The Burden of Gout

Abstract

“Gout- Disease of the Kings”, a long-recognized paradox in which an acute gouty attack is often linked with consumption of large amounts of alcohol and rich meals.  It is the most common inflammatory arthritis causing burden to patient’s health and medical resources in New Zealand. Despite the clinical, and economic burden, patient compliance with urate lowering therapy is poor. Doctor-patient relationship, medication compliance and addressing systemic barriers is necessary to improve patient outcomes. The role of diet is less important as compared to urate lowering therapy, being a patient advocate and active listener. There is the clinical realm to educate patients with gout in a non-accusatory tone and guide them through this journey. A multi-disciplinary approach is imperative to empower patients to self-manage this chronic disease. This paper points out the pathophysiology of gout, barriers leading to treatment failure and current available urate lowering therapy.

The Burden of Gout

General practice (GP) is a fascinating field evidenced by the myriad of cases that walk through the doors. In ancient history, gout was known as “the disease of kings”. With the Pacific Islander, and Maori demographic in South Auckland, seeing a gout patient in daily practice is imminent. A thorough history taking, and physical examination is crucial to avoid missing sinister conditions such as septic arthritis. Often clinicians can postulate a differential diagnosis with a good consult and clinical acumen. A group of 14 health practitioners from primary care clinics in South Auckland looked at the experience of gout patients and their management via a semi-structured interview (Humphrey et al., 2016). The study found multiple “cracks” at different levels in terms of health ownership, systemic barriers, gout risk factors, cultural barriers and potential stigmatization (Humphrey et al., 2016). Most of the clinicians were efficient in acute management of gout but deficient in the long-term prevention of it. This paper emphasizes the aetiology, presentation, treatment options of acute and chronic gout, and holistic approach to gout management.

Case History:

Demographics: 38 years old Samoan male. He presented himself to our GP clinic.

Presenting Complaint: Three-day history of swollen and painful right forefoot.

History of Presenting Complaint: He was unable to walk due to pain. No history of trauma or fevers. Recent intake of beers and oysters in the weekend at a barbeque party. Next morning, he developed severe right foot pain. Stopped taking allopurinol and colchicine six months ago for his gout. Last gout attack was 2 months ago.

Past Medical History:  Gout, Obesity.

Medications: Nil (poor medication compliance). No known drug allergies.

Social History: Builder. Smoker.

Examination:  Afebrile. Antalgic gait. Right first metatarsophalangeal joint (MTPJ) erythematous and swollen. Warm and tender to touch. Limited range of motion. Ankle joint was normal. Neurovascular status intact.

Investigation: Nil. Previous urate raised at 0.57 (one year ago).

Impression: Clinically gout. Low likelihood of septic arthritis. Risk factors- male, Pacific Islander, history of gout, raised urate at 0.57, obesity, poor medication compliance. Also, scores > 8 points on the American College of Rheumatology (ACR) for gout (Engel, Just, Bleckwenn, & Weckbecker, 2017).

Management: He was prescribed high dose of anti-inflammatory for one week. He was prescribed concurrent Colchicine 0.5 mg daily and asked to start Allopurinol 100 mg daily in two weeks after his acute flare of gout. He was advised to keep up his fluid intake, elevate his foot and re-iterated dietary/alcohol education. A follow up consult was advised in four weeks after his blood test with the aim to gradually escalate his allopurinol dosage until serum urate level was < 0.36 mmol/L.

Discussion

Gout occurs when uric acid crystals accumulate in the joint or surrounding joint tissues secondary to hyperuricemia (Engel et al., 2017). Urate is metabolized from purine (Engel et al., 2017). High uric acid occurs mainly either by excess production of uric acid or under excretion of uric acid by the kidney (Engel et al., 2017). Invariably, failure in treatment occurs due to discrepancy in treatment regimens, poor medication compliance and follow up by clinicians (Engel et al., 2017). Patients often lose their trust in the medication and fail to understand the role of long-term urate lowering drug therapy.  

Aetiology and Anatomical Pathology of Gout

In a gouty flare, there is diffuse neutrophilic synovical capsule inflammation (Towiwat, Chhana, & Dalbeth, 2019). Gout crystals consist of monosodium urate (MSU) (Towiwat et al., 2019). MSU crystals dissolve faster at cooler temperatures leading to local joint inflammation and activating the inflammatory cascades (Engel et al., 2017). Macrophages release chemical mediators such as Interleukin-1 which can lead to joint inflammation and destruction (Engel et al., 2017). In some people, tophus is evident which is a chronic organised giant granulomatous tissue consisting of monosodium urate crystal, immune cells and fibrous tissue (Towiwat et al., 2019).

