Gout is a chronic, relapsing disease, lowering uric acid protects against joint, organ damage-Prof. Austin

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 Management of Hyperuricemia and Gout

Gout is a chronic, relapsing disease, lowering
uric acid protects against joint,
organ damage - Prof. Austin

Treatment choice depends on effectiveness of past treatment,
patient preference, joint involvement, severity of the disease,
duration of attacks and the use of concomitant medications

Biological risks of uric acid include Gout,
urate nephropathy and urate stones

KARACHI: Gout is a chronic remitting and relapsing disease. Lowering uric acid protects against joint damage and organ damage. Febuxostat is the first line of therapy for prophylaxis and it is more potent than Allopurinol. The therapy has to be continued for life long for majority of the patients. This was stated by Dr. Austin G. Stack MD, Professor and Chair of Medicine, University Hospital Limerick, Graduate Entry Medical School at University of Limerick, Ireland. He was speaking on Uric Acid, Gout and cardio metabolic consequences at a meeting held at College of Physicians & Surgeons Pakistan on September 15th 2015. The meeting was very well attended by orthopaedic surgeons, rheumatologists, physicians, diabetologists and family physicians. Participants at the CPSP Regional Centers at Hyderabad, Multan, and Quetta also joined in through Video link facility with which these regional centers are linked and they also participated in the discussion.


Prof. Austin Stack

In his hour long presentation Prof. Austin Stack talked about major chronic diseases, the treatment options available for patients with Gout, Hyperuricemia, acute versus chronic Gout, risk and benefit of various medications in detail. Hyperuricemia was defined as elevated uric acid 7mg/dl for men and 6mg/.dl for women. Not every patient with hyperuricemia, Prof. Austin said, will develop Gout. Adult men have 1200mg uric acid while women have 700mg. Uric acid, he further stated is the end product of purine metabolism. Excretion of uric acid through kidney is 2/3rd while one third of uric acid is excreted through intestine. Speaking about pathophysiology of uric acid he mentioned 15% over production and 85-90% under excretion of uric acid. Biological risks of uric acid include Gout, urate nephropathy and urate stones.

Continuing Prof. Austin said that Gout is a chronic disease which can be best described in four stages i.e. Asymptomatic Hyperuricemia (elevated serum urate with no clinical manifestation of gout), Acute Flare (acute inflammation of the joint caused by urate crystallization), Intercritical segments (the interval between acute flares) and Advanced Gout (long term gouty complications of uncontrolled hyperuricemia). In acute phase there is severe pain, redness, warmth, swelling which lasts for 12-24 hours and then resolution takes place in a few days. Intercritical gout is most often asymptomatic. Late complications of Gout include joint deformity, destruction, chronic pain, damage to surrounding tissues and nerve compression. With disease progression the modifiable risk factors include obesity, diet rich in meat, seafood, soda, fruit juices, hypertension, chronic kidney disease, avoiding thiazide and loop diuretics, post menopausal , organ transplant recipient status, avoiding use of Aspirin, Cyclosporine besides toxic exposure to lead. With high uric acid there are high chances of Gout and cardio metabolic risk.


Speaking about the treatment options Prof. Austin said that in acute condition one can use NSAIDs, Colchicine, Corticosteroids, and Interleukin 1 antagonists. In chronic phase Xanthine Oxidaze Inhibitors i.e. Allopurinol and Febuxostat and recombinant urate oxidase. Other options include weight loss, regular exercise; avoid risk factors including dietary and medications.

