Rheumatoid Arthritis: Clinical Features, ACR/EULAR Criteria & Treatment Options

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# **RHEUMATOID ARTHRITIS (RA)**

**Clinical Features • ACR/EULAR 2010 Criteria • Diagnosis • Management (stepwise) • Drugs with MoA, dosing, AEs, contraindications, interactions, monitoring & counselling**

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# **1. Definition**

Rheumatoid arthritis is a **chronic, systemic, autoimmune inflammatory polyarthritis** primarily affecting **synovial joints**, causing **persistent symmetric polyarthritis**, progressive joint destruction, disability, and extra-articular complications. It is mediated by **autoantibodies (RF, anti-CCP)** and **pro-inflammatory cytokines (TNF-α, IL-6, IL-1)**.

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# **2. Pathophysiology (Short but Complete)**

* Genetic: **HLA-DRB1 shared epitope** strongly associated
* Autoantibodies: **RF (IgM anti-Fc)** and **anti-CCP** (highly specific)
* Inflammatory cascade → **synovial hyperplasia (pannus formation)** → cartilage erosion → bone destruction
* Cytokines: **TNF-α, IL-6, IL-1**, JAK-STAT pathway activation
* Extra-articular: vasculitis, nodules, ILD, anemia of chronic disease, scleritis
* Accelerated **atherosclerosis** → ↑ CV mortality

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# **3. Clinical Features**

## **A. Articular**

* **Symmetric small joint polyarthritis** (MCP, PIP, wrists; usually spares DIP)
* **Morning stiffness > 1 hour**
* Joint tenderness, boggy swelling
* **Warm joints but not red**
* **Deformities** (late):

* Ulnar deviation
* Swan-neck deformity
* Boutonnière deformity
* Z-thumb deformity
* Reduced grip strength
* In advanced disease: rheumatoid nodules, tendon rupture (e.g., **extensor tendon**)

## **B. Extra-articular**

* **Rheumatoid nodules**
* **Felty syndrome**: RA + neutropenia + splenomegaly
* Ocular: **scleritis, episcleritis, keratoconjunctivitis sicca**
* Pulmonary: **ILD, pleural effusion (exudative, low glucose)**
* Cardiac: **pericarditis, ↑ CAD risk**
* Hematology: anemia of chronic disease, thrombocytosis
* Neurological: carpal tunnel syndrome, cervical spine (C1–C2) subluxation
* Skin: vasculitic ulcers

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# **4. Investigations & Diagnosis**

### **A. Blood Tests**

* **ESR/CRP** ↑
* **RF** positive in ~70–80%
* **Anti-CCP**: highly specific (~95%), predicts severe disease
* **CBC**: anemia of chronic disease, thrombocytosis
* **LFT/RFT** baseline before DMARD therapy

### **B. Imaging**

* **X-ray early**: soft tissue swelling, peri-articular osteopenia
* **X-ray late**: joint space narrowing, erosions
* **Ultrasound / MRI**: detects early synovitis & erosions

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# **5. ACR/EULAR 2010 Classification Criteria for RA**

A score **≥ 6/10 = definite RA**

### **A. Joint involvement (0–5 points)**

* 1 large joint → 0
* 2–10 large joints → 1
* 1–3 small joints → 2
* 4–10 small joints → 3
* > 10 joints (≥1 small) → 5

### **B. Serology (0–3 points)**

* RF negative & anti-CCP negative → 0
* Low-positive RF or low-positive anti-CCP → 2
* High-positive RF or anti-CCP → 3

### **C. Acute-phase reactants (0–1 point)**

* Normal ESR/CRP → 0
* Abnormal ESR/CRP → 1

### **D. Duration of symptoms (0–1 point)**

* <6 weeks → 0
* ≥6 weeks → 1

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# **6. Differential Diagnoses**

* Osteoarthritis
* Psoriatic arthritis
* SLE arthritis
* Reactive arthritis
* Viral polyarthritis (parvovirus B19, chikungunya)
* Gout/pseudogout
* Polymyalgia rheumatica

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# **7. Management (Stepwise & Evidence-Based)**

## **A. General Principles**

* **Early aggressive treatment** with DMARDs
* Aim: **remission or low disease activity**
* Regular **DAS28** monitoring
* Combination DMARDs if inadequate response
* Avoid long-term steroids

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# **8. Pharmacologic Treatment (Full drug-level details)**

# **1) First-line: Conventional DMARDs**

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## **A. Methotrexate (MTX) – cornerstone**

