Basic Sciences 2023, Jan, 25 | 12:00 am

Rheumatoid arthritis

  • Rheumatoid arthritis (see Table 1.20)

    • Most common inflammatory arthritis

    • Affects 0.5%–1% of population; three times more common in women

    • 15% concordance rate in monozygotic twins

    • Clinical presentation (see Fig. 1.32)

      • Insidious subacute onset over 6 weeks

      • Fatigue, malaise, anemia

      • Morning stiffness and polyarthritis with swelling

      • Hand and foot deformities are most common and are discussed in respective subsequent chapters

      • Also common in the knees, elbows, shoulders, ankles, and cervical spine

      • Subcutaneous rheumatoid nodules (Fig. 1.34)

    • Juxtaarticular erosions and periarticular osteopenia on radiographs

    • 2010 American College of Rheumatology Classification Criteria for RA are summarized in Table 1.21.

      • Diagnosis requires score 6 or more

      • Criteria include

        • Number of joints involved and duration of involvement

        • Positive laboratory test results often found

          • Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)

             

    • Pathogenesis

  • Rheumatoid factor (RF) titer

    • Antibody (immunoglobulin [Ig] M) against the Fc (crystallizable fragment) portion of IgG

    • Positive result in about 80%

  • Test for anticyclic citrullinated protein (anti-CCP) antibodies

    • Also known as anti-CCP antibodies (ACPAs)

    • Most sensitive and specific test (≈90% specific)

    • Presence linked to more aggressive disease

      • T cell–mediated immune response from an infectious or environmental antigen (smoking is one known trigger) in a genetically susceptible individual (HLA-DR4 and HLA-DW4)

      • Mononuclear cells are primary mediator of RA tissue damage

      • Initial response in soft tissues— neovascularization and synovitis

      • CD4+ T lymphocytes (helper cells) activate synovial cells through direct cell-cell contact

      • Synoviocytes produce cytokines

        • Macrophages (type A): main source for TNF-α, IL-1

        • Fibroblast (type B): main source for MMPs, proteases, and RANKL

      • B lymphocytes (plasma cells): make RF, anti-CCP antibodies

      • TNF-α, IL-1, IL-6, IL-7 upregulated

        • IL-1: Regulator of inflammation and matrix destruction

        • TNF-α:

 

  • Upregulates endothelial adhesion molecules and stimulates angiogenesis

 

 

Table 1.20

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Comparison of Common Arthritides

 

 

Age Incidence

Arthritis Group By Sex

Affected

Noninflammatory

Osteoarthritis

Elderly

M > F

Neuropathic

Elderly

M > F

Acute rheumatic fever

Children

M = F

Ochronosis

Adults

M = F

Inflammatory

Rheumatoid

Young

adults

F > M

Systemic lupus erythematosus

Young

adults

F > M

Juvenile

rheumatoid arthritis

Children

F > M

Relapsing

polychondritis

Elderly

M = F

Spondyloarthropathies

Ankylosing spondylitis

Young

adults

M > F

 

 

 

Reactive arthritis (Reiter syndrome)

Young

adults

M > F

Psoriatic

Young

adults

M = F

Enteropathic

Young

adults

M > F

 

 

Age Incidence

Arthritis Group By Sex S

Affected

Crystal Deposition Disease

Gout

Young

M > F

 

Chondrocalcinosis

Elderly

M = F

 

Infectious

Pyogenic

All

M = F

 

Tuberculous

Elderly

M > F

 

Lyme disease

Young

M = F

 

Fungal

All

M > F

 

Hemorrhagic

Hemophilia

Young

M

 

Sickle cell disease

Young

M = F

 

Pigmented

villonodular synovitis

Young

M = F

 

 

 

 

 

↓, Decreased; AFB, acid-fast bacilli; ASO, antistreptolysin O; CPK, creatine phosphokinase; PTT, partial thromboplastin time.

 

 

 

 

FIG. 1.30 Enzyme cascade of IL-1–stimulated degradation of articular cartilage.

TPA, Tissue plasminogen activator. From Simon SR, editor: Orthopaedic basic science, Rosemont, IL, 1994, American Academy of Orthopaedic Surgeons, p 40.

