Vasculitides

Vasculitides are a heterogeneous group of rare autoimmune diseases characterized by blood

vessel inflammation (vasculitis). Inflammation can lead to ischemia, necrosis, and/or
hemorrhage, with subsequent end-organ damage. Vasculitides are either primary (idiopathic) or
secondary to an underlying disease (e.g., HBV infection, cancer, systemic lupus erythematosus)
or drug use. Vasculitides are further classified based on the size of the affected vessels: small-,
medium-, or large-vessel vasculitis, or variable vessel vasculitis. Diagnosing vasculitides is often
challenging, as symptoms are usually nonspecific; vasculitides should be considered in patients
presenting with constitutional symptoms and signs of multisystem disease (e.g.,
palpable purpura, pulmonary infiltrates, unexplained ischemic events). Laboratory studies,
imaging, and histopathology are often required to confirm the diagnosis. Management should
involve a multidisciplinary team (e.g., rheumatology, ophthalmology, neurology) and aims to
promptly prevent the progression of vascular inflammation with immunosuppressive therapy to
avoid organ damage and death. Treatment of the underlying cause (e.g., with antiviral drugs)
and/or symptomatic management (e.g., with NSAIDs) is often necessary.

General principles
Etiology [1]

 Primary (idiopathic)

 Secondary to another disease or drug use, e.g.:

o Infectious diseases
 Viral infection: e.g., HBV, HCV, HIV
 Infectious endocarditis
 Tuberculosis
 Syphilis
o Drugs: e.g., hydralazine, cocaine
o Malignancy: e.g., multiple myeloma, lymphoproliferative disorders
o Autoimmune diseases: e.g., systemic lupus
erythematosus (SLE), Sjogren syndrome, sarcoidosis, IBD

Classification [2]

 Based on the 2012 Chapel Hill Consensus Nomenclature

 Classification is based on the size of the vessel predominantly affected:

o Large-vessel vasculitis
o Medium-vessel vasculitis
o Small-vessel vasculitis
 ANCA-associated vasculitis of small vessels
 Non-ANCA-associated vasculitis of small vessels
o Variable vessel vasculitis
Differential diagnoses
 Infectious diseases

 Thrombotic disorders, e.g.:

o Antiphospholipid syndrome
o Thrombotic thrombocytopenic purpura
o Sickle cell disease
 Thromboangiitis obliterans

 Amyloidosis

 Scurvy

 Ergotamines

The differential diagnoses listed here are not exhaustive.

References
1.
Suresh E. Diagnostic approach to patients with suspected vasculitis. Postgrad Med
J. 2006; 82(970): p.483-488. doi: 10.1136/pgmj.2005.042648.| Open in Read by QxMD
2.

Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised International Chapel Hill Consensus
Conference Nomenclature of Vasculitides. Arthritis & Rheumatism. 2012; 65(1): p.1-
11. doi: 10.1002/art.37715.| Open in Read by QxMD
3.

Younger DS. Overview of the Vasculitides. Neurol Clin. 2019; 37(2): p.171-
200. doi: 10.1016/j.ncl.2019.01.005.| Open in Read by QxMD
4.

Espígol-Frigolé G, Prieto-González S, Alba MA, et al. Advances in the Diagnosis of Large

Vessel Vasculitis. Rheumatic Disease Clinics of North America. 2015; 41(1): p.125-
140. doi: 10.1016/j.rdc.2014.10.001.| Open in Read by QxMD
5.

Kim ESH, Beckman J. Takayasu arteritis: challenges in diagnosis and

management.. Heart. 2018; 104(7): p.558-565. doi: 10.1136/heartjnl-2016-310848.| Open
in Read by QxMD
6.

Bardi M, Diamantopoulos AP. EULAR recommendations for the use of imaging in large
vessel vasculitis in clinical practice summary. Radiol Med (Torino). 2019; 124(10): p.965-
972. doi: 10.1007/s11547-019-01058-0.| Open in Read by QxMD
7.

Micheletti RG, Pagnoux C. Management of cutaneous vasculitis. Presse Med. 2020; 49(3):
p.104033. doi: 10.1016/j.lpm.2020.104033.| Open in Read by QxMD
8.

Goeser MR, Laniosz V, Wetter DA. A Practical Approach to the Diagnosis, Evaluation, and
Management of Cutaneous Small-Vessel Vasculitis. Am J Clin Dermatol. 2014; 15(4):
p.299-306. doi: 10.1007/s40257-014-0076-6.| Open in Read by QxMD
9.

