# Special Populations and Refractory Gout — ACR 2020

## Chronic Kidney Disease (CKD)

### ULT Selection in CKD

- **Allopurinol** remains the preferred first-line ULT agent in patients with CKD stage >= 3 (Strong, Moderate).
- A **xanthine oxidase inhibitor (XOI)** is strongly recommended over probenecid in CKD stage >= 3, because uricosurics have diminished efficacy with reduced renal function (Strong, Moderate).

### Allopurinol Dosing in CKD

| CKD Stage | Starting Dose | Titration |
|---|---|---|
| **CKD stage 1-2** | <= 100 mg/day orally | Titrate by up to 100 mg every 2-5 weeks |
| **CKD stage >= 3** | Lower starting dose (e.g., <= 50 mg/day orally) | Titrate by up to 100 mg every 2-5 weeks |

- Allopurinol may be **titrated above 300 mg/day in CKD** to achieve SU < 6 mg/dL. The prior practice of limiting allopurinol dose based on creatinine clearance is no longer recommended by the ACR.
- Maximum FDA-approved dose remains **800 mg/day** regardless of CKD status, though clinical judgment is required for dose escalation in advanced CKD.

### CKD-Specific Decision Algorithm

```
Gout patient with CKD stage >= 3
  --> First flare?
      --> CKD alone qualifies as conditional indication for ULT
  --> Select ULT: Allopurinol preferred (Strong)
      --> HLA-B*5801 test if Southeast Asian or African American descent
      --> Start at <= 50 mg/day
      --> Titrate by up to 100 mg every 2-5 weeks
      --> Target SU < 6 mg/dL
      --> May exceed 300 mg/day with appropriate monitoring
  --> Flare prophylaxis:
      --> Colchicine dose adjustment may be needed in CKD
          (colchicine is partly renally cleared)
      --> Low-dose glucocorticoid alternative if colchicine contraindicated
```

## Cardiovascular Disease (CVD)

### Febuxostat and CVD Risk

The CARES trial (Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities) raised concerns about **increased cardiovascular and all-cause mortality** with febuxostat compared with allopurinol.

- **Switching from febuxostat to an alternative ULT agent** is conditionally recommended for patients with a **history of CVD or a new cardiovascular event** (Conditional, Moderate).
- This recommendation reflects an abundance-of-caution approach given the CARES trial signal, despite methodological limitations of the trial (57% dropout rate, 45% lost to follow-up, 85% of events occurred after drug discontinuation).

### CVD Decision Algorithm

```
Gout patient currently on febuxostat
  --> History of CVD or new CVD event?
      --> YES --> Conditionally recommend switching to alternative ULT
          --> Preferred: allopurinol (if tolerated, HLA-B*5801 negative)
          --> Alternative: probenecid (if adequate renal function)
      --> NO --> May continue febuxostat, but discuss CVD risk
```

## Refractory Gout: Pegloticase

### Indications for Pegloticase

Pegloticase is a recombinant pegylated uricase administered intravenously. Its use is restricted to specific clinical scenarios.

**Strong Recommendation FOR Pegloticase:**

Switching to pegloticase is strongly recommended for patients who meet **ALL** of the following criteria (Strong, Moderate):

1. XOI treatment, uricosurics, and other interventions have **failed to achieve the SU target**
2. Patient continues to have **>= 2 flares/year OR nonresolving subcutaneous tophi**

**Strong Recommendation AGAINST Pegloticase:**

- Pegloticase is **strongly recommended against as first-line therapy** (Strong, Moderate).
- Pegloticase is **strongly recommended against** for patients who have failed oral ULT but have **< 2 flares/year AND no tophi** (Strong, Moderate).

### Pegloticase Details

| Parameter | Value |
|---|---|
| **Dose** | 8 mg intravenously every 2 weeks |
| **Indication** | Refractory gout after failure of oral ULT agents |
| **Monitoring** | SU level before each infusion; discontinue if SU > 6 mg/dL (loss of response increases infusion reaction risk) |

### Pegloticase Decision Algorithm

```
Patient with gout refractory to oral ULT
  --> Has XOI, uricosuric, and other ULT failed to reach SU < 6 mg/dL?
      --> YES
          --> >= 2 flares/year OR nonresolving tophi?
              --> YES --> Strongly recommend pegloticase (8 mg IV q2 weeks)
              --> NO --> Strongly recommend AGAINST pegloticase
      --> NO --> Continue optimizing oral ULT first
```

## IL-1 Inhibitors for Refractory Flares

For patients experiencing gout flares for whom colchicine, NSAIDs, and glucocorticoids are **ineffective, poorly tolerated, or contraindicated**, an IL-1 inhibitor is conditionally recommended (Conditional, Moderate).

- IL-1 inhibitors include **anakinra** and **canakinumab**.
- These agents are not first-line; conventional anti-inflammatory therapies must be tried or ruled out first.
- ACTH is not recommended over IL-1 inhibitors.

## Allopurinol Hypersensitivity

### Allopurinol Hypersensitivity Syndrome (AHS)

AHS is a rare but potentially fatal adverse reaction to allopurinol. It encompasses:

- **DRESS syndrome** (Drug Reaction with Eosinophilia and Systemic Symptoms)
- **Stevens-Johnson syndrome (SJS)** and **toxic epidermal necrolysis (TEN)**

### Risk Mitigation

| Strategy | Recommendation |
|---|---|
| **HLA-B*5801 testing** | Test Southeast Asian and African American patients before starting allopurinol (Conditional, Very Low) |
| **Low starting dose** | <= 100 mg/day (normal renal function); <= 50 mg/day (CKD stage >= 3) — both are protective (Strong, Moderate) |
| **Gradual titration** | Titrate slowly (every 2-5 weeks) to minimize risk |

### If HLA-B*5801 Positive or Prior AHS

```
HLA-B*5801 positive OR prior allopurinol hypersensitivity
  --> Do NOT start allopurinol
  --> Alternative ULT options:
      --> Febuxostat (if no CVD history)
      --> Probenecid (if adequate renal function)
  --> If no oral ULT options tolerated:
      --> Consider allopurinol desensitization (Conditional, Very Low)
      --> Desensitization should only be performed in experienced centers
```

## Organ Transplant Recipients

The guideline does not provide specific recommendations for organ transplant recipients. Clinicians should consider:

- Drug interactions between ULT agents and immunosuppressive medications (e.g., azathioprine with allopurinol — **absolute contraindication** due to life-threatening myelosuppression).
- Renal function impairment common in transplant recipients.
- Specialist rheumatology and transplant team co-management.

## Limitations

- Febuxostat cardiovascular safety data are derived primarily from the CARES trial, which had significant methodological limitations; the recommendation to switch is conditional and may evolve with further evidence.
- Pegloticase recommendations do not address the emerging evidence on immunomodulatory co-therapy (e.g., methotrexate with pegloticase) to reduce anti-drug antibody formation, as this evidence postdates the guideline.
- IL-1 inhibitor recommendations are limited by access, cost, and the lack of large randomized trials specifically in gout populations.
- HLA-B*5801 testing is based on very low certainty evidence; cost-effectiveness varies by population prevalence.
- The guideline acknowledges that CKD-specific dosing of prophylaxis agents (e.g., colchicine dose adjustment in CKD) is not formally addressed and defers to product labeling and clinical judgment.
