords: 'clinical trials in gout management' were used during the period of 1 st September 2018 to 30 th October 2018. A total of 173 articles were found for further analysis.

Inclusion and Exclusion criteria
To ensure recent and relevant research was the primary focus, the author aimed to include articles published within past ten years and for this purpose articles published before January, 2008 were not considered in this new synthesis (50 out of total 173). As this was a systematic search and review work, there were no strict excluding and including criteria while screening published works. However, articles meeting any of the following criteria were also excluded in this new draft (

Results:
Out of 173, finally 91 articles were considered eligible for further consideration. EULAR and ACR are two premier authorities recommending guidelines for diagnosing and managing rheumatic disorders, however, being unfortunate, the author's search result didn't find articles as of EULAR and ACR based recommendations for the treatment of HU and gout, so, in addition to this 91 PubMed database retrieved articles, the author further included ACR and EULAR updated gout managing guidelines, leaving a total of 93 articles for final analysis ( Figure -1). Among them, narrative review, RCT, systematic review and meta-analysis, Cochrane review were 38, 17, 9, and 6, respectively (Table -1). Other types of articles were -non-RCT (5, 4-phase I, 1-phase III), cohort study (5), time-event series (3), clinical guidelines (3), cross-sectional study (2), exploratory study (1), case-control study (1), Quasi-experimental study (1), post-hoc analysis (1), and practical therapy (1). In the discussion section (4.0), all the retrieved information from the published work has been displayed into two broad sub-headings -nonpharmacological (4.1) and pharmacological (4.2) approaches for gout management. The University of South Wales, UK ethical committee approved the work.  Singh & Schlesinger 2015) and to improve the situation, staff involving with gout management regular arrangement of CME / CPD could be useful. In a recent UK based study with 517 gout patients -nurse-led approach was found superior over general practitioners-led approach in achieving target sUA concentration (less than 6 mg/dL), reducing gout attack and tophi size, hence improve quality of life and quality-adjusted life- year (QALY) gain at 2-year follow-up as well (Doherty et al., 2018). Same results were echoed in a pharmacist-staffed gout management program performed over a 26-week period with 105 gout patients and found helpful in achieving target sUA among patients (Goldfien,

Pressman, Jacobson, Ng and Avins 2016).
According to ACR 2012 guideline, effective gout management should include educating patients' about contribution of diet, drugs, and physical activity in regulating sUA level and managing gout  Education could also include importance of family member screening, where appropriate.
In a prospective study among British people with primary gout, graded correlation between male gout patients and incident gout in 1 st -degree was revealed (Scott & Pollard, 1970). Thereafter, in another study among 1 st degree relatives of Hungarian male gout patients, gout was found more prevalent than that of general population (Mituszova et al., 1992). However, using the PubMed search engine within the given tenure, the author didn't find any published work addressing the issue and it is being hoped that further study could draw a conclusive remark.

