Etiology
The etiologies of inflammatory arthritis are varied, and can be grouped into the following broad categories:
Infectious arthritis
Immune-mediated arthritides
Noninfectious and nonimmune-mediated inflammatory arthritis
Paraneoplastic arthritides
Neoplastic arthritis.
Infectious
For all practical purposes, an acute monoarthritis is due to septic arthritis until proven otherwise. It is by far the most serious cause of an acute "hot joint" and should always be excluded before other conditions are considered.
In disseminated gonococcal infection involving the joint, the acute symptoms of fever, urethritis, and joint pain are accompanied by tenosynovitis and a pustular or vesiculopustular rash.
Tuberculous, nontuberculous mycobacterial, brucellar, and fungal arthritides are much less common than acute pyogenic (septic) arthritis or gonococcal arthritis, and are often indolent. A high index of suspicion is necessary to establish the correct diagnosis, which may be confirmed by synovial biopsy. If the diagnosis is missed, or the wrong treatment is instituted, permanent joint damage can occur. In addition, the disease can disseminate and become life-threatening.
History of an antecedent tick bite in endemic areas (e.g., the northeastern states, the midwest, and the western coastal area of the United States, and in central European and Scandinavian countries) suggests Lyme disease. The rash at the site of the bite has a bull's-eye appearance, with central clearing and vesicular lesions (erythema migrans).
Parvovirus B19 is the same virus that causes erythema infectiosum (fifth disease) in children, and can cause an acute polyarthritis that may resemble rheumatoid arthritis (RA). It can affect people of any age but is most common in children ages 6 to 10 years.[1] There may also be an occupational risk for people working with young children such as daycare workers and elementary school teachers.[2][3] The rash in adults is nonspecific. Circulating B19-specific IgM and IgG antibodies are useful in diagnosing acute infection in an immunocompetent host.[4][5]
Inflammatory arthritis can occur in other viral infections such as rubella, infectious mononucleosis (Epstein Barr virus infection), hepatitis B and C, and HIV infection. It has also been described with coronavirus-19 (COVID-19).[6][7][8][9]
Various arboviruses have been included in the list of emerging viral pathogens associated with acute or chronic inflammatory polyarthritis. An increase in worldwide prevalence of these arboviruses is largely attributable to international travel, and the increasing range of mosquito vectors due to trade, travel, and climate change. In some cases, these infections may lead to an inflammatory arthritis resembling RA. Nearly all symptomatic infections with chikungunya, Ross River virus, Zika, O’nyong nyong, and Mayaro result in significant arthralgia. Chikungunya infection has been reported in travelers returning to the United States, Europe, and Canada. It should be suspected in patients with inflammatory polyarthritis who have a history of travel to endemic areas.[10] A large-joint polyarthritis associated with Ebola virus disease has been described.[11] Moreover, in a cross-sectional study detailing clinical sequelae among 277 survivors of Ebola virus disease, arthralgias were reported in about 76% of patients (predominantly oligoarthralgia pattern [1-4 joints], with bilateral involvement in most patients).[12]
Immune-mediated
RA typically manifests as morning stiffness and a symmetrically distributed swelling and tenderness of the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints, although other joints can also be affected. Rheumatoid nodules are quite specific for RA but are seen in only about 30% of patients.[13]
Although more common in children, acute rheumatic fever (ARF) also occurs in adults. In a typical patient, the arthritis of rheumatic fever affects several joints in quick succession (migratory arthritis), each joint being involved for no more than a week.[14]
The polyarthritis of systemic lupus erythematosus (SLE), which is rarely deforming (Jaccoud arthropathy), causes moderate pain and stiffness. It is worse in the morning and associated with minimal joint swelling. Tenderness and painful range of motion are present in affected joints, but the joints are not typically hot or swollen (as in RA). Avascular necrosis of the epiphysis of long bones (hips, knees, shoulders) can occur in patients with lupus and antiphospholipid syndrome, and can mimic an inflammatory arthritis of the adjacent joint.[15]
Inflammatory arthritis can also develop in other autoimmune rheumatic diseases such as primary Sjögren syndrome, mixed connective tissue disease, systemic sclerosis (scleroderma), relapsing polychondritis, Behçet disease, Henoch-Schönlein purpura, systemic vasculitides (e.g., granulomatosis with polyangiitis [formerly, Wegener granulomatosis], microscopic polyangiitis, polyarteritis nodosa, and Kawasaki disease), antisynthetase syndrome, and MDA-5 dermatomyositis. Detailed discussion of these conditions is beyond the scope of this review.