A. Greco, A. Gallo, M. Fusconi, G. Magliulo, R. Turchetta, C. Marinelli, G.F. Macri, A. De

Virgilio, M. de Vincentiis. Cogan's syndrome: An autoimmune inner ear
disease. Autoimmun Rev. 2013; 12(3): p.396-400. doi: 10.1016/j.autrev.2012.07.012.|
Open in Read by QxMD
Rheumatoid arthritis
Summary
Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disorder that
primarily affects the joints (e.g., causes pain, swelling, synovial destruction, deformities), but may
also manifest with extraarticular features (e.g., rheumatoid nodules, pulmonary fibrosis). The risk
of RA increases with age, and the disease predominantly affects women. The diagnosis is clinical
and may be supported by laboratory tests (e.g., rheumatoid factor, anticitrullinated peptide
antibodies) and imaging studies (e.g., the presence of synovitis on ultrasound and, later in the
disease course, bone erosions and/or joint space narrowing on x-rays). There is no curative
therapy for RA but early intervention with disease-modifying antirheumatic drugs (DMARDs)
using a treat-to-target strategy can prevent disease progression and RA-related disability.

Epidemiology
 Prevalence

o ∼ 0.24% worldwide [1]

o 1% in northern Europe and US [2]

 Sex: ♀ > ♂ (3:1) [3]

 Peak incidence: > 65 years [4]

Epidemiological data refers to the US, unless otherwise specified.

Etiology
 Idiopathic inflammatory autoimmune disorder of unknown etiology

 Risk factors include: [5]

o Genetic disposition: associated with HLA-DR4 and HLA-DR1 [6]

o Environmental factors (e.g., smoking)

o Hormonal factors (premenopausal women are at the highest risk, suggesting
a predisposing role of female sex hormones) [7]

o Infection
o Obesity
o Family history of RA

Pathophysiology
 Certain interstitial tissue proteins (e.g. intracellular filament
protein vimentin, filaggrin, type II collagen) undergo a posttranslational
modification that involves the conversion of arginine to citrulline (citrullination). [8]

 Citrullinated proteins are recognized as foreign by the antigen-presenting cells that

present them to CD4 T cells.+

 Activation of CD4+ T cells leads to the following sequences of events: [9]

o IL-4 production → B-cell proliferation and differentiation → production

of anticitrullinated peptide antibodies → type II hypersensitivity
reaction and type III hypersensitivity reaction
o Migration of CD4 T cells to synovial joints → secretion of cytokines (IFN-
+

γ, IL-17) → recruitment of macrophages → secretion of cytokines (TNF-α, IL-

1, IL-6) → inflammation and proliferation
 Bouts of inflammation, angiogenesis, and proliferation → proliferative granulation
tissue with mononuclear inflammatory cells → pannus and
synovial hypertrophy → invasion, progressive destruction, and deterioration
of cartilage and bone
 Antibodies against Fc portion of IgG (rheumatoid factor, RF) are produced to aid in
removing autoantibodies and immune complexes.
 o RF excess triggers formation of new immune complexes and type III HSR
o Individuals with positive RF are more likely to develop extraarticular
manifestations. [10]

Clinical features
Articular manifestations [11]

 Polyarthralgia

o Symmetrical pain and swelling of affected joints (also at rest)

o Frequently affected joints [12]

 Metacarpophalangeal joints (MCP joints)

 Proximal interphalangeal joints (PIP joints)
 Wrist joints
 Knee joints
 Metatarsophalangeal joints (MTP joints)
o Rarely affected: distal interphalangeal joints (DIP joints), first
carpometacarpal (CMC) joint, and the axial skeleton (except for
the cervical spine)
 Morning stiffness (often > 30 min) that usually improves with activity

 Joint deformities

o Rheumatoid hand is characteristic and typically manifests with one or more

of the following deformities:
 Deepening of the interosseous spaces of the dorsum of
hand
 Swan neck deformity: PIP hyperextension and DIP flexion
 Boutonniere deformity: PIP flexion and DIP hyperextension.
 Hitchhiker thumb deformity (Z deformity of the
thumb): hyperextension of the interphalangeal joint with
fixed flexion of the MCP joint [13]

 Ulnar deviation of the fingers

 Piano key sign: dorsal subluxation of the ulna
o Hammer toe or claw toe
 o Atlantoaxial subluxation (see “Rheumatoid arthritis of the cervical spine”
below)
 Physical examination: compression test (Gaenslen squeeze test)
o Painful compression of hands (or feet) at the level of the MCP
joint (metatarsophalangeal joint)
o Painful handshake is an early sign of arthritis
Extraarticular manifestations [14]

 Constitutional symptoms

o Low-grade fever
o Myalgia
o Malaise
o Fatigue
o Weight loss
o Night sweats
 Rheumatoid nodules
 o Skin
 Nontender, firm, subcutaneous swellings (2 mm–5 cm)
 Commonly occur in areas exposed to higher pressure, e.g.,
extensor side of the forearm, bony prominences
o Lungs
 Typically bilateral and peripheral
 Rheumatoid pulmonary nodules may be accompanied
by fibrosis and pneumoconiosis (Caplan syndrome).
 Lungs

o Pleuritis, pleural effusions

o Interstitial lung disease (e.g., organizing pneumonia) [15]

 Eye: keratoconjunctivitis sicca, scleritis, and episcleritis [16]