Discipline and life-style modifications -
In a RCT with crossover, Dalbeth and colleagues (2010) documented uricosuric effect of milk, whereas ingestion of soy control caused an increase in sUA concentrations by about 10% (p<0.0001) in 16 healthy male volunteers. However, this result could be challenged in large number of study sample (Dalbeth et al., 2010). This study result provide rationale for long-term intervention with such dietary interventions in the management of individuals with HU and gout. Nguyen and colleagues (2017) demonstrated that BMI is directly related to gout risk -the more the BMI, the more the gout risk and vice versa (Nguyen et al., 2017).
Weight loss either by dietary intervention or bariatric surgery is also found effective in reducing serum uric acid concentration. In their study among obese Swedish, Maglio et al., (2017) demonstrated reduced gout incidence following bariatric surgery and it was statistically significant (95% CI, p<0.001); and the number needed to be treated by bariatric surgery to prevent one incident gout and hyperuricaemic event was 32 (95% CI 22 to 59) and was 8 (95% CI 6 to 13), respectively.
Moreover, excessive consumption of meat (beef, pork, lamb) , seafish , sugar-sweetened drinks, fructose rich food, and orange or apple juice, and alcohol (especially beer)  could cause an increase in gout incidence and flares up as well. However, relation between gout incidence and consumption of caffeinated coffee, cherries, skimmed milk, low-calorie yoghurt is inverse -EULAR evidence-based recommendation mentioned skimmed milk powder derivatives has anti-inflammatory effects in acute gout. ACR encourages low-fat or non-fat dairy products and vegetables . So for effective management of gout should include intervention with lifestyle modifications, physical fitness steps, limit use of African Americans with CKD were randomly assigned to metoprolol (a beta-blocker), ramipril (an angiotensin-converting enzyme inhibitors, or amlodipine (a dihydropyridine calcium-channel blocker) and comparison between baseline and 12-month sUA was done.
And study result revealed that, metoprolol increased sUA by 0.3 mg/dl, whereas ramipril or amlodipine had no effect on it; and gout-related hospitalizations rate was not significantly differ between anti-hypertensive users (Juraschek, Appel & Miller 2017).
When considering management of hypertension in patients with gout, EULAR evidencebased recommendation suggest use of losartan and calcium channel blockers and advised to discontinue with loop or thiazide diuretics. This EULAR-recommendation is partially contrast to AASK trial outcome and increased sUA level was not seen in patients receiving were found common -CKD, renal failure, hypertension, ischemic heart disease (IHD), myocardial infarction (Nyberg et al., 2016). Stroke, obesity, peripheral arterial disease and diabetes mellitus (DM) has also been considered as independent risk factor for hyperuricaemia and gout (Richette et al., 2017;. In another review work, Mortada et al (2017)  gout was documented as 86% and 53%, respectively. In the study, CKD appeared to be a major risk factor for gout, however gout might cause renal impairment in the course of the disease, require more research. So at the time of gout diagnosis, staging of CKD based on estimated glomerular filtration rate (eGFR) should be done and then could be done at regular interval to see whether further deterioration of renal function has occurred. Sleep apnea (Zhang, Peloquin, Dubreuil, Roddy, Lu, Neogi & Choi 2015) and air-flow limiting disorders (COPD, bronchial asthma) especially among smokers (Fukuhara et at., 2017) are also found has association with increased sUA level, though further multicenter longitudinal study could provide details whether there is a causal link between them.

4.1.4.2.Conditions cause increased uric production and reduced excretion of uric acid -
genetic and acquired causes of uric acid overproduction, for example, inborn error of purine metabolism, psoriasis, myeloproliferative, or lymphoproliferative disease, etc. and conditions causing reduced uric acid excretion, such as CKD, glomerular, or interstitial renal disease (e.g., analgesic nephropathy, polycystic kidney disease), concomitant use of drugs for other comorbidities should consider when evaluating hyperuricaemia and gout . So when evaluating and treating gout, all these conditions should keep in mind. preexisting renal disease treatment resulted in increased eGFR and no significant elevation of serum creatinine, respectively at 1-year follow-up. However, differences in renal function between the treatment and no-treatment groups were not statistically significant in any of the identified studies and data were scarce to draw a conclusion. HU should be treated to halt gout flaring, developing renal impairment and cardiovascular events (Vinik et al., 2014). However, calculated Framingham 5-year CVD risk was high in patients with hyperuricaemia and gout (with or without tophus) and therefore, implementing CVD screening for these patients could provide better patients' management (Colvine et al., 2008). Based on current evidence, uric acid is considered as a marker of both HTN and CKD and XOIs or uricosuric agents could be effective in these conditions, however, study with large sample could draw a conclusion whether other than gout and tumor lysis syndrome, ULT has any potential in treating HTN halting progression to CKD and CVD (Feig 2014;Mallat et al., 2016).

4.1.4.3.Asymptomatic hyperuricaemia (HU) and its consequences if left untreated
So after reviewing papers on non-pharmacological management of gout it can be summarizedpatients understanding of gout pathophysiology, causation, risk factors, treatment, treatment side effects is important while managing gout. Purine rich diet, alcohol, certain drugs could aggravate gout features, hence restricting and avoiding there use could prevent gout flare up. Low BMI and weight loss also affect gout outcome positively. However, all these outcome are not based on higher LoE and further exploration with large sample size could be of great importance.