 

 

FIG. 1.31 (A)

Radiograph showing joint space narrowing, osteophytes, and bony sclerosis. (B) Macrosection of an osteoarthritic human femoral head demonstrating subarticular cysts, sclerotic bone formation, and a superior femoral head osteophyte. (C) Low-power micrograph of osteoarthritis showing fibrillation, fissures, and cartilage loss. D, Gross pathology of femoral head demonstrating cartilage thinning (1),

subarticular cyst (2

[“geode”]), and normal hyaline cartilage remaining (3).

A Courtesy Marc DeHart, MD, and Texas Orthopedics; B from Simon SR, editor: Orthopaedic basic science, Rosemont, IL, 1994, American Academy of Orthopaedic Surgeons; C and D from Horvai A: Bones, joints, and soft tissue tumors. In Kumar V et al, editors: Robbins and Cotran pathologic basis of disease, ed 9,

Philadelphia, 2015,

Elsevier, Fig. 26-93.

 

 

FIG. 1.32 Differences between rheumatoid arthritis and osteoarthritis. Left side of illustration demonstrates the main historical characteristics of RA, including symmetric involvement (both right and left joints as well as both medial and lateral compartments of the knees). Bilateral hand involvement is characteristic and usually involves wrist joints and proximal metacarpal joints.

Right side of figure demonstrates osteoarthritis, which often is much more severe in one joint or one compartment of the knee. Hand involvement more commonly involves the distal interphalangeal joints (Heberden nodes) and proximal interphalangeal joints (Bouchard nodes) joints as well as the base of the thumb.

 

  • Promotes influx of leukocytes and activates synovial fibroblasts

     

  • Later response

  • Promotes pain receptor pathways

  • Drives osteoclastogenesis

    • Synovial cells invade cartilage “pannus” and release MMPs, causing chondrolysis

    • Periarticular bone erosions

    • Cytokines stimulate osteoblasts and synovial B cells to make RANKL, which joins with RANK to activate osteoclasts. Responsible for bone destruction.

    • Osteoclasts secrete cathepsin K and carbonic anhydrase.

 

 

FIG. 1.33 Neuropathic arthritis. Arthritic degeneration due to lack of sensation can be caused by many diseases. All share radiographic findings that are more severe than the symptoms (often painless) and the fragments from bony destruction. Often findings take many years to develop. (A and B) Diabetic Charcot arthropathy of the foot is easily recognized by most of the industrialized world. (C and D) The most common cause of upper extremity neuropathic joint is syringomyelia (syrinx = fluid-filled sac in central cord that causes insidious loss of pain and temperature early). (E–G) Tabetic arthropathy (tertiary syphilis) is the most common neuropathic arthritis of the knee and can often involve the hip.

From Yablon CM et al: Areview of Charcot neuroarthropathy of the midfoot and

hindfoot: what every radiologist needs to know, Curr Probl Diagn Radiol 39:187–199, 2010; Atalar AC et al: Neuropathic arthropathy of the shoulder associated with syringomyelia: a report of six cases, Acta Orthop Traumatol Turc 44:328–336, 2010; and Allali F et al: Tabetic arthropathy. Areport of 43 cases, Clin Rheumatol 25:858–860, 2006.

 

 

FIG. 1.34 Upper extremity changes in common arthritis types. Left side of figure shows rheumatoid changes. (A) Swan neck deformity of index, middle, and ring fingers, with PIP joints extended and DIP joints flexed. (B) Boutonnière deformity: PIP joints flexed, DIP joints extended. (C) Bilateral wrist swelling with both ulnar metacarpal phalangeal joint deformities and swan neck deformities of fingers and left thumb. (D) Rheumatoid nodes noted on posterior olecranon region. Right side of figure shows osteoarthritic changes. (E) DIP changes (Heberden nodes) and PIP changes (Bouchard nodes). (F) Radiograph showing osteoarthritic changes at the base of the thumb.