Fever of at least 102°F (39°C) with rash, pharyngitis, and polyarthritis involving the wrists, knees, ankles, elbows, PIP joints, and shoulders are features of adult-onset Still disease (AOSD).
Spondyloarthropathy can develop in association with gastrointestinal conditions such as inflammatory bowel disease (Crohn disease and ulcerative colitis), enteric-infection-associated reactive arthritis (Salmonella, Shigella, Yersinia, Campylobacter, and Clostridium difficile), gastric bypass surgery, celiac disease, or Whipple disease. It is sometimes called enteropathic arthritis.
Juvenile-onset spondyloarthropathy causes asymmetric, mostly lower-extremity involvement that begins in boys aged 7 to 16 years. Spondyloarthropathy can also develop without specific characteristics (undifferentiated spondyloarthropathy).
The presence of an inflammatory arthritis, sacroiliitis, and spondylitis in a patient with psoriasis of skin and/or nails makes the diagnosis of psoriatic arthritis likely. Joint-line tenderness and effusions in the affected small and large joints, often in an asymmetric distribution, are typical findings.
Sternoclavicular joint arthritis, vertebral and sacroiliac joint involvement, palmoplantar pustulosis, and acne suggest SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome.
Reactive arthritis follows infection (Chlamydia trachomatis, Chlamydia pneumoniae, or certain gram-negative enteric bacteria such as Salmonella, Shigella, Yersinia, Campylobacter, and Clostridium difficile) and is accompanied by urethritis, conjunctivitis and anterior uveitis, oral ulcers, keratoderma blennorrhagica (yellow-brown vesicopustular waxy lesions on palms and soles that may coalesce to form larger crusty plaques), nail changes similar to psoriasis, and circinate balanitis.
Involvement of the axial joints is an essential feature of ankylosing spondylitis (AS) and helps differentiate this condition from other forms of inflammatory arthritis. Sacroiliac joint tenderness (elicited by direct pressure over the sacroiliac joints), limited spinal mobility, and limited chest expansion are typical findings.
In acute sarcoidosis, polyarthritis, tendinitis, enthesopathy (inflammation of the entheses, the location where a bone has an insertion of a tendon or a ligament), and dactylitis (sausage digit) may manifest.[16]
Juvenile idiopathic arthritis (JIA) is the most common chronic arthropathy of children and includes several subtypes. Polyarticular JIA can progress to adult RA (especially if seropositive), and contrary to what was believed in the past, a substantial percentage of these patients can continue to have active disease as adults. Oligoarticular JIA affects 2 to 4 joints initially and is more common in young girls (toddlers).[17] Diagnosis is made clinically. Laboratory and radiographic testing provide classification and prognostic information, but are not diagnostic. Around 11% to 30% of children with JIA are at risk of developing anterior uveitis (especially if they have positive antinuclear antibodies), which requires regular ophthalmologic examinations to detect and manage.[18][19][20]
Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome presents with acute-onset polyarthritis, with significant pitting edema of the dorsal surfaces of the hands and feet. It is more commonly seen in males, in older patients (≥50 years), and is usually nonerosive. As the name implies, rheumatoid factor is typically negative.[21] RS3PE syndrome could be a form of paraneoplastic arthritis, and an underlying malignancy should be looked for.
In the last few decades, various heritable autoinflammatory syndromes have been recognized both in children and in adults and have raised considerable interest in the scientific community. These conditions include periodic syndromes such as familial Mediterranean fever (FMF); hyper-IgD syndrome (HIDS); tumor necrosis factor receptor-associated periodic syndrome (TRAPS); cryopyrin-associated periodic syndromes (CAPS); Blau syndrome; pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome; periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome, and vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. Inflammatory arthritis can be an important feature in some of these syndromes. Detailed description of these conditions is beyond the scope of this review.[22][23][24]
Various drug classes have been implicated in the induction of an immune-mediated inflammatory arthropathy. Procainamide, hydralazine, minocycline, isoniazid, propylthiouracil, and tumor necrosis factor inhibitors can induce SLE. Serum sickness-like reaction has been seen with oral and parenteral pharmacologic agents, including plasma-derived products and biologics (e.g. infliximab and rituximab). In addition, arthralgia, inflammatory arthritis, and tendinitis have also been associated with the use of aromatase inhibitors, clopidogrel, quinolone antibiotics, and statins. Sitagliptin and saxagliptin (oral hypoglycemics for type 2 diabetes) have been associated with severe, incapacitating polyarthralgia.[25]
Immune-related adverse events, including inflammatory arthritis, have been reported secondary to immune checkpoint inhibitor therapy for cancer.[26][27][28][29] In one retrospective study of 1,293 patients on immune checkpoint inhibitor therapy, 43 had rheumatic immune‐related adverse effects.[30] Clinical syndromes included inflammatory arthritis, myopathy, and other rheumatic syndromes.