Pharmacological options: Based on ACR recommendations, anti-inflammatory agents
for managing acute gout should start within 24 hours of gout symptoms . In case of treating acute gout, ULT should be continued if patients are on ULT already, however, ULT in new patients usually is recommended after settling acute features, but ACR suggests launching of ULT could be appropriate even in acute attack (Khanna et al., , 2147.

Anti-inflammatory drugs (NSAIDs, steroids) -NSAIDs most commonly prescribed
medication in acute gout. COX-1 inhibitors, for example, naproxen, indomethacin, and sulindac are the drug of choice, however, COX-2 inhibitors found effective as well and have better gastrointestinal tolerability than that of COX-1 inhibitors.
However, risk/benefit ratio of celecoxib regimen in terms of gout management is yet to clear .
In a meta-analysis of three RCT, oral prednisolone was compared with NSAID in 584 gout patients and results were as followin terms of effective pain control, during first 6 hours, oral prednisolone (30-35 mg/day) was comparable with naproxen (500 mg/day) and indomethacin (50-100 mg/day) and during the subsequent 4 to 6 days, prednisolone was also found as effective as NSAID both in activity and rest. Prednisolone had less adverse events (AEs) over NSAID, though authors recommended further study (Yu, Lu & Zhou et al., 2018). Before this metaanalysis, Rainer and colleagues (2016)

Neutrophil stabilizers (for example, colchicine) -
ACR adopts task forceps recommendations regarding use of colchicine no later than 36 hours of gout symptoms. And, in acute attack, a loading dose of 1.2 mg, could be followed by 0.6 mg 1 hour later and this regimen can be followed by gout attack prophylaxis dosing 0.6 mg once or twice daily (unless dose adjustment is required) 12 hours later, until the gout attack resolves. In countries where 1.0 mg or 0.5 mg are not available could be replaced with 1.2 mg and 0.6 mg, respectively. ACR say no for parenteral colchicine as this formulation is not availability, could be misused, and with more lethal effects. Prophylactic use of colchicine in patients under ULT therapy, especially during earlier period is indicated. Alongside NSAID, ACR recommends low dose oral colchicine (0.5 or 0.6 mg, once or twice a day, which one is available) as the first-line anti-inflammatory gout prophylactic option. Colchicine dose should be adjusted according to renal function level and potential drug-drug interactions, however, adjusted colchicine dose could be based on the decision of the treating clinician .
Both high and low-dose of colchicine improve gout pain and they are equally effective in relieving pain at 36 hours, though AEs were more with high dose. As of today, trails documenting withdrawal of colchocine because of AEs from either dose of colchicine are lacking (van Echteld et al., 2014). And we are yet to have trials comparing conventional NSAIDs, steroids and colchicine in gout patients (van Echteld et al., 2014). The usual adult dose for acute and prophylactic gout is 1.2 mg/day and 0.5-0.6 mg/day three to four times / week, respectively. In usual dose, colchicine poisoning is rare, but not impossible and failure to recognize such event death could be inevitable. Besides history of colchicine ingestion, gastroenteritis, hypotension, lactic acidosis, and pre-renal azotemia are the signature of colchicine poisoning. Furthermore, co-administration of macrolids (clarithromycin, erythromycin), antifungals (ketoconazole), ciclosporin and grape juice could further increase serum colchicine concentration and thereby makes colchicine poisoning features even prominent. However, gastrointestinal decontamination of colchicine could be done with activated charcoal, but large, recent (<60 min) ingestions warrants gastric lavage. Administration of granulocyte colony-stimulating factor could also be useful (Finkelstein et al., 2010).
We are yet to have its optimal dose with or without impaired renal function; its consideration in patients under dialysis is less explored and warrant further research. Recent time, scope of allopurinol use is being suggested in CKD patients without gout. Based on outcomes of observational studies an association between increased serum urate level and CKD -end stage renal failure has been documented. The effect of allopurinol on progression of kidney disease has been examined in small studies with varying results (Stamp, Chapman & Palmer 2016).
Allopurinol is not recommended within first 10-14 days of acute gout attack.
However, in a recent RCT, difference was not statistically significant between early- dose ranged between 40 and 120 mg was found well tolerated (Zhou et al., 2016).
Dosage adjustments are not needed in elderly patients or patients with mild or moderate renal or hepatic impairment. In a meta-analysis of RCT, febuxostat had the best efficacy and safety profile. Febuxostat 120 mg was reported to be more effective and safer than allopurinol (Li et al., 2016). Hyperuricaemia causes renal impairment, which is a risk factor for gout and hence, a barrier to standard gout management. In a multicenter RCT, ninety-six gout patients with moderate-to-severe renal impairment were followed for 12-months to see whether febuxoxstat is safe or it further deteriorates eGFR. At the end of the study,

