Monoarthritis in adults: Etiology and evaluation

INTRODUCTION — The symptom of joint pain is associated with a variety of disorders. The initial step in evaluating the patient with monarticular pain is confirming that the source of the pain is the joint, rather than the nearby soft tissues. Arthritis is likely when the pain is aggravated by movement, is associated with loss of motion, and is accompanied by swelling and/or erythema. However, deep-seated articulations, such as the shoulder, hip, and sacroiliac joints, may not exhibit the latter two findings. If joint motion is preserved but tenderness can be elicited by palpation over one of the regional bursae, tendons, or ligaments, it is unlikely that the joint pain is due to arthritis. (See "Overview of soft tissue musculoskeletal disorders".)

In addition to a careful history and physical examination, arthrocentesis and synovial fluid analysis is often required in making a definitive diagnosis. The initial evaluation and differential diagnosis of an adult presenting with a single sore joint is presented here (table 1). The approach to a patient with pain in specific joints is addressed elsewhere (see "Approach to the adult with unspecified knee pain" and "Evaluation of the adult with shoulder complaints" and "Evaluation of elbow pain in adults" and "History and examination of the adult with hand pain" and "Approach to the adult with unspecified hip pain"). The evaluation of a child with joint pain is also presented separately. (See "Evaluation of the child with joint pain and/or swelling".)

ETIOLOGY — The major causes of acute monoarticular symptoms include trauma, infection, crystal-induced arthritis, osteoarthritis, systemic rheumatic diseases, and mechanical derangement (table 1) [1-3]. The differential diagnosis of an acute monoarthritis can also overlap with that of polyarthritis since virtually any polyarthritis disorder can initially present as a monoarthritis (table 2). (See "Evaluation of the adult with polyarticular pain".)

Trauma — Trauma sufficient to cause joint pain and swelling is typically recollected by the patient. However, if a loss of consciousness (eg, due to a drug overdose, motor vehicle accident, alcohol ingestion, or concussion) has occurred, the patient may not remember injuring the joint. Thus, if there is a history of joint injury or loss of consciousness, initial immobilization and imaging studies to rule out a fracture or dislocation are appropriately obtained before proceeding with a thorough physical examination of the joint.

Intraarticular fractures, dislocations, ligamentous sprains and complete tears (eg, of the anterior or posterior cruciate ligaments of the knee), and meniscal damage are often associated with hemarthrosis. Intraarticular bleeding may also be related to coagulopathies, anticoagulation therapy, intraarticular tumors, and crystal disease, among other causes. (See "Overview of hemarthrosis".)

Infection

Gonococcal infection — Patients with disseminated gonococcal infection (DGI) typically present with one of two syndromes (table 3):

●A triad of tenosynovitis, vesiculopustular skin lesions (picture 1), and polyarthralgias without purulent arthritis

●Purulent arthritis without associated skin lesions

Diagnosis of this disorder is based upon the history, physical examination, synovial fluid culture, blood cultures, and cultures of any skin lesions, the pharynx, urethra, cervix, or rectum. (See "Disseminated gonococcal infection".)

Nongonococcal bacterial infections — Nongonococcal bacterial arthritis is the most potentially dangerous and destructive form of acute monoarthritis. These infections typically affect large joints such as the hip and knee, although the wrists and ankles are also commonly involved [1]. Staphylococcus aureus is the most common bacterium infecting adult joints, followed by Streptococcus pneumoniae and, less often, Gram-negative organisms (table 4). Patients who are immunocompromised, inject drugs intravenously, have a prosthetic joint, or have underlying conditions such as neoplasia, chronic renal failure, or rheumatoid arthritis are more susceptible to these infections. (See "Septic arthritis in adults".)

Mycobacterial and fungal infection — Mycobacterial species and fungi can produce an indolent, progressive monoarthritis [4]. A high index of suspicion is required to establish these diagnoses; immunocompromised status and travel to endemic areas are the primary risk factors. The diagnosis should also be considered if a patient fails to respond to courses of antibiotic therapy or if synovial fluid cultures fail to identify a causative organism. (See "Bone and joint tuberculosis" and "Candida osteoarticular infections" and "Clinical features and diagnosis of sporotrichosis".)