Acute Gouty flare, Prof. Austin said are self limiting. The treatment objective is to provide rapid relief of symptoms. Treatment must be initiated within 24 hours of gout symptoms and it should be continued for one or two weeks. Earlier start of treatment gives better results. He advised the participants of the meeting not to stop urate lowering therapy adding that treatment options also depend on the patient. Treatment is always targeted according to the disease. In acute gouty attacks, start with Colchicine, NSAIDs and corticosteroids. Urate lowering therapy is also indicated hence initiate prophylactic therapy for mobilization flare and ULT. However there is a caution not to use NSAIDs in peptic ulcer disease and in patients with chronic kidney disease. Colchicine should be used within thirty six hours of acute gouty attacks and it is the first line prophylaxis in patients initiated on urate lowering therapy. As regards it mechanism of action, it reduces inflammatory response to deposited crystals, diminishes PMN crystals and also blocks cellular response to deposited crystals. Adverse effects of Colchicine are dose related and they are more common when the patient has renal or hepatic disease, he added.

 

PharmEvo organized a symposium on management of Hyperuricemia and Gout at CPSP Karachi
recently. Group photograph taken on the occasion shows from (L to R) Dr. Masood Jawaid,
Prof. Shahid Noor,
Prof. Yakoob Ahmedani, Prof. Kamran Hameed, Prof Austin. (Guest Speaker),
Prof. Ejaz Ahmed Vohra,
Prof. I.A. Jokhio, Prof. Hakim Ali Abro, Syed Jamshed Ahmed
and Prof. Abdul Basit.

High uric acid has high chances of Gout and cardio metabolic risk. Speaking about the association of Gout and Uric Acid with cardiovascular diseases, Prof. Austin said that studies have showed the association with hypertension, diabetes, metabolic syndrome and kidney disease. He then gave highlights from a Meta analysis consisting of 18 prospective studies which enrolled 55,609 patients which showed that high uric acid had 40% higher risk of hypertension. Similarly eight prospective studies which enrolled 32,016 patients reported 2930 incidents of diabetes mellitus. It showed that high uric acid leads to new onset of Type 2 diabetes and it had 56% increases in risk. Another Meta analysis of eleven prospective studies showed that high uric acid results in 18% increase in chronic kidney disease.


He then referred to the Guideline recommendations by British Society of Rheumatology (BSR) , European League Against Rheumatology (ELAR) and American College of Rheumatology (ACR). All these guidelines prefer NSAIDS as the first line of therapy. BSR and EULAR recommend corticosteroids as effective alternatives while ACR recommends it as first line drug. BSR guidelines recommend Colchicine as an effective alternative, EULAR and ACR recommends it as First Line drug. While selecting medications, co morbid conditions of the patients, he said must be kept in mind. Treatment choice is also dependent on effectiveness of past treatment, patient preference, joint involvement, severity of the disease, duration of attacks and the use of concomitant medications. High uric acid is also independent risk factor for increase of morbidity and mortality. In general population high uric acid leads to high cardiovascular events, there is 54% increase in cardiovascular deaths.

Prof. Austin then talked about safety and efficacy of Allopurinol vs. placebo. It results in reduced uric acid production. Starting dose is 50-100mg daily and it can be increased up to 300mg daily in divided doses. Its maximum dose is 800mg per day. Its dose has to be adjusted according to creatinine clearance and it does not provide adequate control of Hyperuricemia in patients with Gout. Serious reactions include fever, rash, epidermal necrolysis, target skin lesions, mucous membrane erosions. Allopurinol is rarely prescribed in its maximum dose, he added.


While selecting a drug one should always look for co-morbidity. Indications for Urate Lowering Therapy are frequent attacks, chronic kidney disease stage two and urolethiasis. The treatment goals, Prof. Austin said is to prevent frequent attacks, deformity and destruction of joints, reduce tissue level of uric acid besides prevention of chronic inflammation.

Speaking about the use of Febuxostat, Prof. Austin said that one can start with a daily dose of 40mg and it can be increased to 80-120mg. It is much potent drug as compared to Allopurinol and also has a better side effect profile. It can be safely used in mild to moderate kidney disease, it is safe in elderly. It has dose dependent decrease in uric acid levels. He then showed highlights from the CONFIRM and FACT Trial wherein Febuxostat was compared with Allopurinol in the treatment of Gout and chronic kidney disease and in patients with Hyperuricemia and Gout respectively.


