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Arthritis

Rheumatoid arthritis

Authors: Nabeel Ashraf, M.D., Laura Warmke, M.D.

Editorial Board Member: Jose G. Mantilla, M.D.

Deputy Editor-in-Chief: Borislav A. Alexiev, M.D.

Last author update: 8 August 2024

Last staff update: 8 August 2024

Copyright: 2002-2024, PathologyOutlines.com, Inc.

PubMed Search: Rheumatoid arthritis

Table of Contents

Cite this page: Ashraf N, Warmke L. Rheumatoid arthritis. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/jointsra.html. Accessed December 22nd, 2024.

Definition / general

Rheumatoid arthritis (RA) is a chronic autoimmune disorder often characterized by symmetrical and progressive destructive arthritis
RA can also affect other tissues and organs, such as the skin, eyes, lungs and blood vessels, often resulting in significant disability if not adequately managed (Lancet 2016;388:1984)

Essential features

Rheumatoid arthritis often affects women and frequently presents with symmetric arthritis, often involving the small bones of the hands and feet
Patients may have an increase in serum acute phase reactants and positive autoantibodies, including rheumatoid factor and anticitrullinated protein antibodies
Microscopic findings typically show thickening of the synovial lining, abundant lymphocytes and plasma cells, angiogenesis and erosion of bone and cartilage
Extra-articular manifestations are common and can include rheumatoid nodules, pleuritis, vasculitis and scleritis

Terminology

Chronic inflammatory polyarthritis
2 types of rheumatoid arthritis: seropositive and seronegative
Caplan syndrome (rheumatoid pneumoconiosis)

ICD coding

ICD-10: M06.9 - rheumatoid arthritis, unspecified

Epidemiology

RA affects about 0.5 - 1.0% of the global population (Ann Rheum Dis 2014;73:1316)
Annual incidence is estimated to be around 20 - 50 cases per 100,000 individuals (Arthritis Rheum 2010;62:1576)
Twice as common in women than men; M:F between 1:2 and 1:4
May begin at any age with peak frequency in the fourth and fifth decades
Higher prevalence rates in Northern Europe and North America
Lower prevalence rates in Asia and certain Afro-Caribbean groups

Sites

Affects all joints, predominantly the small joints of the hands and feet
May also affect larger joints such as knees, hips, elbows and shoulders (Lancet 2016;388:2023)

Pathophysiology

Disease process begins with activation of immune cells, such as T and B lymphocytes, which infiltrate the synovium, initiating a cascade of inflammatory cytokine release, including TNFα, IL1 and IL6 (Lancet 2001;358:903)
Inflammatory setting promotes synovial hyperplasia and angiogenesis, leading to pannus formation, cartilage destruction and bone erosion
Plasma cells manufacture rheumatoid factors, along with other antibodies (e.g., against type II collagen)
Activation of periosteal osteoclasts leads to periarticular bone erosion
Damage to articular surfaces is mediated by matrix degrading enzymes (e.g., matrix metalloproteinases)

Etiology

One or more sporadic conditions of unknown cause
Autoimmune disorder influenced by genetic and environmental factors
Genetic association with major histocompatibility complex (MHC), polymorphisms of HLA-DRB1 affect disease severity
Earlier onset and greater severity with DRB1*0401/*0404 compound genotype
Environmental factors such as smoking, infections (e.g., Epstein-Barr virus) and hormonal triggers (e.g., estrogen deficiency in postmenopausal women) can act as triggers (Arthritis Care Res (Hoboken) 2020;72:1766)

Diagrams / tables

Images hosted on other servers:

Etiology

1987 revised criteria for classification

Clinical features

Variable clinical course
Periods of remission and relapse
Symmetrical joint pain, swelling and stiffness, often affecting small joints such as those in the hands, wrists and feet (Ann Rheum Dis 1976;35:357)
Morning stiffness, often lasting over 30 minutes, which may improve with movement (J Rheumatol 1999;26:1052)
Joint deformities, such as swan neck deformity, boutonniere deformity and ulnar deviation, due to chronic inflammation and joint damage
Rheumatoid nodules commonly found over pressure points or on the extensor surfaces of joints (Am J Med 1984;76:279)
Rheumatoid nodules present in ~20% of cases (Histopathology 1991;19:193)
Fatigue, malaise, low grade fever and unintentional weight loss may be present
Extra-articular manifestations include but are not limited to dry eyes, scleritis, vasculitis, pericarditis, pleuritis and peripheral neuropathy (Ann Rheum Dis 2003;62:722)