Noninfectious and nonimmune-mediated inflammatory arthritis
Osteoarthritis is a degenerative joint disorder. The prevalence increases with age. Although this is predominantly a degenerative rather than an inflammatory process, clinically sometimes it can be difficult to differentiate from the latter, hence its inclusion in the differential diagnosis. The most commonly affected joints are the knee, hip, finger joints (proximal and distal interphalangeal and first carpometacarpal joints), and lumbar and cervical spine. Patients present with joint pain and stiffness that is typically worse with activity. Erosive osteoarthritis, sometimes referred to as inflammatory osteoarthritis, is characterized by a more severe, aggressive type of hand arthritis that may become acutely symptomatic, similar to inflammatory arthritis.
Joint pain and swelling in a patient with a recent history of trauma to the affected joint always raises the possibility of fracture, dislocation, or internal derangement. Occasionally (e.g., with drug overdose, alcohol intoxication, or a history of seizure or concussion), the history of joint injury may not be available; hence, if there is any suspicion of trauma to a joint, immobilization and appropriate imaging studies are necessary to rule out a fracture or other anatomic derangement.
Acute gout is more common in men, often affecting the foot with intense pain localized to the great toe.[31]
Pseudogout involves acute attacks of crystal precipitation of calcium pyrophosphate dihydrate (CPPD) that produce symptoms very similar to those of acute gout. In this case, the typically affected joint is the knee. However, it can also affect the wrist, elbow, shoulder, ankle, metacarpophalangeal joints, and symphysis pubis.[Figure caption and citation for the preceding image starts]: Calcium pyrophosphate dihydrate (CPPD) crystals in synovial fluid under compensated polarized light microscopyFrom the collection of Dr Soumya Chatterjee [Citation ends].
In addition to gout and pseudogout, other crystal-induced arthropathies (such as those associated with deposition of calcium hydroxyapatite, basic calcium phosphate, calcium oxalate, etc.) rarely occur, and can be missed unless specifically considered and investigated.
The hemarthrotic joint is swollen and warm, and has a very painful and restricted range of motion. Superficial bruising and ecchymoses can be seen. Possible underlying causes to consider include fracture of an adjacent bone, a bleeding disorder (e.g., hemophilia A or B, acquired factor VIII inhibitor, or over-anticoagulation), scurvy, or a tenosynovial giant cell tumor (formerly, pigmented villonodular synovitis.
Rare conditions affecting the synovium include tenosynovial giant cell tumor (formerly, pigmented villonodular synovitis, characterized by inflammation and synovial overgrowth due to an unknown trigger) and synovial osteochondromatosis (where multiple osteochondral loose bodies form inside a joint, causing pain, swelling, and repeated episodes of locking).
Fibroblastic rheumatism is a rare disorder characterized by development of an erosive polyarthritis with multiple cutaneous nodules. Skin and synovial biopsy reveal proliferation of myofibroblast-like cells within a background matrix of collagen.[32]
Paraneoplastic
Hypertrophic osteoarthropathy (HOA) is a clinical syndrome of clubbing of the fingers and toes, enlargement of the extremities, and painful, swollen joints. HOA is characterized by symmetric periostitis involving the radius and fibula and, to a lesser extent, the femur, humerus, metacarpals, and metatarsals. The syndrome can be primary or secondary with associated malignancy.
Other paraneoplastic articular syndromes include: palmar fasciitis with polyarthritis syndrome (PFPAS); paraneoplastic arthritis; paraneoplastic RS3PE syndrome; amyloid arthritis (seen in multiple myeloma); pancreatitis, polyarthritis, and panniculitis (PPP) syndrome (occasionally seen in pancreatic cancer); and multicentric reticulohistiocytosis.[21][33][34] Detailed description of these conditions is beyond the scope of this review.
Neoplastic
Lipoma arborescens is a very rare primary benign synovial neoplasm that can involve one or more joints. Involvement of the knees, ankles, hips, shoulders, and elbows has been described.[35]
Synovial sarcoma is a rare malignancy that affects young adults between 20 and 40 years old, with a median age of 35 years at the time of diagnosis. The lower-extremity joints are the most common sites affected. With early diagnosis, a cure can be achieved in those patients with localized disease; however, missed diagnosis can lead to local joint destruction and incurable metastatic disease.
Intra-articular metastasis may be the first manifestation of a malignancy in which the primary source is unknown. A high index of suspicion is necessary in patients with known malignancy. It is difficult to establish the correct diagnosis without synovial fluid cytology and a synovial biopsy.
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