From O’Dell JD: Rheumatoid arthritis. In Goldman L, Schafer AI, editors: Goldman-

Cecil medicine, Philadelphia, 2016, Elsevier, Fig. 264-3; Sweeney SE et al: Clinical features of rheumatoid arthritis. In Firestein GS et al: Kelley’s textbook of rheumatology, Philadelphia, 2013, Elsevier, Fig. 70-4; and http://medsci.indiana.edu/c602web/602/c602web/jtcs/docs/heber1.html

 

  • Systemic manifestations

    • Rheumatoid vasculitis

    • Distal splinter hemorrhage

    • Cutaneous ulcers (pyoderma gangrenosum)

    • Visceral arteritis

    • Pericarditis and pericardial effusion

    • Pulmonary disease including nodules and fibrosis

    • Felty syndrome: severe erosive RA with splenomegaly and leukopenia

  • Treatments and their perioperative considerations

    • Regimen variable and often employs multiple agents

    • NSAIDs: help symptoms early—antiinflammatory effects

      • Should be held for 7–10 days preoperatively.

    • Low-dose steroids

      • Decrease prostaglandins and leukotrienes

      • Used initially as “bridge therapy” to disease-modifying antirheumatic drugs (DMARDs)

      • “Stress dose” steroid should be used perioperatively for patients on longterm steroid therapy

    • DMARDs

 

  • Intended to address underlying autoimmune response

  • Conventional DMARDs take 2–6 months to work

  • Methotrexate: folate analogue

    • Inhibits purine metabolism and T-cell activation

    • Inhibits neovascularization

    • Adverse reactions (ADRs): toxic to bone marrow, liver, and lung

    • Usually can continue through surgery

  • Azathioprine: immunosuppressive agent

    • ADR: neutropenia

    • Cyclosporine: immunosuppressive agent

      • Inhibits activation of

        CD4+ T cells

      • ADRs: nephrotoxicity, neurotoxicity, gingival hyperplasia

    • Hydroxychloroquine (Plaquenil)

      • Inhibits toll-like receptor 9 (TLR9)

      • ADR: retinal toxicity (requires ophthalmology followup)

         

        Table 1.21

         

        The 2010 ACR-EULAR Classification Criteria for Rheumatoid Arthritis

         

         

        Criteria Score

        A. 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 joint)

        5

        B. Serology (at least 1 test result is needed)

        Negative RF and negative ACPA

        0

        Low-positive RF or low-positive ACPA

        2

        High-positive RF or high-positive ACPA

        3

        C. Acute-Phase Reactants (at least 1 test result is needed)

        Normal CRP and normal ESR

        0

        Abnormal CRP or abnormal ESR

        1

        D. Duration of Symptoms

        <6 weeks

        0

        >6 weeks

        1

         

         

        From Aletaha D et al: 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative, Arthritis Rheum 62:2569–2581, 2010.

         

      • Usually can continue through surgery

    • Sulfasalazine

      • Decreases synthesis of inflammatory mediators

      • ADRs: granulocytopenia, hemolytic anemia (glucose-6-phosphate dehydrogenase [G6PD])

      • Usually can continue through surgery

    • Minocycline

      • Inhibits MMP collagenase

      • ADR: cutaneous hyperpigmentation

    • Biologic DMARDs

      • Target TNF-α: etanercept, infliximab, adalimumab

      • Targets IL-1: anakinra

      • Targets CD20: rituximab

      • Surgery should be scheduled at end of dosing cycle (e.g., in a patient taking etanercept schedule, surgery should occur the second week after the first withheld dose).

      • Risks of opportunistic infection and lymphoma

      • Surgical treatment is discussed within respective chapters.

  • Juvenile idiopathic arthritis (JIA) is discussed in Chapter 3, Pediatric Orthopaedics.

  • Systemic lupus erythematosus (Fig. 1.35; see Table 1.20)

    • Chronic inflammatory disease of unknown origin

    • 90% of cases in women (blacks > whites)

    • Initially mediated by tissue-binding autoantibodies and immune complexes (type III hypersensitivity)

    • Pathophysiology

      • Susceptible genetics stimulated by environment

      • Immune system autoregulatory failure

      • Sustained production of antibody to self-antigens

      • Antinuclear antibodies (ANAs)—best screen; positive in 95%

      • Anti-dsDNA, anti-Sm, anti-La (SS-B), antihistone antibodies—drug-induced lupus

      • Immune complexes accumulate in various tissues and cause chronic inflammation

         

    • Clinical findings

      • Skin/joints—rash and arthritis

      • Heart/kidney—pericarditis/nephritis

      • Blood vessels—vasculitis

        • Bone and joint involvement—most common feature

          • Nonerosive polyarthritis affects over 75% (hand and wrist most common).