Diagnosis

Diagnosis of RA is supported by at least 1 swollen joint not otherwise explained and meeting classification criteria of the American College of Rheumatology (Arthritis Rheum 1988;31:315)
Serologic testing for rheumatoid factor
Xray to look for bone erosions

Laboratory

Rheumatoid factor (antibodies to the Fc portion of IgG) is the only established marker, although not specific
Elevated acute phase reactants, such as erythrocyte sedimentation rate (ESR) and C reactive protein (CRP), indicating systemic inflammation
Presence of autoantibodies, including rheumatoid factor (sensitivity: 60 - 80%, specificity: 70 - 90%) and anticitrullinated protein antibodies (sensitivity: 80%, specificity: 95%) (Ann Intern Med 2007;146:797)

Radiology description

Radiographic hallmarks are soft tissue swelling, osteoporosis, joint space narrowing and margin erosions (Helms: Fundamentals of Skeletal Radiology, 5th Edition, 2019)
Progressive loss of joint space due to cartilage destruction
Erosions appear as well defined areas of bone loss, usually at the joint margins (J Rheumatol 1989;16:585)
Marked joint space narrowing in the wrist is known as carpal crowding
Joint deformities include ulnar deviation, swan neck deformity and boutonniere deformity
On magnetic resonance imaging (MRI), rheumatoid nodules are low to intermediate signal on T1 weighted (T1W) images and isointense to muscle (Clin Imaging 1998;22:216)

Radiology images

Contributed by Lauren M. Ladd, M.D.

RA involving hands

RA involving elbow

RA involving knees

RA involving feet

RA involving shoulder

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Xray, hands

Xray, forefoot

MRI, rheumatoid nodules

Prognostic factors

High disease activity score (DAS) is associated with worse outcome (J Rheumatol 2009;36:1873)
Greater degree of joint deformity with positive rheumatoid factor, high titers are associated with more severe disease
Extra-articular manifestations, such as rheumatoid nodules, rheumatoid vasculitis or interstitial lung disease, indicates more aggressive disease
Increased incidence of comorbidity with septic arthritis and immune system malignancy
Presence of comorbid conditions, such as cardiovascular disease, osteoporosis or obesity can complicate management
Rapid and sustained response to disease modifying antirheumatic drugs (DMARDs), particularly within the first few months of treatment initiation, is associated with better long term outcome

Case reports

30 year old woman with 7 year history of pain in lumbosacral area and 1 year history of pain in joints of both hands (Chin Med J (Engl) 2011;124:3430)
48 year old woman with a nodule in the upper lip (J Oral Maxillofac Surg 2014;72:1532.e1)
49 year old woman with chief complaint of restricted mouth opening without pain, lasting ~4 months (Braz Dent J 2012;23:779)
52 year old woman had pain in the right wrist joint for 6 months (Case #308)
53 year old woman with mass in cubital fossa (J Family Med Prim Care 2020;9:4434)
72 year old woman with 6 month history of progressive painful swelling of wrists (Int J Surg Case Rep 2011;2:208)
Woman with pain and edema in second, third and fourth proximal interphalangeal (PIP) joints of hands and wrists (Rev Bras Reumatol 2012;52:648)

Treatment

Nonsteroidal anti-inflammatory drugs (NSAIDs)
Disease modifying antirheumatic drugs (DMARDs), such as methotrexate, TNF inhibitors, IL6 inhibitors and JAK inhibitors among others (Rheum Dis Clin North Am 2022;48:679)
Joint replacement therapy

Clinical images

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Subcutaneous rheumatoid nodules

