# Rheumatoid Arthritis: Early Diagnosis and DMARD Therapy

## Introduction

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by symmetric inflammatory polyarthritis that leads to progressive joint destruction if untreated. Early diagnosis and prompt initiation of disease-modifying antirheumatic drugs (DMARDs) fundamentally alter disease trajectory. The internist is often the first to encounter early RA and must recognize it, initiate appropriate workup, and facilitate timely rheumatology referral.

## Epidemiology and Pathophysiology

- Prevalence approximately 0.5-1% worldwide; **female-to-male ratio 2-3:1**
- Peak onset in the fifth and sixth decades; can occur at any age
- Genetic predisposition: **HLA-DRB1 shared epitope** is the strongest genetic risk factor
- Environmental triggers: smoking is the most important modifiable risk factor (especially in seropositive disease)
- Pathology: synovial inflammation leads to **pannus formation**, cartilage destruction, and bone erosion

## Clinical Presentation

### Articular Features

- **Symmetric inflammatory polyarthritis** of small joints: MCPs, PIPs, wrists, MTPs
- Morning stiffness lasting **> 30 minutes** (often > 1 hour)
- DIP joints are typically spared (helps distinguish from osteoarthritis)
- Boggy synovitis on examination; tenderness on metacarpal squeeze test
- Late findings: ulnar deviation, swan-neck and boutonniere deformities, subluxation

### Extra-Articular Manifestations

- **Rheumatoid nodules**: firm subcutaneous nodules over extensor surfaces; seropositive disease
- **Pulmonary**: interstitial lung disease (ILD), pleural effusions, rheumatoid nodules
- **Ocular**: scleritis, episcleritis, keratoconjunctivitis sicca (secondary Sjogren syndrome)
- **Cardiovascular**: accelerated atherosclerosis; pericarditis
- **Hematologic**: anemia of chronic disease, Felty syndrome (RA + splenomegaly + neutropenia)
- **Cervical spine**: atlantoaxial subluxation; evaluate before intubation in longstanding disease

![Clinical photograph showing symmetric MCP joint swelling and early ulnar deviation in RA](/images/residency/ra-hand-deformities.jpg)

## Diagnosis

### 2010 ACR/EULAR Classification Criteria

| Domain | Criteria | Score |
|--------|----------|-------|
| Joint involvement | 1 large joint | 0 |
| | 2-10 large joints | 1 |
| | 1-3 small joints | 2 |
| | 4-10 small joints | 3 |
| | >10 joints (at least 1 small) | 5 |
| Serology | Negative RF and anti-CCP | 0 |
| | Low-positive RF or anti-CCP | 2 |
| | High-positive RF or anti-CCP (>3x ULN) | 3 |
| Acute-phase reactants | Normal ESR and CRP | 0 |
| | Abnormal ESR or CRP | 1 |
| Duration | < 6 weeks | 0 |
| | ≥ 6 weeks | 1 |
| **Score ≥ 6/10 = classifies as RA** | | |

- Designed for early disease; score >= 6/10 classifies as RA
- **Joint involvement**: number and size of affected joints (small joints score higher)
- **Serology**: RF and anti-CCP (high-titer positive scores highest)
- **Acute-phase reactants**: elevated ESR or CRP
- **Duration of symptoms**: >= 6 weeks

### Key Laboratory Tests

- **Rheumatoid factor (RF)**: sensitivity ~70%; not specific (elevated in infections, liver disease, other autoimmune diseases)
- **Anti-citrullinated peptide antibody (anti-CCP)**: sensitivity ~70%, **specificity > 95%**; can precede symptoms by years
- **ESR and CRP**: markers of inflammation; useful for monitoring disease activity
- CBC, CMP, hepatitis B and C serologies (baseline before DMARD initiation)

### Imaging

- **X-rays of hands and feet**: baseline; look for periarticular osteopenia, joint space narrowing, erosions
- **Ultrasound**: detects subclinical synovitis and early erosions; increasingly used in clinic
- **MRI**: most sensitive for early bone edema and erosions; not routinely needed