Arthritis may represent either an articular infection or a sterile extrapulmonary manifestation of either histoplasmosis or coccidioidomycosis (see "Pathogenesis and clinical features of pulmonary histoplasmosis", section on 'Rheumatologic manifestations'). Arthralgia, usually polyarticular, may accompany the panniculitis of erythema nodosum that can occur with pulmonary infection with these fungal organisms and others. (See "Erythema nodosum".)

Lyme disease — Later stages of Lyme disease include the development of a prominent monoarticular synovitis in approximately 10 percent of patients; the knee is most commonly involved. Clinical difficulties that may arise include the lack of history of a tick bite or an antecedent skin rash. Culture of the synovial fluid or tissue is routinely negative; confirmation of the diagnosis requires serologic testing. (See "Diagnosis of Lyme disease".)

Crystal-induced arthritis — At least 80 percent of initial attacks of acute gout involve a single joint, typically in the lower extremity, most often at the base of the great toe (first metatarsophalangeal joint, known as podagra), at the midfoot, in the ankle, or in the knee. However, the fingers, elbows, and wrists may become inflamed and cause diagnostic confusion.

The typical attack is intensely inflammatory, and is characterized by severe pain, redness, swelling, and disability. The maximal severity of the attack is usually reached over several hours. Complete resolution of the earliest attacks almost inevitably occurs within a few days to weeks, even in untreated individuals. The signs of inflammation associated with acute gout often extend beyond the confines of the joint that is primarily involved and, in the foot or ankles, may give the impression of arthritis in several contiguous joints, of tenosynovitis, or cellulitis. Involvement in an ankle or instep or in a wrist, finger, or olecranon bursa more commonly occurs in a recurrent episode of a gout flare. (See "Clinical manifestations and diagnosis of gout".)

The knee is the most common joint involved in patients with calcium pyrophosphate dihydrate (CPPD) crystals (pseudogout). The wrist, shoulder, ankle, and occasionally smaller joints may also be targets, and bilateral wrist involvement is common in older patients [1]. (See "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease".)

Systemic disorders — Several systemic disorders may present with an acute monoarthritis:

●Seronegative spondyloarthritis (eg, reactive arthritis, psoriatic arthritis, inflammatory bowel disease-associated arthritis) can present as a monoarthritis, typically involving the lower-extremity joints. The effusion may be quite large when the knee is affected, while toe joint involvement can appear as a "sausage" swelling due to the periosteal bone involvement; the latter finding can distinguish these disorders from rheumatoid arthritis (picture 2). (See "Reactive arthritis" and "Clinical manifestations and diagnosis of peripheral spondyloarthritis in adults" and "Clinical manifestations and diagnosis of psoriatic arthritis".)

●Sarcoid periarthritis typically presents with pain and swelling around the ankle joints; erythema nodosum over the distal tibial region may be a helpful clue. (See "Sarcoid arthropathy".)

●Rheumatoid arthritis can occasionally present as a monoarthritis in its earliest stages. (See "Clinical manifestations of rheumatoid arthritis".)

●Myelodysplastic and leukemic disorders may cause arthralgia or an acute arthritis. (See "Malignancy and rheumatic disorders", section on 'Leukemia' and "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Autoimmune/inflammatory conditions'.)

Osteoarthritis — Osteoarthritis of a single joint, although usually associated with mild symptoms and a relatively noninflammatory synovial fluid (white blood cell [WBC] <2,000 cells/mm³), can present as an acutely painful synovitis which may mimic infection [5]. (See "Clinical manifestations and diagnosis of osteoarthritis".)