Swelling of PIP and MCP joints of the hand

Rheumatoid nodule

Rheumatoid vasculitis

Gross description

Synovium is thickened, swollen and red with villous folds (Klein: Non-Neoplastic Diseases of Bones and Joints, 1st Edition, 2011)
Hypertrophic synovium grows onto the surface of cartilage and around intra-articular structures, forming an erosive pannus, which destroys the underlying tissue
Marginal erosions observed at the periphery of joints, especially interphalangeal joints in the fingers and atlantoaxial joint in cervical spine

Microscopic (histologic) description

Rheumatoid arthritis (joint involvement)

Synovial hypertrophy and hyperplasia
Synoviocyte layer can have 5 or more cells in thickness
Hypertrophic synoviocytes have microvilli protruding from the surface
Synovium can be replaced by granulation tissue and fibrin with increased blood vessels
Synovium with prominent lymphocytic and polyclonal plasma cell infiltrate
Lymphocytes tend to aggregate, forming follicles and occasionally germinal centers
Mixed inflammatory infiltrate includes T lymphocytes, B lymphocytes, macrophages, plasma cells and mast cells
Neutrophils may be present, especially in an acute flare and early arthritis
Tendons may have necrosis, myxoid degenerative change and vascular growth

Rheumatoid nodules

Rheumatoid nodules have zones of central eosinophilic fibrinoid necrosis surrounded by palisading histiocytes and an outer layer of granulation tissue, chronic inflammation and fibrous tissue
Rheumatoid nodules become more hyalinized and fibrotic as they mature, extent of necrosis varies with age of the lesion
Fibrosis may be extensive (Am J Dermatopathol 1988;10:1)

Microscopic (histologic) images

Contributed by Laura Warmke, M.D. and @MirunaPopescu13 on Twitter

Chronic synovitis

Plasma cells

Lymphoid aggregates

Fibrinoid necrosis

Rheumatoid nodule

Palisading histiocytes

Layers of rheumatoid nodule

Fibrosis

Rheumatoid arthritis

Negative cytokeratin

Virtual slides

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Rheumatoid nodules

Synovial pannus

Cytology description

Synovial fluid had fragments of fibrin and ragocytes
Döhle and Rieder cells may be present
Fragments of amorphous necrotic debris with metachromasia, better appreciated on Papanicolaou stained smears (Diagn Cytopathol 2003;28:322)
Pathognomonic triad of rheumatoid arthritis includes elongated macrophages, multinucleated macrophages and necrotic background material (Acta Cytol 1990;34:465)
Presence of long fibrin strands in necrotic background occasionally with epithelioid histiocytes arranged in a loose granulomatous pattern may be a clue

Cytology images

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Pleural fluid sediment

Immunofluorescence description

Direct immunofluorescence shows immunoglobulin and complement deposition in vessel walls (Clin Exp Immunol 1971;8:249)

Positive stains

IgM occasionally positive in vessel walls (Am J Dermatopathol 1988;10:1)

Negative stains

Cytokeratin
INI1 (demonstrates normal retained expression)
AFB (no acid fast bacilli)
GMS (no fungal organisms)
Gram stain (no microorganisms)
Alcian blue (negative in necrobiosis) (Am J Dermatopathol 1988;10:1)
Colloidal iron (negative for mucin in necrobiosis)

Videos

Rheumatoid nodule - palisaded necrobiotic granuloma

Rheumatoid nodule & granuloma annulare

Sample pathology report

Soft tissue, forearm mass, excision:
- Palisading granulomatous inflammation with fibrinoid necrosis (see comment)
- Comment: Excision of the forearm mass shows central fibrinoid necrosis surrounded by palisading granulomatous inflammation and fibrosis. An immunohistochemical stain for cytokeratin is negative. Special stains for microorganisms (AFB, GMS and Gram stain) are negative. All control slides stained appropriately. Taken together, the findings are suggestive of a rheumatoid nodule with the differential diagnosis including a deep granuloma annulare. Clinical and serologic correlation is recommended to assess for the possibility of rheumatoid arthritis.