![X-ray of hands showing periarticular erosions and joint space narrowing in established RA](/images/residency/ra-hand-xray-erosions.jpg)

## Treatment

### Guiding Principles

- **Treat-to-target strategy**: aim for clinical remission or low disease activity
- **Early aggressive therapy** prevents irreversible joint damage; the "window of opportunity"
- Reassess disease activity every 3 months and adjust therapy if target not met
- Use validated disease activity scores: DAS28, CDAI, SDAI

### Conventional Synthetic DMARDs (csDMARDs)

- **Methotrexate**: first-line DMARD; start 15 mg weekly, titrate to 25 mg weekly
  - Supplement with **folic acid 1 mg daily** to reduce side effects
  - Monitor CBC, LFTs, creatinine every 3 months
  - Contraindicated in pregnancy (teratogenic); ensure reliable contraception
  - Screen for hepatitis B/C and check baseline chest X-ray
- **Leflunomide**: alternative to methotrexate; 20 mg daily
- **Sulfasalazine**: add-on or monotherapy; well tolerated
- **Hydroxychloroquine**: mild disease or combination therapy; annual eye exam required

### Biologic DMARDs (bDMARDs)

- Added when csDMARDs fail to achieve target; typically combined with methotrexate
- **TNF inhibitors**: etanercept, adalimumab, infliximab, certolizumab, golimumab
- **IL-6 receptor inhibitor**: tocilizumab, sarilumab
- **T-cell costimulation inhibitor**: abatacept
- **B-cell depleting**: rituximab (typically after TNF inhibitor failure)
- Screen for **latent tuberculosis** (IGRA) and **hepatitis B** before starting biologics

### Targeted Synthetic DMARDs (tsDMARDs)

- **JAK inhibitors**: tofacitinib, baricitinib, upadacitinib
- Oral agents; effective after csDMARD failure
- Increased risk of VTE, major cardiovascular events, and malignancy in some populations (ORAL Surveillance trial)
- Currently recommended preferentially in patients without cardiovascular risk factors

### Corticosteroids

- **Bridge therapy** during DMARD initiation: low-dose prednisone (<=10 mg/day)
- Taper and discontinue as DMARDs take effect (typically 4-8 weeks)
- Intra-articular injections for mono- or oligoarticular flares
- Chronic corticosteroid use should be avoided; associated with infections, osteoporosis, and metabolic complications

![Treatment algorithm for RA showing stepwise escalation from csDMARDs to biologics](/images/residency/ra-treatment-algorithm.jpg)

## Monitoring and Preventive Care

- Disease activity assessment every 3 months until target reached, then every 6 months
- Annual chest X-ray consideration for ILD screening in high-risk patients
- Pneumococcal and influenza vaccination before immunosuppression when possible
- Bone density screening with chronic corticosteroid use
- Cardiovascular risk assessment: RA itself is an independent cardiovascular risk factor

## Key Clinical Pearls

- Anti-CCP is the most specific serologic test for RA and can be positive years before symptom onset
- Start methotrexate early; delayed DMARD initiation leads to irreversible erosive damage
- Always supplement methotrexate with folic acid and screen for hepatitis B/C and tuberculosis
- Morning stiffness > 30 minutes with symmetric small-joint swelling strongly suggests inflammatory arthritis
- RA patients have increased cardiovascular risk; manage traditional risk factors aggressively

## References

1. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an ACR/EULAR collaborative initiative. *Arthritis Rheum*. 2010;62(9):2569-2581.
2. Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. *Arthritis Care Res*. 2021;73(7):924-939.
3. Smolen JS, Landewe RBM, Bergstra SA, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. *Ann Rheum Dis*. 2023;82(1):3-18.
4. Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis (ORAL Surveillance). *N Engl J Med*. 2022;386(4):316-326.