 Endocrine and exocrine glands: secondary Sjogren syndrome

 Hematological

o Anemia
 Anemia of chronic disease (normocytic anemia)
 NSAIDs and/or steroids → increased risk of GI bleeding → iron
deficiency anemia (microcytic anemia)
 Methotrexate → decreased folate level → macrocytic anemia
o Neutropenia
o Splenomegaly
o Large granular lymphocyte leukemia
o Lymphoma
 Musculoskeletal

o Tenosynovitis and bursitis

o Carpal tunnel syndrome
 Typical nocturnal paresthesia of volar hand, thumb, index and
middle fingers
 Atrophy of thenar muscles → difficulty making a fist and inability
to oppose the thumb
o Tarsal tunnel syndrome
 Heart

o Pericarditis and myocarditis

o Increased risk of myocardial infarction, stroke, CHF, and atrial fibrillation [17]

 Vascular

o Peripheral vasculitis, manifests as livedo reticularis

o Raynaud phenomenon
o Purpura
o Vasculitic ulcers
o Necrosing fingertips
o Peripheral neuropathy
Pathology
 Synovial pannus formation and bone invasion: pathological layer of
proliferative granulation tissue, mononuclear inflammatory cells, and fibroblast-
like mesenchymal cells, releasing cytokines and enzymes, which, in turn, damage and
invade the surrounding connective tissue [18]

 Synovial lining hyperplasia with mononuclear cell infiltrate

 Perivascular inflammatory infiltrates

 Angiogenesis
 Fibrin deposition on synovial surfaces
 Rheumatoid nodules: central fibrinoid necrosis with
palisading histiocytes (epithelioid cells)
Diagnostics
Approach [22][25][26]

 The diagnosis of RA is clinical.

o Consider RA in patients with arthralgia, joint stiffness, and synovitis lasting ≥

6 weeks (see “Clinical features”).
o Consider alternative diagnoses in patients with atypical presentations (see
“Differential diagnoses”).
 Perform diagnostic studies to further support the diagnosis and help establish disease
severity.
 o Routine laboratory tests. [22][26]

o X-ray as the initial imaging study

 Consult rheumatology, particularly if the diagnosis is uncertain and when choosing a
treatment regimen.

Laboratory studies [22][26]

Routine studies
 Nonspecific parameters

o ↑ Inflammatory markers
 ↑ CRP and ↑ ESR
 Other acute phase reactants may also be elevated (e.g., ferritin).
o CBC: anemia of chronic disease, thrombocytosis
o TFTs: to rule out an autoimmune thyroid disease, which is common in
patients with RA
o Serology: ↑ ANAs in 30–50% of patients with RA [21]

 Specific parameters (serological studies) [22][27]

o Anticitrullinated peptide
antibodies (ACPA), e.g., anticyclic citrullinated peptide (anti-CCP) [28]

o Rheumatoid factor (RF): IgM autoantibodies against the Fc region of IgG

antibodies [21]

o Serological studies may be negative (i.e., seronegative RA)

Additional studies
Additional studies should be considered on an individual basis.

 Synovial fluid analysis: not routinely recommended [26]

o Indications
 Suspicion of septic arthritis
 Atypical presentation, to rule out differential diagnoses (e.g., gout)
o Findings are nonspecific [21]

 Cloudy, yellow appearance

 Sterile specimen with leukocytosis (WBC
count 5000–50,000/mcL)
 ↑ Neutrophils, granulocytes, and ragocytes
 ↑ Protein level
 Possibly RF

Imaging studies [26][30][31]

While x-ray is recommended as the initial test, ultrasound and MRI might additionally be
necessary to assess joint disease severity.

 X-ray: initial test

o Studies
 Baseline radiographs of both hands (dorsopalmar view) and feet
 Radiographs of symptomatic joints
o Findings
 Early: soft tissue swelling, osteopenia (juxtaarticular)
 Late: joint space narrowing, marginal erosions of cartilage and
bone, osteopenia (generalized), subchondral cysts
 Ultrasound [32]

o Indication: If available, perform on affected joints to detect clinical or

subclinical synovitis.
 o Supportive findings
 Early signs of inflammation: e.g.,
subclinical synovitis (synovial hyperemia)
 Synovial proliferation (pannus formation)
 Joint effusion: increased fluid (e.g., pus, blood, inflammatory
infiltrate) within the synovial compartment of a joint
 Using contrast can increase the sensitivity of detecting
inflammation.
 MRI of the affected joints (with or without contrast)
o Can help detect early changes in large joints (e.g.,
subclinical synovitis)
o Consider especially if cervical spine involvement is suspected (see
“Atlantoaxial subluxation”).
 Further imaging studies: Perform if extraarticular manifestations are suspected
(e.g., a CT scan for interstitial lung disease, an echocardiogram for pericarditis).

