Rheumatoid Arthritis-related Lymphadenopathy

L. Jeffrey Medeiros, MD

Key Facts

Terminology

Lymphadenopathy accompanying rheumatoid arthritis (RA)

Etiology/Pathogenesis

Smoking is risk factor
Infectious agent may act as antigenic trigger of RA
Genetic susceptibility and impaired T-cell function are involved in RA

Clinical Issues

Lymphadenopathy occurs in ˜ 75% of RA patients at some point in their clinical course
Can be localized or systemic

Microscopic Pathology

Marked follicular hyperplasia in cortex and medulla of lymph node
- “Starry sky” pattern within germinal centers
- Hyaline-like eosinophilic deposits(+/-)
Interfollicular areas show marked plasmacytosis
Capillary endothelial hyperplasia

Ancillary Tests

Immunophenotype
- Polytypic B cells and plasma cells; normal T cells
EBER(+) in ˜ 20% of RA-related lymph nodes
No monoclonal Ig or TCR gene rearrangements

Diagnostic Checklist

It is unusual for RA-related lymphadenopathy to be initial manifestation of RA
Clinical history is often available to support diagnosis
- Joint symptoms &/or physical manifestations
- Laboratory results supporting diagnosis of RA

Lymphadenopathy in an untreated patient with rheumatoid arthritis (RA). A follicle with a hyperplastic germinal center and many tingible body macrophages resulting in a “starry sky” pattern is shown.

Lymphadenopathy in an untreated patient with rheumatoid arthritis. MIB-1 (Ki-67) antibody highlights numerous proliferating cells in 2 reactive germinal centers

TERMINOLOGY

Definitions

Lymphadenopathy accompanying rheumatoid arthritis (RA)

ETIOLOGY/PATHOGENESIS

Environmental Exposure

Smoking is risk factor
- Increases risk of developing RA
- Correlates with increased disease severity

Autoimmune Disease

Infectious agent may act as antigenic trigger of RA
- Possible/suspected organisms include
  - Epstein-Barr virus (EBV), Cytomegalovirus (CMV), Parvovirus
  - Rubella virus, Mycoplasma species
Genetic susceptibility is involved in RA
- Association with HLA-DR1 and HLA-DR4
- Recently reported loci at chromosomes 10p15, 12q13, and 22q13
T-cell function is impaired in RA
RA is mediated by inflammatory mediators and cytokines released by macrophages and synovial lining cells
- Activated by CD4(+) T helper cells
- Important cytokines: Tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6
- Bone and cartilage destruction mediated by prostaglandins, matrix metalloproteinases, RANKL

CLINICAL ISSUES

Epidemiology

Incidence
- RA affects 0.8% of world population
Age
- ˜ 80% of patients develop RA between 35-50 years
- Can affect patients at any age
Gender
- Male to female ratio = 1:3-5

Site

Most common sites of lymphadenopathy: Cervical, supraclavicular, axillary
- Any lymph node group can be affected

Presentation

RA usually has insidious onset
- 10% of patients have acute onset with rapid polyarticular involvement
Initial symptoms may be nonspecific and generalized
- Fatigue, weakness, anorexia, fever, musculoskeletal pain
Joint involvement often follows generalized symptoms
- Small joints in hands and feet are affected before large joints
- Typically symmetric
Lymphadenopathy occurs in ˜ 75% of RA patients at some point in their clinical course
- Can be localized or systemic
Felty syndrome = RA, splenomegaly, and autoimmune neutropenia
In 1987, American Rheumatism Association proposed criteria to help establish diagnosis of RA
- Total of 4 of 7 criteria support diagnosis of RA
  - Morning stiffness
  - Arthritis in 3 or more joints
  - Arthritis of hand joints
  - Symmetric arthritis
  - Rheumatoid nodule(s)
  - Serum rheumatoid factor (RF)(+)
  - Typical radiographic changes

Laboratory Tests

Rheumatoid factor (RF)
- RF = immunoglobulins that react with Fc portion of IgG molecules
  - Most standard tests detect IgM
- ˜ 60% of patients with RA have elevated RF in serum
- RF can be elevated in other autoimmune diseases
  - Sjögren syndrome, systemic lupus erythematosus
- Serum RF levels can be positive in healthy individuals
  - ˜ 5%; positivity tends to increase with age
Anti-cyclic citrullinated peptide antibodies (anti-CCP)
- Positive 80-85% of RA patients; more sensitive than RF
- Higher specificity for RA (90-96%) than RF (50-80%)

Natural History

RA is progressive disease that can be crippling in untreated patients
RA-related lymphadenopathy can wax and wane

Treatment

Drugs
- Immunomodulator agents
  - Methotrexate is commonly used
  - Anti-TNF α and other recently developed biological therapies
- Therapies used more commonly in the past
  - Azathioprine
  - Gold

Prognosis

Patients with RA have increased risk of malignant lymphoma
- Risk is ˜ 2x greater than general population
- Increased risk of lymphoma is attributable to RA itself
  - Highest risk in patients who are serum RF(+)
  - Can be detected after 5 years of follow-up
- Therapy of RA patients also may increase risk of developing lymphoma
Common types of lymphoma that occur in RA patients
- Diffuse large B-cell lymphoma (DLBCL) is most common
  - ˜ 60-70% of all lymphomas in RA patients
- Classical Hodgkin lymphoma (HL)
  - Nodular sclerosis or mixed cellularity most often reported
- Other lymphoma types reported with some frequency in RA patients
  - Follicular lymphoma
  - Mantle cell lymphoma
  - Marginal zone B-cell lymphomas
  - Peripheral T-cell lymphoma not otherwise classified
- Evidence of EBV present in subset of DLBCL and classical HL of RA patients
  - ˜ 20% of DLBCLs are EBV(+)

IMAGE FINDINGS

Radiographic Findings

Joints show juxtaarticular osteopenia and bone erosion with narrowing of joint spaces
Lymphadenopathy can be detected by various imaging methods

MICROSCOPIC PATHOLOGY

Histologic Features

Marked follicular hyperplasia in cortex and medulla of lymph node
- Follicles of various sizes and shapes
- “Starry sky” pattern within reactive germinal centers
- ± hyaline-like eosinophilic deposits in germinal centers
  - Can be extensive and replace lymph node parenchyma
  - Dystrophic calcification can occur
  - PAS(+), Congo red(-)
- “Cracking artifact” around follicles in poorly fixed tissues
Interfollicular areas
- Plasmacytosis is present and often prominent
  - Small aggregates or sheets of plasma cells without atypia
  - Cytoplasmic globules of Ig in plasma cells (Russell bodies)
- Capillary endothelial hyperplasia
Neutrophils in sinuses and interfollicular areas
± sarcoid-like granulomas
After immunosuppressive therapy lymph nodes often show
- Reduced follicular hyperplasia
- Expanded interfollicular regions and paracortical hyperplasia
After gold therapy lymph nodes may show
- Nonbirefringent crystalline structures throughout parenchyma
  - Free within spaces or in histiocyte cytoplasm
RA patients can develop lymphoplasmacytic infiltrates of lung
- Interstitial or nodular pattern
- ± reactive germinal centers
- Aggregates of small lymphocytes and plasma cells
- Can be associated with amyloid
- Rheumatoid nodules can occur in lung ± lymphoplasmacytic infiltrate