# Urate-Lowering Therapy in Gout — ACR 2020

## Indications for Initiating ULT

### Strong Recommendations to Start ULT

ULT is **strongly recommended** for patients with any of the following (High/Moderate certainty):

- **1 or more subcutaneous tophi** (Strong, High)
- **Radiographic damage attributable to gout** on any imaging modality (Strong, Moderate)
- **Frequent gout flares** defined as >= 2 flares per year (Strong, High)

### Conditional Recommendations

- **> 1 prior flare but < 2/year:** Conditionally recommended to initiate ULT (Conditional, Moderate)
- **First gout flare only:** Conditionally recommended **against** starting ULT (Conditional, Moderate)
  - **Exception:** First flare WITH any of the following warrants conditional recommendation **for** ULT (Conditional, Very Low):
    - CKD stage >= 3
    - Serum urate (SU) > 9 mg/dL
    - Urolithiasis
- **Asymptomatic hyperuricemia** (SU >= 6.8 mg/dL, no prior flares or tophi): Conditionally recommended **against** ULT (Conditional, High)

### Timing of ULT Initiation

Starting ULT **during a gout flare** is conditionally recommended over delaying until the flare has resolved (Conditional, Moderate). Low-dose allopurinol can be started with concurrent anti-inflammatory therapy without worsening the flare.

## ULT Decision Algorithm

```
Patient with confirmed gout diagnosis
  --> Tophi, radiographic damage, OR >= 2 flares/year?
      --> YES --> Strongly recommend starting ULT
  --> > 1 prior flare but < 2/year?
      --> YES --> Conditionally recommend starting ULT
  --> First flare only?
      --> CKD stage >= 3, SU > 9 mg/dL, OR urolithiasis?
          --> YES --> Conditionally recommend starting ULT
          --> NO --> Conditionally recommend AGAINST starting ULT
  --> Asymptomatic hyperuricemia (no flares, no tophi)?
      --> Conditionally recommend AGAINST ULT
```

## First-Line Agent Selection

### Allopurinol — Preferred First-Line ULT

Allopurinol is **strongly recommended as the preferred first-line ULT agent for all patients**, including those with CKD stage >= 3 (Strong, Moderate).

**Rationale:** Lower cost compared to febuxostat, extensive clinical experience, and cardiovascular safety concerns with febuxostat from the CARES trial.

### HLA-B*5801 Testing Prior to Allopurinol

| Population | HLA-B*5801 Prevalence | Testing Recommendation |
|---|---|---|
| **Southeast Asian descent** (Han Chinese, Korean, Thai) | ~7.4% | Conditionally recommend testing prior to starting allopurinol (Conditional, Very Low) |
| **African American** | ~3.8% | Conditionally recommend testing prior to starting allopurinol (Conditional, Very Low) |
| **White / Hispanic** | ~0.7% each | Conditionally recommend **against** routine testing (Conditional, Very Low) |

- If HLA-B*5801 is **positive**, allopurinol should **not** be started.
- The HLA-B*5801 allele is associated with an **80- to 580-fold increased likelihood** of allopurinol hypersensitivity syndrome (AHS), including DRESS syndrome and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).

### Xanthine Oxidase Inhibitor (XOI) vs. Uricosuric

A xanthine oxidase inhibitor (allopurinol or febuxostat) is **strongly recommended over probenecid** in patients with CKD stage >= 3 (Strong, Moderate).

## ULT Dosing and Titration

### Allopurinol

| Parameter | Recommendation |
|---|---|
| **Starting dose (normal renal function)** | <= 100 mg/day orally (Strong, Moderate) |
| **Starting dose (CKD stage >= 3)** | Lower starting dose, e.g., <= 50 mg/day orally |
| **Titration increment** | Up to 100 mg every 2-5 weeks |
| **Maximum FDA-approved dose** | 800 mg/day |
| **Titration principle** | Titrate upward guided by serial SU measurements until target achieved |

- Allopurinol doses **may be titrated above 300 mg/day** even in patients with CKD to reach the SU target. The historical practice of capping allopurinol at creatinine-clearance-based doses is no longer recommended.
- Titration should occur over a reasonable time frame: **weeks to months, not years**.

### Febuxostat

| Parameter | Recommendation |
|---|---|
| **Starting dose** | <= 40 mg/day orally (Strong, Moderate) |
| **Titration** | Increase to 80 mg/day if SU target not achieved |
| **Cardiovascular safety** | See Special Populations section |

### Probenecid

| Parameter | Recommendation |
|---|---|
| **Starting dose** | 500 mg once or twice daily orally |
| **Titration** | Dose titration guided by SU measurements |
| **Limitation** | Less effective than XOIs, particularly in CKD |

## Treat-to-Target Strategy

A **treat-to-target management strategy** is **strongly recommended** over a fixed-dose "start low, don't titrate" approach (Strong, Moderate).

### Serum Urate Target

- **Target: SU < 6 mg/dL** for all patients on ULT (Strong, High)
- Serial SU measurements guide dose titration
- Achieving and maintaining SU < 6 mg/dL reduces flare frequency and allows tophi to resolve

### Monitoring Protocol

```
ULT initiated (e.g., allopurinol 100 mg/day)
  --> Check SU in 2-5 weeks
      --> SU >= 6 mg/dL?
          --> Increase dose by up to 100 mg (allopurinol)
          --> Recheck SU in 2-5 weeks
          --> Repeat until SU < 6 mg/dL or maximum dose reached
      --> SU < 6 mg/dL?
          --> Maintain current dose
          --> Continue monitoring SU periodically
```

## Duration of ULT

Continuing ULT **indefinitely** is conditionally recommended over stopping ULT (Conditional, Very Low). Discontinuation of ULT risks recurrence of flares and re-accumulation of urate deposits.

## Switching ULT

### After First XOI Failure

If the first XOI fails to achieve the SU target despite adequate dose titration, **switching to a second XOI** is conditionally recommended over adding a uricosuric agent, for patients with persistent high SU and >= 2 flares/year or nonresolving tophi (Conditional, Very Low).

### Allopurinol Hypersensitivity

For patients with a prior allergic response to allopurinol who cannot be treated with other oral ULT agents, **allopurinol desensitization** is conditionally recommended (Conditional, Very Low).

## Limitations

- The treat-to-target strategy, while strongly recommended, requires ongoing patient engagement and regular laboratory monitoring, which may not be feasible in all clinical settings.
- HLA-B*5801 testing recommendations are based on very low certainty evidence; prevalence data in some ethnic subgroups remain limited.
- The optimal titration interval (e.g., every 2 weeks vs. every 4 weeks) has not been definitively established by randomized trials.
- The guideline does not provide a recommendation for or against specific allopurinol dose caps relative to renal function, noting only that doses above 300 mg/day in CKD can be used with monitoring.