Differential diagnoses
 Other differential diagnoses
o Autoimmune-related arthritis (e.g., sarcoidosis, SLE, rheumatic
fever, mixed connective tissue disease, polymyalgia rheumatica)
o Enteropathic arthritis
o Vasculitides
o Hemochromatosis
o Viral arthritis (e.g., parvovirus B19, hepatitis viruses)
o Lyme arthritis
o Reactive arthritis (post-urethritis, post-enteritis)
o CPPD disease
o Basic calcium phosphate crystal deposition diseases
o Fibromyalgia
o Soft tissue rheumatic disorders: a group of common nonsystemic
focal syndromes characterized by nonarticular pain
o Hypertrophic osteoarthropathy: typically characterized by periosteal
reaction in the metaphyses and diaphyses of long bones and
associated with lung disease (e.g., lung cancer)
TREATMENT
Approach [22][26][35]

 Initiate acute antiinflammatory treatment with glucocorticoids and NSAIDs for disease
flares.
 Long-term treatment

o Initiate treatment with conventional DMARD monotherapy.

 o Consider short-term concomitant antiinflammatory treatment.
 Initiate nonpharmacological management.

 Consider surgical treatment in specific cases (e.g., patients with severe joint deformities).

Acute antiinflammatory treatment [22][26][35]

Temporary (< 3 months) symptomatic treatment

with glucocorticoids and/or NSAIDs is indicated for disease flares (i.e., episodes of increased
disease activity and symptom worsening). [36]

 Glucocorticoids

o Systemic prednisone
 Short-term (i.e., < 3 months) therapy at the lowest effective
dose is preferred.
 Longer-term therapy: Only use in patients with highly
active RA who do not respond to maximum doses of DMARDs. [22]

[35]

o Intraarticular injections (e.g., with triamcinolone acetonide) can be

considered by specialists alongside treatment with DMARDs.
 NSAIDs and selective COX-2 inhibitors: relieve symptoms, but do not improve the
prognosis
o Ibuprofen
o Diclofenac
o Celecoxib
 Other measures: If a flare occurs due to medication tapering, restart the previous
effective treatment regimen.
Long-term pharmacological treatment [22][26][31][35]

Initiation of treatment
 All
patients (regardless of baseline disease activity or disease duration):
monotherapy with a conventional DMARD
 Consider short-term concomitant use of acute antiinflammatory therapy
(i.e., glucocorticoids and/or NSAIDs) for symptom control until the onset of action
of DMARDs (e.g., ≥ 6 weeks). [35]

Treat-to-target strategy [31][35]

Long-term treatment is guided by disease activity scoring systems for RA involving clinical and
laboratory features, e.g., CDAI. The 2021 ACR guideline does not provide definitions for different
stages of disease activity.

Disease-modifying antirheumatic drugs (DMARDs) [26][31][35]

DMARDs are used as long-term therapy. They interfere with the inflammatory mechanisms
of RA, which can potentially lead to remission. DMARD therapy reduces RA mortality
and morbidity by up to 30%. Prevention and monitoring of potential adverse effects are
required (see also “Adverse effects” in “Immunosuppressants”). [12]
Synthetic DMARDs
Biologic DMARDs [31]

 Indication:
persistent moderate or severe disease activity after 3
months of conventional DMARD therapy
 Agents

o TNF-α inhibitors: e.g., adalimumab, infliximab, etanercept (see also

“Contraindications to anti-TNF-α treatment”)
oOthers: rituximab (anti-CD20), anakinra (IL-1 receptor antagonist,
particularly for Still disease), tocilizumab (IL-6 receptor antagonist)
 Adverse effects include:
o Infections
o TB reactivation
o Hepatitis B reactivation

Prevention and monitoring of adverse effects [26][35][37][38]

Perform studies and vaccinations before the initiation of therapy based on the patient's
individual risk and potential adverse effects of the prospective agent.

 CBC, liver transaminases, and serum creatinine at baseline

 Vaccinations for patients receiving biologic DMARDs

o Influenza, pneumococcus, and hepatitis B

o Herpes zoster

Nonpharmacological management [26]

 ASCVD prevention measures are associated with improved outcomes in patients

with RA.
 Physical and occupational therapy can improve mobility.

 Heat or cold packs for pain management.

Surgical treatment [26][39]

 Indications

o Consider in patients with extensive joint deformity.

o Rarely, surgery may be used for symptom control in patients who do not
respond to or cannot tolerate the recommended pharmacological regimen.
 Procedures
 o Total joint replacement (e.g., hip joint replacement): Consider in patients
with severe joint damage or concomitant osteoarthritis.
o Synovectomy: surgical removal of the synovial tissue
o Radiation synovectomy: ablation of inflamed synovia via injection of
radioactive agents (beta particles) into the synovial cavity of affected joints [40]

 Inhibits synovial growth and fibrosis of the synovia

 May reduce inflammatory activity and pain
 Also indicated in patients with other chronic
inflammatory joint diseases (e.g., active arthrosis, psoriatic arthritis)
who do not respond to pharmacological treatment

Classification
The ACR/EULAR classification criteria were developed for research purposes and should not be
used as diagnostic criteria. These criteria are for targeted use in patients who have at least
one joint with clinical synovitis that is not better explained by another cause, e.g. trauma or
degenerative joint conditions. [25]
Complications
Untreated and/or severe cases can result in permanent damage to the joints with stiffening and
deformity.

