Rheumatology and Immunology

Learning Objectives

By the end of this chapter, you should be able to:

• State the diagnostic criteria and typical joint pattern of rheumatoid arthritis (RA).
• List the antibodies used to diagnose RA and systemic lupus erythematosus (SLE), and know which is most specific for each.
• Describe the classic organ involvement and diagnostic workup of SLE.
• Classify vasculitides by vessel size and name a representative disease for each category.
• Differentiate inflammatory arthritis from osteoarthritis based on history, joint distribution, and lab findings.
• Outline the first-line and escalation drug therapy for RA and SLE.

Quick Answer

Rheumatology studies autoimmune and inflammatory diseases of joints, connective tissue, and blood vessels. The three exam-heavy diseases are rheumatoid arthritis (symmetric small-joint polyarthritis, anti-CCP and RF positive, treated with methotrexate), SLE (multisystem autoimmune disease driven by ANA and anti-dsDNA antibodies, causing malar rash, nephritis, and cytopenias), and the vasculitides (inflammation of blood vessel walls, classified by vessel size — large, medium, or small — each with a signature antibody or biopsy finding). These diseases matter because they are common causes of chronic disability, they are highly testable via antibody-disease pairing, and early immunosuppressive treatment prevents irreversible organ damage.

Rheumatoid Arthritis

What it is and why it happens

RA is a chronic, symmetric, inflammatory polyarthritis caused by an autoimmune attack on the synovium. Citrullinated self-proteins are misread as foreign, triggering T-cell and B-cell activation, synovial macrophage infiltration, and pannus formation — a proliferative, invasive synovial tissue that erodes cartilage and juxta-articular bone. Untreated, this produces the classic deformities students memorize: ulnar deviation, swan-neck and boutonnière deformities, and MCP joint subluxation.

Clinical picture

• Symmetric polyarthritis of small joints: proximal interphalangeal (PIP), metacarpophalangeal (MCP), and wrist joints. DIP joints are spared — a key discriminator from osteoarthritis.
• Morning stiffness lasting more than 1 hour, improving with activity (inflammatory pattern, opposite of OA).
• Extra-articular disease: rheumatoid nodules (pressure points like the olecranon), interstitial lung disease, episcleritis, and Felty syndrome (RA + splenomegaly + neutropenia).

Diagnosis

• Rheumatoid factor (RF): sensitive (~70%) but not specific — also positive in Sjögren syndrome, hepatitis C, and some healthy elderly patients.
• Anti-cyclic citrullinated peptide (anti-CCP): the most specific antibody for RA (~95%) and can predate symptoms by years; it also predicts more erosive disease.
• Elevated ESR/CRP reflect disease activity, not diagnosis.
• X-rays show periarticular osteopenia and marginal erosions, in contrast to OA's osteophytes and joint space narrowing localized to weight-bearing joints.

Treatment

Start a DMARD (disease-modifying antirheumatic drug) as soon as RA is diagnosed — do not wait for joint damage. Methotrexate is first-line. NSAIDs and short-course steroids bridge symptom control while the DMARD takes effect (usually 6-8 weeks). If methotrexate fails to control disease, escalate to a biologic, most often a TNF-alpha inhibitor (etanercept, infliximab, adalimumab). Screen for latent TB before starting biologics, since TNF suppression can reactivate it.

Systemic Lupus Erythematosus (SLE)

What it is and why it happens

SLE is a multisystem autoimmune disease in which the immune system generates antibodies against nuclear components of the patient's own cells (loss of tolerance to self-nuclear antigens). Immune complexes deposit in tissues — skin, kidneys, joints, serosal surfaces, and the CNS — triggering complement activation and local inflammation. It disproportionately affects women of childbearing age, especially of African, Asian, and Hispanic descent, hinting at both hormonal and genetic contributions.