Differential diagnosis

Infectious granulomas:
- Necrotizing granulomas
- Special stains for AFB and GMS will highlight acid fast bacilli and fungal organisms respectively
Suture granulomas:
- Palisading granulomas have been described
- Fragments of birefringent suture material present (Am J Surg Pathol 1993;17:920)
Chronic osteomyelitis:
- Clinical presentation is different, often with history of known infection
- Cultures might grow microorganisms
- Plasma cell infiltrate can be present in joints adjacent to areas of chronic osteomyelitis
Subcutaneous granuloma annulare:
- Absence of arthritis and constitutional symptoms
- Lesions often in pretibial region, dorsum of hand and occipital scalp (N Engl J Med 2006;354:2697)
- Pale, edematous necrobiosis with bluish hue suggestive of extracellular mucin
- Multinucleated giant cells are not observed
- Lesser degree of fibrosis
- Alcian blue stains necrobiosis (Am J Dermatopathol 1988;10:1)
- Colloidal iron shows mucin deposition in necrobiosis
- Negative for IgM
Epithelioid sarcoma:
- Predilections for deep soft tissue of extremities in young adults
- Tumor cells epithelioid to spindled with at least mild nuclear atypia
- True tumor necrosis is present
- Tumor cells positive for cytokeratin, EMA and occasionally CD34
- Loss of INI1 expression is characteristic
Osteoarthritis:
- Eburnation, subchondral sclerosis and osteophyte formation
- Typically shows less intense inflammation
- Patients do not have increased systemic inflammatory markers
Gout:
- Acute inflammation with neutrophils and needle shaped monosodium urate crystals
- Tophus formation
- Patients may have hyperuricemia (Ther Umsch 2016;73:137)
Necrobiotic xanthogranuloma:
- Classically presents as erythematous plaque in periorbital area
- Patients with a history of monoclonal gammopathy
- Necrosis, granulomatous inflammation and several giant cells, including Touton giant cells
- Cholesterol clefts frequently encountered
Necrobiosis lipoidica:
- Commonly presents as atrophic yellowish plaques on the shins
- Alternating layers of granulomatous inflammation and necrobiosis
- Plasma cells are frequently present
- Often occurs in patients with diabetes

Board review style question #1

A 45 year old woman presents with a 6 month history of joint pain, swelling and morning stiffness lasting more than 1 hour. Physical examination reveals symmetrical swelling of the metacarpophalangeal and proximal interphalangeal joints. Laboratory testing reveals a positive rheumatoid factor (RF). A synovial biopsy is performed. Which of the following histologic findings is most characteristic of rheumatoid arthritis?

Dense infiltration of lymphocytes and plasma cells in the synovium with formation of lymphoid follicles
Deposition of monosodium urate crystals in the synovial fluid
Formation of osteophytes in the joint margin
Presence of noncaseating granulomas in the synovium

Board review style answer #1

A. Dense infiltration of lymphocytes and plasma cells in the synovium with formation of lymphoid follicles. In rheumatoid arthritis, the synovium typically shows dense infiltration of inflammatory cells, including plasma cells and lymphocytes, often forming lymphoid follicles. This chronic inflammatory process leads to synovial hyperplasia and pannus formation, which invades and erodes cartilage and bone. Answer D is incorrect because noncaseating granulomas are characteristic of sarcoidosis. Answer B is incorrect because monosodium urate crystals are associated with gout. Answer C is incorrect because osteophyte formation is a feature of osteoarthritis.

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Reference: Rheumatoid arthritis

Board review style question #2

If a subcutaneous soft tissue nodule is excised and shows palisading granulomatous inflammation, which of the following findings is most supportive of a rheumatoid nodule?

Fibrinoid necrosis without mucin
Immunohistochemical expression of cytokeratin
Polarizable foreign material compatible with sutures
Presence of fungal organisms

Board review style answer #2

A. Fibrinoid necrosis without mucin. A rheumatoid nodule characteristically has palisading granulomatous inflammation with fibrinoid necrosis. Extracellular mucin is more commonly seen in the necrobiosis associated with subcutaneous granuloma annulare. Answer D is incorrect because it is most consistent with a fungal infection. Answer C is incorrect because it describes a suture granuloma. Answer B is incorrect because it would be concerning for the possibility of an epithelioid sarcoma.

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Reference: Rheumatoid arthritis

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