 Complications in the upper limbs: rheumatoid hand deformities (see “Clinical features”
above)
 Complications in the lower limbs
o Baker cyst due to inflammatory joint effusion
o Foot impairment: pes plano-valgus (flat feet) [42]

 Other complications

o Muscle weakness
o Vasculitis involving the kidneys
o Amyloid A amyloidosis (AA amyloidosis)
o Septic arthritis [43]

o Osteopenia, osteoporosis, and bone fractures [44]

Prognosis
 Factors associated with poor prognosis
 o Cardiovascular disease and infections are the most common causes of
death. [12]

o Male sex [45]

o Smoking
o Social factors (e.g., low socioeconomic status, low level of education)
o Presence of extraarticular disease
 Elevated laboratory values associated with poor prognosis

o CRP
o ESR
o ACPA
o RF

Tips and Links

 2010 Rheumatoid arthritis classification criteria: an American College of
Rheumatology/European League Against Rheumatism collaborative initiative

 2021 American College of Rheumatology Guideline for the Treatment of

Rheumatoid Arthritis

References
1.

Cross M, Smith E, et al. The global burden of rheumatoid arthritis: estimates from the
global burden of disease 2010 study. Ann Rheum Dis. 2014; 73(7): p.1316-
22. doi: 10.1136/annrheumdis-2013-204627.| Open in Read by QxMD
2.

Hunter TM, Boytsov NN et al. Prevalence of rheumatoid arthritis in the United States
adult population in healthcare claims databases, 2004-2014. Rheumatol Int. 2017; 37(9):
p.1551-1557. doi: 10.1007/s00296-017-3726-1.| Open in Read by QxMD
3.

Cojocaru M, Cojocaru IM, Silosi I, Vrabie CD, Tanasescu R. Extra-articular Manifestations

in Rheumatoid Arthritis. Maedica (Buchar). 2010. pmid: 21977172. | Open in Read by
QxMD
4.
Pease CT, Bhakta BB, Devlin J, Emery P. Does the age of onset of rheumatoid arthritis
influence phenotype?: a prospective study of outcome and prognostic
factors.. Rheumatology (Oxford). 1999; 38(3): p.228-
34. doi: 10.1093/rheumatology/38.3.228.| Open in Read by QxMD
5.

Wasserman AM. Diagnosis and Management of Rheumatoid Arthritis. Am Fam

Physician. 2011; 84(11): p.1245-1252. pmid: 22150658. | Open in Read by QxMD
6.

Alvarez I, Collado J, Daura X, et al. The rheumatoid arthritis-associated allele HLA-DR10

(DRB1*1001) shares part of its repertoire with HLA-DR1 (DRB1*0101) and HLA-DR4
(DRB*0401). Arthritis Rheum. 2008; 58(6): p.1630-1639. doi: 10.1002/art.23503.| Open in
Read by QxMD
7.

Kumar, Clark. Kumar and Clark's Clinical Medicine, 9th edition. Elsevier; 2016
8.

Walther J van Venrooij, Ger J M Pruijn. Citrullination: a small change for a protein with
great consequences for rheumatoid arthritis. Arthritis Res. 2000; 2(4):
p.249. doi: 10.1186/ar95.| Open in Read by QxMD
9.

Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. The Lancet. 2010; 376(9746):
p.1094-1108. doi: 10.1016/s0140-6736(10)60826-4.| Open in Read by QxMD
10.

van Zeben D, Hazes JM et al. Clinical significance of rheumatoid factors in early

rheumatoid arthritis: results of a follow up study. Ann Rheum Dis. 1992; 51(9): p.1029-
35. pmid: 1417131. | Open in Read by QxMD
11.

Rheumatoid Arthritis Fact Sheet. https://www.cdc.gov/arthritis/basics/rheumatoid-

arthritis.html. Updated: March 13, 2017. Accessed: April 10, 2017.
12.

Kasper DL, Fauci AS, Hauser S, Longo D, Jameson LJ, Loscalzo J . Harrisons Principles of
Internal Medicine . McGraw-Hill Medical Publishing Division; 2016
13.

Hitchhiker thumb deformity. https://radiopaedia.org/articles/hitchhiker-thumb-

deformity. Updated: April 10, 2017. Accessed: April 10, 2017.
14.
Young A, Koduri G. Extra-articular manifestations and complications of rheumatoid
arthritis. Best Pract Res Clin Rheumatol. 2007; 21(5): p.907-
927. doi: 10.1016/j.berh.2007.05.007.| Open in Read by QxMD
15.