Besides frequent painful acute gout flares, if left untreated, gout can cause irreversible cartilage damage and bone erosions (Towiwat et al., 2019) (Figure 1).

There is some evidence that high levels of urate being an independent risk factor for cardiovascular, cerebrovascular and chronic kidney disease (Rees, Hui, & Doherty, 2014). Nevertheless, this remains anecdotal evidence and requires further concrete high quality research.

Clinical Presentation of Gout

Gout is a painful monoarthritis. It often involves the first MTPJ which is also known as podagra (Stewart, Dalbeth, Vandal, & Rome, 2016). A meta-analysis by Stewart S. et al. looking at 45 studies supports the notion that first MTPJ arthritis is common in initial gout attacks (Stewart et al., 2016). Hypothetical evidence suggesting that biomechanical loading and physical stress put through the ankle and forefoot might be responsible for urate crystal deposition and release in these joints (Stewart et al., 2016). An acute flare usually evolves within 24 hours (Towiwat et al., 2019). Gout has a predilection for peripheral joints such as ankle, feet, hands, and elbows (Rees et al., 2014). Clinical diagnosis is often based on a good medical history and clinical examination after ruling out red flags (Engel et al., 2017). The list of important red flags are septic arthritis, trauma, inflammatory arthritis, and pseudogout (Engel et al., 2017).

Gold standard diagnosis would be joint aspiration of the involved joint with laboratory evidence of monosodium urate crystals but often this is not feasible in primary care setting. Occasionally, patients having an acute gout episode will have normal serum urate levels on blood test. A normal serum urate level does not exclude gout as a possible cause. Nevertheless, raised serum urate increases the likelihood of gout (Engel et al., 2017). A blood test should be done a few weeks after an acute flare to prevent underestimating serum urate levels as gout crystals are deposited in the joints during an acute flare leading to reduced circulating blood levels (Engel et al., 2017).

Table 1. Diagnostic criteria for gout [adapted from (Engel et al., 2017)].

Treatment for Acute Gout

The goal here is to resolve joint inflammation, reduce bony erosion, and reduce the patient’s discomfort (Engel et al., 2017). There are two main forte for gout treatment: non-pharmacological and pharmacological therapies(Engel et al., 2017). Patient education of their lifestyle habits (obesity, lack of exercise), dietary education and resting the joint are crucial advice during an acute flare up. Nonsteroidal anti-inflammatory drug(NSAID), corticosteroids and colchicine are often first line drugs for acute gout attack (Engel et al., 2017). NSAID are first line during an acute attack and should be commenced within 24 hours of an acute attack. Corticosteroid is another option. Caution should be applied when using these medications by taking into account patient comorbidities (Engel et al., 2017).

Long term Treatment for Chronic Gout

The main goal for gout long-term treatment is achieving a target urate of less than 0.36 mmol/L primarily by keeping the urate levels below the saturation point at which urate crystal can form (Rees et al., 2014). For patients with gouty tophi, a lower target of less than 0.30 mmol/L is recommended for faster dissolution of gout crystals (Rees et al., 2014). Chronic gout therapy is often lifelong. We know from previous research that keeping the urate at optimal levels helps with dissolution of monosodium urate crystal with subsequent reduction in gout flare-ups (Stamp et al., 2017). Interestingly, a paper by Perez-Ruiz F. et al. showed that prescription from a non-specialist for urate lowering therapy is a predictor for poorer outcomes compared to rheumatologist (Perez-Ruiz & Desideri, 2018). This could be due to patients not being thoroughly educated on the risks of gout flares. Instructing a patient to lower their serum blood urate to target level is not sufficient to succeed in long term treatment.

Allopurinol is the most widely used drug worldwide for gout treatment. It is a well-established, cheap and effective treatment for lowering urate levels. It is a purine analogue nonspecific inhibitor of xanthine oxidase (Rees et al., 2014). Clinicians are wary with prescribing large doses due to possible adverse events. This is often seen in the first eight weeks of initiating treatment (Stamp et al., 2017). Possible side effects are gastrointestinal, cardiac, deranged renal or liver function tests, or rash symptoms  (Stamp et al., 2017). A rare serious side effect is “DRESS syndrome” (drug reaction with eosinophilia and systemic symptoms) (Rees et al., 2014). A standard dose regimen would be 300 to 400 mg daily up to maximum 900 mg per day (Stamp et al., 2017). It is usually initiated two weeks after an acute flare (Engel et al., 2017).  Ideally, allopurinol dose should be gradually escalated and adjusted to renal function, e.g., creatinine clearance-based doses (Stamp et al., 2017).