Findings from these studies showed that significantly more patients receiving Febuxostat than Allopurinol achieved the desired serum uric concentrations of 6mg/dl which proved that Febuxostat was better than Allopurinol. Uric acid risk factors include stroke and heart attacks. The treatment goal should be to prevent first attack, terminate second attack and prevent the recurrent attacks.

Indications for Urate Lowering Therapy (ULT)

American College of Rheumatology, Prof. Austin said, recommends that one can start the use of ULT in acute episode while Philippines Guidelines say that ULT can be started ten to fifteen days after resolution of the acute attack. ACR guidelines recommend the use of Uric Lowering Therapy for long term which means life long. Allopurinol and Febuxostat are the first line drugs. With the use of Allopurinol in high uric acid, there was 11% reduction in mortality. Gout, Prof. Austin said is under treated disease. Less than 50% of desired uric acid is achieved simply because the drug is not used at right time and in right dosage. At present 36-52% of patients are not controlled with existing therapy because there is lack of primary care guidelines, target threshold of uric acid is not met and there is uncertainty about ULT initiation.

Health Research Advisory Board, Prof. Austin opined should seize this opportunity and come up with a set of Guidelines on treatment of Hyperuricemia and Gout. Guidelines, he further sated, are important way to go. Multidisciplinary team will affect quality of care. Management of Hyperuricemia and Gout is not a straight line but implementation of the Guidelines is the real challenge we all face, he concluded.


The presentation was followed by lively discussion wherein delegates at Karachi as well as from CPSP Regional Centers at Multan, Quetta and Hyderabad also participated. Replying to a question from Prof. I. A.Jokhio, Prof. Austin said that diet has a role in the management of Hyperuricemia just like salt reduction helps in control of blood pressure. However, diet does not reduce Gouty attacks. One should avoid red meat and Seafood. Responding to a question from Prof. Ejaz Ahmad Vohra regarding treatment of asymptomatic Hyperuricemia, Prof. Austin said that at present there is no evidence to treat these patients but since high uric acid is a risk factor, it needs treatment and it works. Asymptomatic Hyperuricemia is a risk factor for Gout. Responding to another question as to how far uric acid should be reduced, Prof. Austin said that less than 6mg/dl is better and even less than 5mg/dl is ideal. Even if it is reduced further, there won’t be any side effects.

Another participant asked how Hyperuricemia leads to Type 2 diabetes and what is the mechanism of action? At this Prof. Abdul Basit remarked that it may be related to insulin resistance. When we treat insulin resistance, it treats Hyperuricemia as well. One of the participants from Hyderabad asked about the treatment of post transplant patients to which Prof. Austin said that they are at risk of Hyperuricemia and Gout. One should avoid NSAIDs in these patients because of drug interaction with azothioprine. Question asked from the Multan Center was why there was difference in numbers for men and women regarding uric acid? Prof. Austin remarked that both men and women have different metabolism and excretion. However, the normal limits of serum uric acid should not vary much between men and women. Responding to a question regarding treatment of acute Gout, Prof. Austin said that you can use Colchicine, corticosteroids and you can also use ULT. Continue Colchicine for two to four weeks. Prof. Kamran Hameed remarked that since there is 85% under excretion of uric acid, kidney is the main culprit. Prof. Austin said that despite lot of research, there still exist some gaps in our knowledge. Under and over excretion do have different risks between them. Prof. Austin remarked that blocking uric acid production works. Replying to another question Prof. Austin said that even after you have achieved uric acid level of 6 mg/dl, continue treatment with Febuxostat as the disease requires life long treatment. ULT therapy is for life to prevent further attacks and deformity. One can however use the lowest dose.

Earlier Dr. Masood Jawaid Director Medical Affairs in PharmEvo in his welcome address introduced the guest speaker. Mr. Shakil Ahmad Director Marketing & Sales PharmEvo presented vote of thanks.

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