Neoplasms — Juxtaarticular benign and malignant neoplasms or, less often, tumors in the synovium or other soft tissues of the joint may cause monoarticular pain. (See "Radiologic evaluation of knee tumors in adults", section on 'Intraarticular tumors and tumor-like lesions' and "Radiologic evaluation of knee tumors in adults", section on 'Juxtaarticular bone or soft tissue tumor' and "Bone tumors: Diagnosis and biopsy techniques" and "Treatment for tenosynovial giant cell tumor and other benign neoplasms affecting soft tissue and bone", section on 'Desmoplastic fibroma of bone' and "Treatment for tenosynovial giant cell tumor and other benign neoplasms affecting soft tissue and bone", section on 'Tenosynovial giant cell tumor'.)

Plant thorn synovitis — Plant thorn synovitis is a foreign-body granulomatous inflammation that is caused by direct subcutaneous inoculation of plant material. The most common plants reported include rose thorn, black thorn, and date palms. Following initial penetration of the thorn, there may be a mild synovitis that may subside. Over time, the symptoms of pain, stiffness, and joint warmth may bring the patient to medical attention. A high degree of suspicion is required since imaging studies fail to identify the plant thorn [6].

EVALUATION — The history and physical examination often provide sufficient information to eliminate many disorders in the differential diagnosis (table 1).

History — Specific symptoms and/or patient characteristics help narrow the underlying possible causes of monoarticular pain (table 1).

Symptoms suggestive of a musculoskeletal emergency — The evaluation of monoarticular pain begins by ruling out potential musculoskeletal emergencies. These conditions generally have an acute presentation and are important to identify since failure to make the correct diagnosis could lead to permanent harm to the patient. Important historical points include the following [7]:

●Hot or swollen joints may suggest infection. (See "Septic arthritis in adults".)

●Constitutional symptoms (high-grade fever, weight loss, malaise) also raise the suspicion of infection or sepsis.

●Weakness may be a symptom of a compartment syndrome or an acute myelopathy. However, lack of strength can also be due to pain in the joint or periarticular tissues or myopathy.

●Burning pain, numbness, or paresthesia may suggest an acute myelopathy, radiculopathy, or neuropathy.

Joint symptoms — It is important to obtain a detailed history of the character of the joint pain, including pain quality, time of onset, exacerbating or remitting factors, severity, and duration.

●In most forms of systemic inflammatory arthritis, symptoms may worsen with immobility ("morning stiffness"). However, morning stiffness lasting more than one hour reflects a severity of joint inflammation which rarely occurs in diseases other than rheumatoid arthritis or polymyalgia rheumatica.

●By contrast, the pain of osteoarthritis is usually aggravated by motion and weightbearing and is lessened by rest.

●A history of prior joint pain or swelling (single or multiple, symmetric or asymmetric, migratory or additive, small or large joints) should be ascertained.

●Pain that has been present for weeks is less likely to be acute gout or bacterial arthritis but could be chronic tophaceous gout, a mycobacterial or fungal arthritis, or a spondyloarthritis.

●Antecedent trauma may point towards a fracture, meniscal tear, or hemarthrosis.

Systemic symptoms — The presence of extraarticular symptoms may help to limit the differential diagnosis:

●Signs and symptoms of multisystem involvement (fatigue, rash, adenopathy, alopecia, oral and nasal ulcers, pleuritic chest pain, Raynaud phenomenon, or dry eyes and mouth) are often observed in patients with systemic rheumatic diseases.

●High-grade fever suggests infection, although low-grade elevation in body temperature may accompany crystal-induced arthritis as well as many systemic rheumatic diseases.

●Gastrointestinal or genitourinary complaints and recent sexual exposures suggest possible infectious portals of entry or may be associated with a seronegative spondyloarthritis (eg, reactive arthritis, psoriasis, or inflammatory bowel disease).

Patient characteristics — Specific patient characteristics should also be considered when narrowing the differential diagnosis.

●A family history of some systemic rheumatic diseases (eg, psoriatic arthritis) may predispose the patient to the same conditions.

●A history of immunosuppression, either due to underlying disease or medical therapy, may predispose the patient to unusual infectious agents. (See "Septic arthritis in adults".)