Clinical picture (remember: SLE can affect almost any organ)

• Malar ("butterfly") rash sparing the nasolabial folds, photosensitivity, discoid rash.
• Arthritis: symmetric, non-erosive (unlike RA — joints don't show bony destruction on X-ray, a classic distinguishing point).
• Renal: lupus nephritis is the most prognosis-determining complication; proteinuria or hematuria on urinalysis should prompt a renal biopsy.
• Hematologic: autoimmune hemolytic anemia, leukopenia, thrombocytopenia.
• Serositis: pleuritis and pericarditis causing chest pain.
• Neuropsychiatric: seizures, psychosis ("lupus cerebritis").

Diagnosis

• ANA (antinuclear antibody): the best screening test — sensitive (~95-98%) but not specific; a negative ANA makes SLE very unlikely.
• Anti-dsDNA: highly specific for SLE and correlates with disease activity and lupus nephritis flares.
• Anti-Smith (anti-Sm): the most specific antibody for SLE, but less sensitive; does not track disease activity.
• Low complement levels (C3, C4) during flares reflect ongoing immune-complex consumption.
• Drug-induced lupus (procainamide, hydralazine, isoniazid) is associated with anti-histone antibodies and resolves after stopping the offending drug.

Treatment

Hydroxychloroquine is baseline therapy for nearly all SLE patients — it reduces flares and improves long-term survival. Add corticosteroids for flares, and immunosuppressants (mycophenolate mofetil, cyclophosphamide, azathioprine) for major organ involvement such as nephritis. Because hydroxychloroquine can cause retinal toxicity, patients need annual ophthalmologic screening.

Vasculitis

What it is and why it happens

Vasculitis is inflammation and necrosis of blood vessel walls, which narrows the lumen and causes downstream ischemia. The most useful way to organize the vasculitides for exams is by the size of vessel predominantly affected.

Key distinguishing features

• Giant cell arteritis (GCA): patients over 50, unilateral headache, jaw claudication, and risk of sudden irreversible vision loss from ophthalmic artery involvement. Markedly elevated ESR. Treat with high-dose steroids immediately, even before temporal artery biopsy confirms it, to prevent blindness. Strongly associated with polymyalgia rheumatica.
• Granulomatosis with polyangiitis (GPA, formerly Wegener's): c-ANCA (anti-PR3) positive; classic triad of upper respiratory tract (sinusitis, saddle-nose deformity), lower respiratory tract (pulmonary nodules/hemoptysis), and renal (rapidly progressive glomerulonephritis) involvement.
• Microscopic polyangiitis (MPA): p-ANCA (anti-MPO) positive; similar to GPA but spares the upper airway and lacks granulomas.
• IgA vasculitis (Henoch-Schönlein purpura): most common vasculitis in children, follows an upper respiratory infection; palpable purpura on the buttocks/legs, arthralgia, abdominal pain, and IgA nephropathy.

Key Terms

Term	Definition
Autoimmunity	Loss of immune tolerance leading to an immune response against the body's own antigens
Rheumatoid factor (RF)	Antibody (usually IgM) against the Fc portion of IgG; sensitive but nonspecific for RA
Anti-CCP	Antibody against citrullinated peptides; the most specific serologic marker for RA
ANA	Antinuclear antibody; sensitive screening test for SLE and other connective tissue diseases
Anti-dsDNA	Antibody specific for SLE that correlates with disease activity, especially lupus nephritis
Anti-Sm (Smith)	Highly specific antibody for SLE; does not track disease activity
Pannus	Proliferative, invasive synovial tissue in RA that erodes cartilage and bone
ANCA	Anti-neutrophil cytoplasmic antibody; c-ANCA (PR3) in GPA, p-ANCA (MPO) in MPA
DMARD	Disease-modifying antirheumatic drug; alters disease course rather than just relieving symptoms (e.g., methotrexate)
Complement (C3/C4)	Immune proteins consumed during immune-complex-mediated inflammation; low levels indicate active SLE

Common Mistakes

Misconception: "A positive rheumatoid factor means the patient has rheumatoid arthritis." Why it's wrong: RF is sensitive but poorly specific — it is also positive in Sjögren syndrome, hepatitis C, endocarditis, and up to 5% of healthy older adults. Correct understanding: Diagnosis relies on the clinical pattern (symmetric small-joint polyarthritis with prolonged morning stiffness) plus anti-CCP, which is far more specific than RF.