Kim DS. Interstitial lung disease in rheumatoid arthritis: recent advances. Curr Opin Pulm
Med. 2006; 12(5): p.346-353. doi: 10.1097/01.mcp.0000239552.55326.ee.| Open in Read
by QxMD
16.

Jabs DA, Mudun A, Dunn JP, Marsh MJ. Episcleritis and scleritis: clinical features and
treatment results. Am J Ophthalmol. 2000; 130(4): p.469-476. doi: 10.1016/s0002-
9394(00)00710-8.| Open in Read by QxMD
17.

Rawla P. Cardiac and vascular complications in rheumatoid

arthritis. Reumatologia/Rheumatology. 2019; 57(1): p.27-
36. doi: 10.5114/reum.2019.83236.| Open in Read by QxMD
18.

Bresnihan B. Are synovial biopsies of diagnostic value?. Arthritis Res Ther. 2003; 5(6):
p.271. doi: 10.1186/ar1003.| Open in Read by QxMD
19.

Kasper DL, Fauci AS, Hauser SL, Longo DL, Lameson JL, Loscalzo J. Harrison's Principles
of Internal Medicine. McGraw-Hill Education; 2015
20.

Magadur-Joly G, Billaud E, et al. Epidemiology of adult Still's disease: estimate of the

incidence by a retrospective study in west France. Ann Rheum Dis. 1995; 54(7): p.587-
90. doi: 10.1136/ard.54.7.587.| Open in Read by QxMD
21.

West SG. Rheumatology Secrets. Elsevier Mosby; 2014

22.

Smolen JS, Aletaha D, Barton A, et al. Rheumatoid arthritis. Nature Reviews Disease
Primers. 2018; 4(1). doi: 10.1038/nrdp.2018.1.| Open in Read by QxMD
23.

Krabben A, Huizinga TWJ, van der Helm-van Mil AHM. Undifferentiated arthritis
characteristics and outcomes when applying the 2010 and 1987 criteria for rheumatoid
arthritis. Ann Rheum Dis. 2011; 71(2): p.238-241. doi: 10.1136/annrheumdis-2011-
200205.| Open in Read by QxMD
24.
Van der Helm-vanMil AHM, le Cessie S, van Dongen H, Breedveld FC, Toes REM,
Huizinga TWJ. A prediction rule for disease outcome in patients with Recent-onset
undifferentiated arthritis: How to guide individual treatment decisions. Arthritis
Rheum. 2007; 56(2): p.433-440. doi: 10.1002/art.22380.| Open in Read by QxMD
25.

Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an
American College of Rheumatology/European League Against Rheumatism collaborative
initiative. Arthritis Rheum. 2010; 62(9): p.2569–2581. doi: 10.1002/art.27584 .| Open in
Read by QxMD
26.

Sparks JA. Rheumatoid Arthritis. Ann Intern Med. 2019; 170(1):

p.ITC1. doi: 10.7326/aitc201901010.| Open in Read by QxMD
27.

Song YW, Kang EH. Autoantibodies in rheumatoid arthritis: rheumatoid factors and
anticitrullinated protein antibodies. QJM. 2009; 103(3): p.139-
146. doi: 10.1093/qjmed/hcp165.| Open in Read by QxMD
28.

Aggarwal R, Liao K, Nair R, Ringold S, Costenbander KH. Anti-citrullinated peptide

antibody assays and their role in the diagnosis of rheumatoid arthritis. Arthritis Care &
Research. 2009; 61(11): p.1472-1483. doi: 10.1002/art.24827.| Open in Read by QxMD
29.

Slater CA. Antinuclear Antibody Testing. Arch Intern Med. 1996; 156(13):
p.1421. doi: 10.1001/archinte.1996.00440120079007.| Open in Read by QxMD
30.

Jacobson JA, Roberts CC, Bencardino JT, et al. ACR Appropriateness Criteria ® Chronic
Extremity Joint Pain—Suspected Inflammatory Arthritis. J Am Coll Radiol. 2017; 14(5):
p.S81-S89. doi: 10.1016/j.jacr.2017.02.006.| Open in Read by QxMD
31.

Aletaha D, Smolen JS. Diagnosis and Management of Rheumatoid Arthritis. JAMA. 2018;
320(13): p.1360. doi: 10.1001/jama.2018.13103.| Open in Read by QxMD
32.

Jeka S, Zuchowski P, Dura M, Zwierko B, Waszczak-Jeka M. The role of ultrasonography

in the diagnostic criteria for rheumatoid arthritis and monitoring its therapeutic
efficacy. Advances in Clinical and Experimental Medicine. 2018; 27(9): p.1303-
1307. doi: 10.17219/acem/69133.| Open in Read by QxMD
33.
England BR, Tiong BK et al. 2019 Update of the American College of Rheumatology
Recommended Rheumatoid Arthritis Disease Activity Measures. Arthritis Care Res. 2019;
71(12): p.1540-1555. doi: 10.1002/acr.24042.| Open in Read by QxMD
34.

Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/European

League Against Rheumatism provisional definition of remission in rheumatoid arthritis
for clinical trials. Arthritis & Rheumatism. 2011; 63(3): p.573-586. doi: 10.1002/art.30129.|
Open in Read by QxMD
35.

Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology
Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care &
Research. 2021. doi: 10.1002/acr.24596.| Open in Read by QxMD
36.

Bykerk VP, Bingham CO, Choy EH, et al. Identifying flares in rheumatoid arthritis:
reliability and construct validation of the OMERACT RA Flare Core Domain Set. RMD
Open. 2016; 2(1): p.e000225. doi: 10.1136/rmdopen-2015-000225.| Open in Read by
QxMD
37.

Singh JA, Saag KG, Bridges SL, et al. 2015 American College of Rheumatology Guideline
for the Treatment of Rheumatoid Arthritis. Arthritis Care & Research. 2015; 68(1): p.1-
25. doi: 10.1002/acr.22783.| Open in Read by QxMD
38.

Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008
recommendations for the use of nonbiologic and biologic disease-modifying
antirheumatic drugs in rheumatoid arthritis. Arthritis & Rheumatism. 2008; 59(6): p.762-
784. doi: 10.1002/art.23721.| Open in Read by QxMD
39.

Massardo L, Gabriel SE, Crowson CS, O'Fallon WM, Matteson EL. A population based
assessment of the use of orthopedic surgery in patients with rheumatoid arthritis.. J
Rheumatol. 2002; 29(1): p.52-6. pmid: 11824971. | Open in Read by QxMD
40.

Chojnowski MM, Felis-Giemza A, Kobylecka M. Radionuclide synovectomy – essentials

for rheumatologists. Reumatologia. 2016; 3: p.108-116. doi: 10.5114/reum.2016.61210.|
Open in Read by QxMD
41.
Aggarwal R, Ringold S, Khanna D, et al. Distinctions between diagnostic and
classification criteria?. Arthritis Care Res (Hoboken). 2015; 67(7): p.891-
7. doi: 10.1002/acr.22583.| Open in Read by QxMD
42.

Turner DE, Helliwell PS, Emery P, Woodburn J. The impact of rheumatoid arthritis on foot
function in the early stages of disease: a clinical case series. BMC Musculoskelet
Disord. 2006; 7: p.102. doi: 10.1186/1471-2474-7-102.| Open in Read by QxMD
43.

Septic
Arthritis. http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/
rheumatology/septic-arthritis/. Updated: August 1, 2010. Accessed: April 10, 2017.
44.

Haugeberg G, Ørstavik RE, Kvien TK. Effects of Rheumatoid Arthritis on Bone. Curr Opin
Rheumatol. 2003; 15(4): p.469-475. pmid: 12819477. | Open in Read by QxMD
45.

Myasoedova E, Davis JM, Crowson CS, Gabriel SE. Epidemiology of Rheumatoid Arthritis:
Rheumatoid Arthritis and Mortality. Curr Rheumatol Rep. 2010; 12(5): p.379-
385. doi: 10.1007/s11926-010-0117-y.| Open in Read by QxMD
46.

Whiting PF. Systematic Review: Accuracy of Anti–Citrullinated Peptide Antibodies for

Diagnosing Rheumatoid Arthritis. Ann Intern Med. 2010; 152(7):
p.456. doi: 10.7326/0003-4819-152-7-201004060-00010.| Open in Read by QxMD
47.

Agha-Abbaslou M, Bensaci AM, Dike O, Poznansky MC, Hyat A. Adult-Onset Still’s

Disease: Still a Serious Health Problem (a Case Report and Literature Review). American
Journal of Case Reports. 2017; 18: p.119-124. doi: 10.12659/ajcr.901846.| Open in Read
by QxMD
48.

Steinbrocker et al.. Therapeutic criteria in rheumatoid arthritis. JAMA: The Journal of the
American Medical Association. 1949; 140(8):
p.659. doi: 10.1001/jama.1949.02900430001001.| Open in Read by QxMD

Thromboangiitis obliterans
(Buerger disease)
Summary
Thromboangiitis obliterans (TAO), also known as Buerger disease, is an inflammatory,
nonatherosclerotic, vasoocclusive disease affecting small and medium-sized vessels of the
extremities. TAO most commonly affects adult males with a significant history of tobacco
consumption (e.g., smoking, chewing, vaping). In susceptible individuals, tobacco exposure
causes inflammation of the tunica intima, with the formation of a highly cellular thrombus that
occludes the affected vessel. Patients frequently present with intermittent claudication, Raynaud
phenomenon, and migratory superficial thrombophlebitis. Eventually, critical limb
ischemia develops and the patient presents with rest pain, absent pulse in the extremities,
and/or digital ulcerations. Angiography can determine the extent of the disease and
differentiate TAO from other causes of peripheral vasculopathy. The most important therapeutic
measure is the complete avoidance of tobacco exposure. Additionally, prostaglandin analogues
(e.g., iloprost) may be used to improve ulcer healing and decrease rest pain. Patients
with TAO who develop gangrene require amputation.