●Recent travel to endemic regions (eg, the Northeastern United States for Lyme disease, resource-limited countries for mycobacterial and parasitic infections) may suggest a specific pathogen.

Physical examination — The most important objective of the physical examination in a patient with monoarticular pain is to establish the presence or absence of an effusion or synovitis [7]. Detecting an effusion or synovitis limits the differential to the inflammatory arthritides (including infection) and systemic rheumatic diseases. The hallmarks of synovitis include:

●Soft tissue swelling

●Warmth over a joint

●Joint effusion

Assessing range of motion of the joint is also important. Reduced active range of motion with preserved passive range of motion suggests soft tissue disorders such as bursitis, tendinitis, or muscle injury (see "Overview of soft tissue musculoskeletal disorders"). If, on the other hand, both active and passive ranges of motion are decreased, then soft tissue contracture, synovitis, and a structural abnormality of the joint are more likely [7].

Some extraarticular findings may suggest a specific disease process:

●A search for subcutaneous nodules may reveal rheumatoid nodules (picture 3) or tophi (picture 4) suggestive of rheumatoid arthritis or gout, respectively. Erythema nodosum (picture 5), particularly over the shins, may herald an ankle periarthritis that can be seen in some patients with sarcoidosis.

●Particular attention should be given to the skin since some disorders are associated with characteristic rashes (eg, psoriasis, systemic lupus erythematosus, viral exanthems, and adult-onset Still's disease).

●Eye involvement is a feature of some rheumatic illnesses (eg, keratoconjunctivitis sicca, uveitis, conjunctivitis, and episcleritis).

Imaging studies

Radiographs — Patients with a history of significant trauma or focal bone pain should have radiographs to rule out a fracture, tumor, or osteonecrosis [5]. Radiographs may also confirm the presence of a joint effusion, particularly in joints such as the elbow, ankle, and hip, where they may be difficult to ascertain on physical examination. Chondrocalcinosis, tophaceous erosions, or joint space narrowing may also be visible. Soft tissue calcification (or calcific tendonitis) may be noted adjacent to affected joints. (See "Imaging techniques for evaluation of the painful joint", section on 'Radiography' and "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease".)

Ultrasonography — Musculoskeletal ultrasound provides a simple technique for the detection of joint effusions, and is more sensitive than physical examination in the detection of synovitis [8,9]. It can also be used to guide joint aspirations and injections. (See "Musculoskeletal ultrasonography: Clinical applications" and "Musculoskeletal ultrasonography: Guided injection and aspiration of joints and related structures".)

Computed tomography — Computed tomography (CT) should be reserved for the evaluation and proper needle placement for joint aspiration of difficult-to-access areas such as the hip, sacroiliac, or sternoclavicular joints. (See "Imaging techniques for evaluation of the painful joint", section on 'Computed tomography'.)

Magnetic resonance imaging — Magnetic resonance imaging (MRI) is useful for diagnosing effusions in deep-seated joints such as the hips and shoulders, which may be difficult to detect on physical examination. MRI can also be used to distinguish synovitis from ligamentous or other soft tissue injuries or abnormalities. (See "Imaging techniques for evaluation of the painful joint", section on 'Magnetic resonance imaging'.)

Joint aspiration — Arthrocentesis with synovial fluid analysis should be attempted in all patients with joint pain of unknown cause who have an effusion or have signs suggestive of inflammation within the joint [10]. (See "Joint aspiration or injection in adults: Technique and indications".)

The main purpose of synovial fluid analysis is to narrow the differential diagnosis by categorizing the effusion as noninflammatory, inflammatory, hemorrhagic, or septic (table 5). Analysis of the joint fluid should include the following (see "Synovial fluid analysis", section on 'Routine components of synovial fluid analysis'):

●Gross appearance – The volume, clarity, color and viscosity of the joint fluid should be noted. As examples, xanthochromia is suggestive of a recent hemorrhage due to a fracture or other trauma, or a coagulopathy; clear fluid may be normal or relatively noninflammatory; cloudy fluid may be suggestive of inflammatory or septic fluid. (See "Synovial fluid analysis", section on 'Gross appearance'.)