**Indication:** First-line DMARD for all moderate-severe RA
**Mechanism:** Inhibits dihydrofolate reductase → ↓ purine synthesis; ↑ adenosine (anti-inflammatory)
**Dose:**

* Start 7.5–15 mg once weekly → titrate to **25 mg weekly**; give **folic acid 1 mg/day**
**PK:** Hepatic metabolism, renal excretion
**Common AEs:** GI upset, stomatitis, hair loss
**Serious AEs:** Hepatotoxicity, myelosuppression, pneumonitis
**Contraindications:** Pregnancy, liver disease, alcohol use disorder, severe renal impairment
**Interactions:** TMP-SMX ↑ MTX toxicity; avoid NSAID excess
**Monitoring:** CBC, LFT, RFT every 6–12 weeks
**Counselling:** Once weekly dosing, avoid alcohol, report dyspnea

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## **B. Leflunomide**

**MoA:** Inhibits dihydroorotate dehydrogenase → ↓ pyrimidine synthesis
**Dose:** 10–20 mg daily
**AEs:** Hepatotoxicity, diarrhea, alopecia, teratogenic
**Contra:** Pregnancy; need cholestyramine washout
**Monitoring:** CBC, LFT every 8 weeks

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## **C. Sulfasalazine**

**MoA:** Anti-inflammatory; modulates cytokines
**Dose:** 500 mg/day → 2–3 g/day
**AEs:** Rash, GI upset, reversible oligospermia
**Contra:** Sulfa allergy
**Monitoring:** CBC, LFT

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## **D. Hydroxychloroquine**

**MoA:** Inhibits antigen presentation & TLR pathways
**Dose:** 200–400 mg/day
**AEs:** Retinopathy (dose-dependent)
**Monitoring:** Baseline eye exam + annual screening after 5 yrs
**Use:** Mild RA or combination therapy

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# **2) Biologic DMARDs (if inadequate response to MTX)**

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## **A. Anti-TNF Agents**

* **Etanercept**
* **Infliximab**
* **Adalimumab**
* **Golimumab**
* **Certolizumab**

**MoA:** TNF-α blockade
**AEs:** TB reactivation, infections, demyelination, CHF worsening
**Contra:** Active infection, demyelinating disease
**Monitoring:** TB screening, CBC, LFT
**Counselling:** Report fever; maintain vaccination

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## **B. Anti-IL-6 (Tocilizumab, Sarilumab)**

**MoA:** IL-6 receptor blockade
**AEs:** ↑ cholesterol, infections, GI perforation (esp. diverticulitis)

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## **C. Anti-CD20 (Rituximab)**

**MoA:** B-cell depletion
**Use:** Refractory RA or when biologics contraindicated
**AEs:** Infusion reactions, hepatitis B reactivation

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## **D. CTLA-4 Fusion Protein (Abatacept)**

**MoA:** Inhibits T-cell activation
**AEs:** Infections, COPD exacerbation

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# **3) Targeted Synthetic DMARDs – JAK Inhibitors**

* **Tofacitinib**
* **Baricitinib**
* **Upadacitinib**

**MoA:** JAK-STAT inhibition → ↓ cytokine signaling
**AEs:** Herpes zoster, ↑ LDL/HDL, thrombosis risk
**Monitoring:** CBC, lipids, LFT
**Counselling:** Vaccinate for zoster before therapy

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# **4) Glucocorticoids**

* Used as **bridge therapy** until DMARDs act
* Dose: **Prednisolone 5–10 mg/day short-term**
* AEs: osteoporosis, weight gain, infection, HTN
* Avoid chronic use
* Provide **calcium + vitamin D**

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# **5) NSAIDs**

* Symptomatic relief only
* Do NOT prevent joint damage
* Contra: renal disease, peptic ulcer, CVD

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# **9. Non-Pharmacologic Management**

* Physiotherapy + joint-protection exercises
* Smoking cessation (smoking worsens RA)
* Weight optimisation
* Vaccination: influenza, pneumococcal before biologics
* Occupational therapy
* Surgery: joint replacement in advanced destruction

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# **10. Follow-Up & Monitoring**

* DAS28 scoring every 3 months
* Monitor DMARD toxicity: CBC, LFT, RFT
* Eye exams for hydroxychloroquine
* TB screening annually for biologics

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# **11. Prognostic Factors**

**Poor prognosis indicators:**

* High RF/anti-CCP titers
* Early erosions on X-ray
* High disease activity (DAS28)
* Extra-articular disease
* Smoking
* Early disability

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