# Biologic and Targeted Synthetic DMARDs in Rheumatoid Arthritis — ACR 2021

## Overview of DMARD Classes

### Biologic DMARDs (bDMARDs)

| Class | Mechanism | Agents |
|---|---|---|
| **TNF inhibitors (TNFi)** | Block tumor necrosis factor | Etanercept, adalimumab, infliximab, golimumab, certolizumab pegol |
| **T-cell costimulation inhibitor** | Blocks CD80/CD86-CD28 interaction | Abatacept |
| **IL-6 receptor inhibitors (IL-6Ri)** | Block interleukin-6 signaling | Tocilizumab, sarilumab |
| **Anti-CD20 antibody** | Depletes B cells | Rituximab |

### Targeted Synthetic DMARDs (tsDMARDs)

| Class | Mechanism | Agents |
|---|---|---|
| **JAK inhibitors (JAKi)** | Block Janus kinase signaling | Tofacitinib, baricitinib, upadacitinib |

**Safety note:** Safety concerns released in early 2021 associated with JAK inhibitors (increased risk of major adverse cardiovascular events, malignancy, thrombosis, and serious infections in older patients with cardiovascular risk factors) further support the recommendation of methotrexate monotherapy over tsDMARDs as initial DMARD therapy. The FDA recommends that JAK inhibitors only be used in patients with an inadequate response or intolerance to one or more TNF inhibitors.

## Escalation from Methotrexate to bDMARD/tsDMARD

For patients on maximally tolerated methotrexate who are not at target:

- **Addition of a bDMARD or tsDMARD to methotrexate is conditionally recommended over triple therapy** (adding sulfasalazine + hydroxychloroquine) (Conditional, Very low certainty)
  - The patient panel **strongly prioritized maximizing improvement as quickly as possible**
  - Patients valued greater persistence of methotrexate + bDMARD/tsDMARD compared to triple therapy

### No Preference Among bDMARD/tsDMARD Classes for Initial Biologic

The guideline does not recommend one class of bDMARD or tsDMARD over another for initial biologic therapy. Selection should be based on:

- Patient comorbidities and contraindications (see Special Populations below)
- Patient preference and values
- Insurance coverage and access
- Route of administration preferences
- Shared decision-making

## Switching After Inadequate Response to bDMARD/tsDMARD

- **Switching to a bDMARD or tsDMARD of a DIFFERENT class is conditionally recommended over switching to a drug within the SAME class** (Conditional, Very low certainty)
  - Example: If a patient fails a TNF inhibitor, switching to abatacept, tocilizumab, sarilumab, rituximab, or a JAK inhibitor is preferred over trying a different TNF inhibitor

### Switching Decision Algorithm

1. **Not at target on first bDMARD/tsDMARD** -> Switch to a different class
2. **Not at target on second bDMARD/tsDMARD (different class)** -> Switch to yet another class
3. Consider treat-to-target reassessment at each step (minimum 3-month intervals)

## Class-Specific Considerations

### TNF Inhibitors

- Most commonly used first bDMARD class
- Five available agents with differing routes and frequencies
- **Avoid in NYHA Class III-IV heart failure** (see below)
- **Avoid in patients with nontuberculous mycobacterial (NTM) lung disease** — TNF inhibitors are associated with increased rates of mycobacterial infections
- Biosimilars are available and considered equivalent

### Abatacept (T-Cell Costimulation Inhibitor)

- Available as subcutaneous or intravenous formulation
- **Conditionally recommended over other bDMARDs/tsDMARDs for patients with NTM lung disease** who have moderate-to-high disease activity despite csDMARDs (Conditional, Very low certainty)

### IL-6 Receptor Inhibitors (Tocilizumab, Sarilumab)

- Effective as monotherapy (without methotrexate) — may be preferred when methotrexate is contraindicated or not tolerated
- Monitor lipids and neutrophil counts

### Rituximab (Anti-CD20)

- **Conditionally recommended over other DMARDs for patients with a history of lymphoproliferative disorder** for which rituximab is an approved therapy, with moderate-to-high disease activity (Conditional, Very low certainty)
- Requires hepatitis B screening prior to initiation (see Special Populations)
- May cause hypogammaglobulinemia — for patients at target with persistent hypogammaglobulinemia **without infection**, continuation of rituximab is conditionally recommended over switching (Conditional, Very low certainty)

### JAK Inhibitors (Tofacitinib, Baricitinib, Upadacitinib)

- Oral administration (no injections required)
- **Post-marketing safety concerns** (ORAL Surveillance study, 2021): increased risk of major adverse cardiovascular events, malignancy, thrombosis, and serious infections compared to TNF inhibitors in patients >=50 years with at least one cardiovascular risk factor
- FDA boxed warning: JAK inhibitors should only be used after inadequate response or intolerance to >=1 TNF inhibitor

## Comorbidity-Specific DMARD Selection

### Heart Failure (NYHA Class III-IV)

- **Non-TNF inhibitor bDMARD or tsDMARD is conditionally recommended over TNF inhibitor** for patients with NYHA Class III-IV heart failure who have an inadequate response to csDMARDs (Conditional, Very low certainty)
- **Switching to a non-TNF inhibitor bDMARD or tsDMARD is conditionally recommended** for patients who develop heart failure while on a TNF inhibitor (Conditional, Very low certainty)
- Rationale: TNF inhibitors have been associated with worsening heart failure

### Subcutaneous Nodules

- Methotrexate is conditionally recommended for patients with moderate-to-high disease activity despite subcutaneous nodules (Conditional, Very low certainty)
- **Switching to a non-methotrexate DMARD is conditionally recommended for progressive subcutaneous nodules** on methotrexate (Conditional, Very low certainty)

### Pulmonary Disease

- **Methotrexate is conditionally recommended over alternative DMARDs** for patients with mild, stable airway or parenchymal lung disease and moderate-to-high disease activity (Conditional, Very low certainty)
- Patients with preexisting lung disease should be **informed of their increased risk of methotrexate pneumonitis** prior to initiating treatment

### Previous Serious Infection (Within 12 Months)

- **Addition of csDMARDs is conditionally recommended over addition of bDMARD/tsDMARD** for patients with moderate-to-high disease activity despite csDMARD monotherapy who had a serious infection within the past 12 months (Conditional, Very low certainty)
- Rationale: lower risk of infection associated with combination csDMARDs compared to biologics
- **Optimizing DMARDs is conditionally recommended over initiation or dose escalation of glucocorticoids** (Conditional, Very low certainty)

### Nonalcoholic Fatty Liver Disease (NAFLD)

- **Methotrexate is conditionally recommended over alternative DMARDs** for DMARD-naive patients with NAFLD (normal liver enzymes and function, no advanced fibrosis) with moderate-to-high disease activity (Conditional, Very low certainty)
- Requires **more frequent liver monitoring (every 4-8 weeks)**
- Consider noninvasive testing to diagnose and stage liver fibrosis prior to initiation

## Limitations

- The guideline does not specify a preferred order among bDMARD/tsDMARD classes for first-line biologic therapy
- Most evidence for bDMARD/tsDMARD switching is of very low certainty
- The JAK inhibitor safety concerns emerged during guideline development and may not fully capture evolving post-marketing data
- Biosimilar availability and formulary restrictions may limit shared decision-making in practice