Epidemiology
 Prevalence: up to 20 cases per 100,000 individuals [1]

 Sex: ♂ > ♀ (3:1)

 Age of onset: before the age of 45 years [2]

Epidemiological data refers to the US, unless otherwise specified.

Etiology
 The exact etiology of TAO is unknown.

 Tobacco consumption is the single most important risk factor for TAO. [3]

Pathophysiology
TAO is an inflammatory, nonatherosclerotic, vasoocclusive disease affecting small and medium-sized
vessels of the extremities.

Histopathological phases [4]

 Acute phase

o Inflammation of the tunica intima (i.e., endarteritis) with neutrophilic infiltration

and microabscess formation
 o Inflammation may extend to the tunica media but the internal elastic
lamina usually remains intact.
o Formation of a highly cellular inflammatory thrombus
 Intermediate (subacute) phase
o Mononuclear cells, fibroblasts, and giant cells replace neutrophils
o Thrombus organization
 Chronic phase

o Organized thrombus
o The inflammatory process may extend to the adjacent vein and nerve, resulting in
the encasement of the artery, vein, and nerve in a fibrous sheath.

Clinical features
TAO affects the small and medium vessels of the extremities. Other systems are only very rarely
involved.

Extremities [2][5]

 Migratory superficial thrombophlebitis (recurrent): often seen prior to the onset of

limb ischemia [3][6]

o Tender nodules along the course of the affected vein

o Induration
o Erythema
 Raynaud phenomenon

 Chronic or acute limb ischemia: may progress from distal to proximal vessels

o Intermittent claudication
o Pain at rest, cool extremities, and/or diminished or absent pulses
o Ulceration and/or gangrene of fingertips and/or toes (digits may
autoamputate)

Diagnostics

Laboratory studies [2][3]

The following studies are normal

 ESR and CRP

 Autoantibodies (e.g., ANA, RF, anticentromere antibodies)

  Coagulation studies (see “Hypercoagulable states”)

Imaging studies [2][3]

 Angiography

o Findings
 Segmental occlusions in the distal vessels of the extremities
 Corkscrew-shaped collateral vessels around the site of occlusion
 Normal proximal arteries without evidence of atherosclerosis

Additional studies
 Ankle-brachial index (ABI): may be decreased [3]

 Biopsy
o May be considered in patients with tender nodules and/or superficial
thrombophlebitis, atypical locations (e.g., large vessel involvement), or
age of onset > 45 years [2][5]

o Typically shows acute inflammation of all layers of the vessel wall

accompanied by occlusive thrombosis
Differential diagnoses
 Peripheral artery disease; see “Differential diagnosis of claudication.”
Treatment

Prevention and supportive care [2][3]

 Abstinence from tobacco in any form (e.g., smoking or chewing tobacco, nicotine
patches or gum)
o Most effective measure for reducing symptoms
o Decreases the risk of amputation if started early in the disease course
 Protection of fingers and toes from cold and mechanical injuries (e.g., wearing gloves
and appropriate footwear)
Symptomatic therapy [2][6]

 Calcium channel blockers (nifedipine, amlodipine)

 Iloprost

Surgical therapy [4][6]

 Patients with ulcers may require debridement and antibiotic therapy for soft tissue
infections. [1]

 Patients who develop gangrene require amputation.

 Revascularizationprocedures (e.g., bypass grafting, angioplasty) are rarely

feasible because vascular involvement tends to be diffuse and distal.
References
1.

Vanda Cristina Jorge, Ana Carolina Araújo, Manuel Vaz Riscado. Buerger’s disease
(Thromboangiitis obliterans): a diagnostic challenge. BMJ Case Reports. 2011.
2.

Perttu ET Arkkila. Thromboangiitis obliterans (Buerger's disease). Orphanet Journal of

Rare Diseases. 2006.
3.

Piazza G, Creager MA. Thromboangiitis Obliterans. Circulation. 2010; 121(16): p.1858-

1861. doi: 10.1161/circulationaha.110.942383.| Open in Read by QxMD
4.

Kumar V, Abbas AK, Aster JC. Robbins & Cotran Pathologic Basis of Disease. Elsevier
Saunders; 2014
5.

Jeffrey W. Olin. Thromboangiitis Obliterans (Buerger's Disease). N Engl J Med. 2000;

343(12): p.864-869. doi: 10.1056/nejm200009213431207.| Open in Read by QxMD
6.
Vijayakumar A, Tiwari R, Kumar Prabhuswamy V. Thromboangiitis Obliterans (Buerger’s
Disease)—Current Practices. Int. J. Inflamm.. 2013; 2013: p.1-
9. doi: 10.1155/2013/156905.| Open in Read by QxMD