Misconception: "RA and OA are basically the same disease at different severities." Why it's wrong: They have entirely different mechanisms — RA is autoimmune/inflammatory, OA is degenerative "wear and tear." Correct understanding: RA classically spares the DIP joints and causes prolonged morning stiffness that improves with movement; OA affects DIPs/PIPs and weight-bearing joints, with stiffness that is brief and worsens with activity.

Misconception: "A negative ANA rules in SLE if other features are present, since ANA is 'the lupus test.'" Why it's wrong: Students confuse sensitivity with specificity. ANA is highly sensitive, so a negative result makes SLE unlikely, but a positive ANA alone does not confirm SLE — it's also positive in Sjögren syndrome, scleroderma, and even healthy people at low titer. Correct understanding: Use ANA to screen (rule out if negative), then confirm with the more specific anti-dsDNA or anti-Sm antibodies.

Comparison and Connections

Feature	Rheumatoid Arthritis	Osteoarthritis	SLE
Mechanism	Autoimmune synovitis	Mechanical cartilage degeneration	Autoimmune, immune-complex mediated
Joint pattern	Symmetric, MCP/PIP/wrist, DIP spared	Weight-bearing joints, DIP/PIP/first CMC	Symmetric, non-erosive
Morning stiffness	>1 hour, improves with use	<30 minutes, worsens with use	Variable, often with systemic fatigue
Key antibody	Anti-CCP (specific), RF (sensitive)	None (not autoimmune)	Anti-dsDNA/anti-Sm (specific), ANA (sensitive)
X-ray finding	Erosions, periarticular osteopenia	Osteophytes, joint space narrowing	Usually normal/non-erosive
First-line drug	Methotrexate	Weight loss, NSAIDs, physical therapy	Hydroxychloroquine

Practice Questions

Recall 1: Which antibody is most specific for rheumatoid arthritis? Answer guidance: Anti-CCP (anti-cyclic citrullinated peptide), roughly 95% specific.

Recall 2: Name the antibody associated with drug-induced lupus. Answer guidance: Anti-histone antibody.

Understanding 1: Why does RA spare the DIP joints while osteoarthritis commonly affects them? Answer guidance: RA targets synovium-lined joints under sustained mechanical/immune load driven by autoimmune synovitis affecting MCP/PIP/wrist; DIP involvement in OA reflects localized cartilage wear from repetitive mechanical stress, an unrelated degenerative mechanism, so the two diseases have essentially non-overlapping joint distributions.

Understanding 2: Explain why ANA is used to screen for SLE but anti-dsDNA is used to confirm it. Answer guidance: ANA has high sensitivity (~95-98%), so a negative result effectively excludes SLE; but it lacks specificity since many other conditions are ANA-positive. Anti-dsDNA is much more specific for SLE and additionally correlates with disease activity, so it is used both to confirm the diagnosis and monitor flares (particularly nephritis).

Application 1: A 42-year-old woman has 8 weeks of symmetric swelling and pain in both wrists and MCP joints, with 90 minutes of morning stiffness. RF is positive. What is the most likely diagnosis and first-line treatment? Answer guidance: Rheumatoid arthritis; start methotrexate promptly (a DMARD) rather than relying on NSAIDs alone, to prevent joint erosion.

Application 2: A 55-year-old man develops a new unilateral headache, jaw pain while chewing, and a markedly elevated ESR. What should be done immediately, and why not wait for biopsy confirmation? Answer guidance: Start high-dose corticosteroids immediately for suspected giant cell arteritis; delaying treatment risks irreversible vision loss from ophthalmic artery involvement, and biopsy remains positive for about 1-2 weeks even after starting steroids.