          • Osteonecrosis (especially with steroids)

        • Butterfly malar rash—classic feature

        • Fever, pancytopenia

      • Pharmacologic treatment similar to that for RA.

  • Seronegative spondyloarthropathies

    • Characterized by negative RF titer result and, often, positive HLA-B27 test result

    • Symptoms

      • Inflammatory back pain

      • Peripheral arthritis

      • Enthesitis—heel pain

      • Dactylitis—sausage digit

      • Eye—uveitis (iritis), conjunctivitis

      • Skin, mucosal, GI, urethral

    • Similar treatment routines, including NSAIDs, steroids, and DMARDs

  • Ankylosing spondylitis (AS) (Fig. 1.36; see Table 1.20)

    • Male/female ratio 3:1; ages 20–40 years

    • Most common in Northern European whites

    • 90% HLA-B27 positive (Table 1.22)

    • Symptoms and findings

      • Bilateral sacroiliitis (earliest symptom)

      • Improves with exercise, not better with rest, pain at night

      • Associated morning stiffness

      • Progressive spinal flexion deformities over life

      • Hip involvement at young age—poor prognosis

      • Enthesitis: inflammation of tendon insertion

      • Loss of chest expansion

      • Uveitis: red, painful eye in 40%

      • Aortic insufficiency and heart block

    • Radiographic changes

    • Surgical treatment for AS is discussed within Chapter 8, Spine.

  • Reactive arthritis (Reiter syndrome) (Fig. 1.37; see Table 1.20)

    • Classical triad presentation: “Can’t see, can’t pee, can’t climb a tree.”

    • Young white males (18–40 years)

    • Follows an infection at another site (hence “reactive”)

      • Chlamydia, Shigella, Yersinia, Salmonella

    • Findings

    • Treatment: NSAIDs and PT

       

       

      FIG. 1.36 Ankylosing spondylitis is an axial seronegative spondyloarthropathy that causes progressive cervical and thoracic kyphosis and bamboo spine but has earliest involvement in the sacroiliac joints. (A) Early sacroiliitis demonstrated by loss of clarity and sclerosis in the lower third of the sacroiliac joints, particularly affecting the iliac side of the right sacroiliac joint (hip joints are normal). (B) Advanced disease with ankylosis or fusion of both the sacroiliac and hip joints. (C) Schober test; two marks made 10 cm apart on lumbar spine in erect stance should be less than 14 to 15 cm during forward flexion.

      From Raychaudhuri S: The classification and diagnostic criteria of ankylosing spondylitis, J

      Autoimmun 48–49:128–133, 2014.

       

  • Psoriatic arthropathy (PsA) (see Table 1.20)

    • Affects 5%–30% of patients with psoriasis

    • Usually skin disease precedes arthritis

    • Men and women (aged 30–40 years) equally affected

    • Characteristic changes

      • Distal interphalangeal (DIP) involvement (rare in other inflammatory arthritides)

      • Nail changes in 90%

        • Pitting, fragmentation, and discoloration

      • 30% have sausage digits

      • Prominent enthesitis and tenosynovitis

      • Arthritis mutilans—most destructive form

      • Telescoping (shortening) of digits

    • Pathophysiology

      • Upregulated RANKL in synovium (B-type cells)

      • Marked increase in osteoclast precursors

    • Radiographic findings

      • Pencil-in-cup deformity, DIP

      • Small joint ankylosis

      • Osteolysis of metacarpal (MC) and phalangeal bone

      • Periostitis and bony enthesitis

  • Enteropathic arthritis (see Tables 1.20 and 1.22)

    • Arthritis in presence of inflammatory bowel disease

    • Varied clinical picture, but joint erosions uncommon

    • 10%–50% of patients experience peripheral joint arthritis.

      • Acute monoarticular synovitis precedes bowel symptoms.

      • Nondeforming arthritis

      • More common in large weight-bearing joints

      • 10%–15% of cases associated with ankylosing spondylitis