A randomized non-blinded controlled trial done by Stamp LK. and colleagues in New Zealand looked at the efficacy of titrating up allopurinol dose gradually until target serum urate level was achieved in people with gout (Stamp et al., 2017).183 patients on allopurinol based on creatinine clearance were randomized and followed up to 12 months. Participants were randomized to continue current dose (control group) and escalating allopurinol dose for one year (Stamp et al., 2017). Allopurinol dose was increased until target serum urate was achieved. There were no significant differences in renal function or adverse effects in both groups. The study concluded that allopurinol dose escalation was well tolerated and effective in reducing serum urate levels (Stamp et al., 2017). There was no difference on gout flares in both groups during dose escalation. Although this study had some limitations such as not blinded leading to bias, its population was truly representative of the patients we see in South Auckland. A large number of the study population had comorbidities such as diabetes, hypertension, chronic kidney disease, previous cardiovascular and cerebrovascular event (Stamp et al., 2017).

We know from previous studies, asymptomatic hyperuricemia is not an indication to initiate urate lowering drug (Engel et al., 2017). To date, there is no good research on asymptomatic hyperuricemia treatment.

The table below illustrates pharmacological treatment options for chronic gout.

Table 3. Treatment options for chronic gout [adapted from (Engel et al., 2017)].

The two most common xanthine oxidase inhibitors prescribed in New Zealand are allopurinol followed by Febuxostat. Febuxostat is a non-purine, highly specific xanthine oxidase inhibitor (Rees et al., 2014). Febuxostat is excreted via the hepatic system and has the advantage of being used in chronic renal failure patients. In addition, Febuxostat has a fixed dosing regime, with standard daily dose of 80 -120 mg (Rees et al., 2014). Currently, Febuxostat requires special authority application for its use if patients cannot tolerate Allopurinol. Febuxostat is a newer and more expensive drug (Rees et al., 2014). The table below shows the comparison between these two drugs.

Table 4. Comparison of Allopurinol and Febuxostat [adapted from (Rees et al., 2014)].

There is some emerging evidence on the role of biologic agents that inhibit IL-1. Although being superior, this is not feasible as this biologics are expensive and are still unlicensed for acute and chronic gout treatment (Rees et al., 2014). Other less commonly used drugs are uricosuric drugs such as Benzbromarone, Probenecid and Sulfinpyrazone which are less available in most countries (Rees et al., 2014).

Educating Patients- Avoid Shaming and Blaming

Paper published by Humphrey C. and colleagues showed patients were often stigmatised and failed in long term gout treatment when diet was over emphasized rather that urate lowering therapy (Humphrey et al., 2016). A long-term therapeutic relationship between the clinician and patient is imperative. Patients often harbour guilt feeling because of the relationship of gout with diet and alcohol (Humphrey et al., 2016). This brings me to explaining to my gout patients, especially to a “young Pacific Islander or Maori male” who enjoy their seafood and red meat.

“You have a swollen and painful foot because of gout which is not your fault! 70% of this is genetic-related due to uric acid collection in your joint. We can make this better by working as a team where I guide you with your long-term gout medications so that you can enjoy your favourite food and be pain free.”

Figure 2. clearly demarcates the contribution of genetic factors and diet for uric acid metabolism:

Figure 2. Risk factors of gout and urate metabolism [adapted from (Rees et al., 2014)]

Identifying factors associated with good compliance for urate lowering therapy is the way forward for this “crippling” disease. Below is the list of things that should be put in place for gout patients (Perez-Ruiz & Desideri, 2018):

Regular blood serum urate monitoring; Follow-up system, Initial prophylactic anti-inflammatory use when starting urate lowering therapy; Pharmacy or nurse-led programmes; Address other comorbid health issues; Patient self-empowerment to self-manage their gout.

Conclusion

Although there is a dearth of literature on gout, treating gout can be a challenging task for clinicians. Health professional’s clinical acumen skills is required to battle this inflammatory endemic. Current New Zealand guidelines recommend starting urate lowering therapy at the first gout attack. A non-accusatory and holistic approach considering patient risk factors and barriers is essential in battling this prevalent inflammatory disease. The stereotype view of gout of being associated with gluttony, poor life style choices and alcohol indulgence is a fallacy (Rees et al., 2014). It is important clinicians educate their patients and address their perception of gout to empower them which allows them to make changes in their lifestyle and steer their own “health ship”. Clinicians need to be aware of their own education to bridge the existing gaps and to improve patient outcomes and treatment adherence.