Analysis 1: Compare the joint erosion pattern seen on X-ray in RA versus SLE, and explain the underlying reason for the difference. Answer guidance: RA shows marginal erosions and periarticular osteopenia because pannus physically invades and destroys cartilage/bone. SLE arthritis is typically non-erosive because the joint disease is driven by immune-complex deposition and synovitis without the destructive pannus seen in RA — so ligamentous laxity (Jaccoud arthropathy) can occur without bony erosion.

Analysis 2: A patient has hematuria, low complement levels, and a positive anti-dsDNA. What complication should be evaluated urgently, and why does complement level matter here? Answer guidance: Evaluate for lupus nephritis with a renal biopsy — hematuria plus rising anti-dsDNA and falling complement (C3/C4) signals an active flare, since complement is being consumed by immune-complex deposition in the kidney; early detection and treatment (immunosuppression) prevents irreversible renal damage.

FAQ

Is rheumatoid factor required to diagnose RA? No. Roughly 20-30% of RA patients are "seronegative" (RF-negative). Diagnosis is primarily clinical, supported by anti-CCP, ESR/CRP, and imaging.

Can SLE occur without a rash? Yes. Many patients present with arthritis, serositis, renal disease, or cytopenias without ever developing the malar rash; the rash is classic but not universal.

Why is methotrexate preferred over NSAIDs as first-line therapy in RA? NSAIDs only control symptoms; methotrexate is disease-modifying and slows or halts the joint erosion that causes permanent disability.

How do you tell GPA and microscopic polyangiitis apart? GPA (c-ANCA/PR3) involves the upper respiratory tract with granuloma formation (sinusitis, saddle-nose deformity); MPA (p-ANCA/MPO) spares the upper airway and does not form granulomas, though both can cause pulmonary-renal syndrome.

Why must temporal artery biopsy not delay treatment in suspected giant cell arteritis? Because the main risk is sudden, irreversible blindness from ophthalmic artery ischemia; steroids should start immediately on clinical suspicion, and the biopsy remains diagnostic for one to two weeks afterward.

Quick Revision

• RA: symmetric small-joint polyarthritis, DIP spared, morning stiffness >1 hour improving with activity.
• Anti-CCP is the most specific antibody for RA; RF is sensitive but not specific.
• RA treatment: start a DMARD (methotrexate first-line) early; escalate to TNF-alpha inhibitor biologics if inadequate response.
• SLE: multisystem autoimmune disease — malar rash, non-erosive arthritis, nephritis, cytopenias, serositis.
• ANA screens for SLE (high sensitivity); anti-dsDNA and anti-Sm confirm it (high specificity); anti-dsDNA tracks disease activity.
• Drug-induced lupus is linked to anti-histone antibodies and resolves on stopping the drug.
• Low C3/C4 complement indicates active immune-complex consumption, often signaling a lupus flare or nephritis.
• Hydroxychloroquine is baseline SLE therapy; requires annual eye exams for retinal toxicity.
• Vasculitis is classified by vessel size: large (GCA, Takayasu), medium (PAN, Kawasaki), small (ANCA-associated: GPA/MPA, and IgA vasculitis).
• GCA: elderly patient, jaw claudication, high ESR — treat with steroids immediately to prevent blindness.
• GPA = c-ANCA/PR3 + upper airway + granulomas; MPA = p-ANCA/MPO, no upper airway involvement.
• OA differs fundamentally from RA: degenerative not autoimmune, affects DIP/weight-bearing joints, brief stiffness worsened by activity.

Related Topics

Prerequisites: Basic immunology (innate vs. adaptive immunity, antibody structure, complement pathway), general joint anatomy and physical examination technique.

Related Topics: Clinical immunology (hypersensitivity reactions, immunodeficiency syndromes), musculoskeletal disorders and orthopedics, dermatology (rashes in autoimmune disease), nephrology (glomerulonephritis and lupus nephritis).

Next Topics: Spondyloarthropathies (ankylosing spondylitis, psoriatic arthritis, reactive arthritis), crystal arthropathies (gout, pseudogout), pediatric rheumatology.