Uricosuric agents -
Among various uricosuric agents, probenecid, benzbromarone are recommended as add-on therapy when XOI alone is not effective in gout management   -Niño et al., 2017).
Moreover, its significance in reducing gout flares or tophi size is yet to register.
Comparative uricosuric safety profile is yet to have and more research are required phase-I study also revealed that administration of IV PEG in chronic tophaceous gout requiring hemodialysis for end-stage renal disease (ESRG) appeared to be feasible (Bleyer, Wright & Alcorn 2015).
In an open-label, multicenter, phase-III study, Digumarti and colleagues documented rasburicase, another uricase analogue safe and effective in preventing and treating malignancy-associated hyperuricaemia (Digumarti, Sinha, Nirni, Patil & Pedapenki 2014 When gout patients fail to sustain improvement with NSAIDs, colchicine, and steroid, anti-interleukin-1 (IL-1) could play a pivotal role in resolution of gout manifestations and could be used successfully as a 4 th -line anti-inflammatory agent in treating this common metabolic arthritis based on outcomes of clinical trials. Anti-IL is not cost effective and further trials with large patients' size are warranted to see its clinical efficacy and safety concern as well (Schlesinger 2011). Other than anakinra, rilonacept, and canakinumab are also found effective-anakinra is an IL-1 receptor antagonist that inhibits the activity of both IL-1α and IL-1β, rilonacept is a soluble decoy receptor and canakinumab is an anti-IL-1β monoclonal antibody. Anakinra was found effective in reducing acute gout pain, whereas, rilonacept caused a decrease in gout attacks. But, canakinumab has caused both a reduction in gout inflammation and gout attack. All three IL-1 inhibitors are reportedly well tolerated (Schlesinger 2014). IL-1 inhibitors may also be helpful in polyarticular and tophaceous gout as they when patients are on uric acid lowering-lowering therapy. (Tran, Pham, Shafeeq, Manigault & Arya 2013;Schlesinger 2011). ACR and US-FDA don't recommend use of anti-IL-1 inhibition in critically ill patients  NSAIDs or colchicine . Intramuscular (IM) single dose triamcinolone acetonide (60 mg), followed by oral prednisone or prednisolone could also be useful, though consensus for the use of IM triamcinolone acetonide as monotherapy has not been reached . In NPO patients with acute gout, there was no consensus on the use of IM-ketorolac or IM -triamcinolone acetonide monotherapy .
advancing age, could impede use of commonly used drugs for gout management; and situation like these, ACTH injection could be a solution and clinical experiment revealed that a fast-acting and relieves pain within 24 hours of introduction and the duration of pin relief with IM-ACTH is almost similar to that of triamcinolone injection (Nisar 2018). Patients usually respond after 1-3 doses of IM-ACTH and is found to be well-tolerated with transient AEs.
ACTH has no clinically significant effect on serum glucose and potassium levels or blood pressure, however more studies are required (Nisar 2018).
There is no consensus whether ACTH should be used for acute gout in patients who are able to take oral NSAIDs medications . ACR recommends use of subcutaneous synthetic ACTH at an initial dose of 25-40 IU, with repetition of doses as clinically indicated .