●Crystal analysis – Examination of synovial fluid for monosodium urate crystals (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals with a polarizing microscope should be done to evaluate for gout and pseudogout, respectively. (See "Synovial fluid analysis", section on 'Routine components of synovial fluid analysis'.)

●Nucleated (white) cell count and differential – In normal synovial fluid or in noninflammatory joint effusions, polymorphonuclear (PMN) leukocytes represent a small proportion of the nucleated cells present. Noninflammatory fluids generally have fewer than 2,000 white blood cells/mm³, with fewer than 75 percent PMN leukocytes [11]. Inflammatory and septic fluids have increasing proportions of PMNs present. (See "Synovial fluid analysis", section on 'Nucleated (white) cell count and differential'.)

●Gram stain and culture – If there is a clinical suspicion of joint infection, gram stain and culture of synovial fluid should be requested. Unless there are clinical features that suggest gonococcal, mycobacterial, or fungal infection, routine bacterial culture for aerobic and anaerobic bacteria are generally appropriate. If gonococcal infection is suspected, the microbiology laboratory should be informed so that the appropriate media can be used to improve the yield. (See "Synovial fluid analysis", section on 'Gram stain' and "Microbiology specimen collection and transport" and "Synovial fluid analysis", section on 'Routine components of synovial fluid analysis'.)

Chemistry studies of synovial fluid such as the concentrations of glucose, lactate dehydrogenase, or protein have only limited value; a reduction in glucose concentration and elevation in lactate dehydrogenase (LDH) level are consistent with bacterial infection but are not sufficiently sensitive (table 5). Complement levels and immune complex analysis of synovial fluid are also of limited use and are not generally recommended for diagnostic purposes [11]. (See "Synovial fluid analysis".)

Interpretation of synovial fluid analysis — After a careful history and physical examination of the patient with monoarthritis, the results of the synovial fluid analysis can be interpreted as follows (algorithm 1):

●For hemorrhagic effusions, the clinician should consider trauma, mechanical derangement, or a coagulopathy as possible etiologies.

●Non-hemorrhagic effusions should be classified as either inflammatory or noninflammatory (table 6).

•Synovial fluid with a nucleated (white) cell count <2,000 white blood cells/mm³ is noninflammatory. Examples of conditions associated with noninflammatory synovial fluid include osteoarthritis, avascular necrosis, or a meniscal tear.

•Synovial fluid with a nucleated cell count ≥2,000 white blood cells/mm³ is considered inflammatory. A wide range of conditions are associated with inflammatory synovial fluid such as septic arthritis, crystal-induced arthritis, or a spondyloarthritis. The range of nucleated (white) cell counts that can be observed with each of these conditions overlap considerably [12]. However, the higher the leukocyte count (eg, >10,000/mm³) and the greater the proportion of PMN leukocytes (eg, >90 percent) in the differential, the higher is the likelihood of septic arthritis. (See "Synovial fluid analysis", section on 'Nucleated (white) cell count and differential'.)

●Inflammatory synovial fluid should also be evaluated for crystals (monosodium urate crystals and CPPD crystals) with a polarizing microscope. In cases of suspected septic arthritis, the fluid should also be sent for gram stain and culture as the presence of crystals does not exclude infection.

Laboratory studies — Laboratory studies in addition to imaging studies and synovial fluid analysis should be considered in certain circumstances [7]. The patient with bloody synovial fluid and no evidence of trauma, for example, should have a prothrombin (PT), partial tissue thromboplastin time (PTT), platelet count, and bleeding time. The patient with inflammatory joint fluid should have blood cultures and, in the sexually active patient, cultures of any skin lesions, the pharynx, urethra, cervix, or rectum as appropriate to assess for gonococcal infection. (See "Disseminated gonococcal infection".)

In addition, more extensive laboratory studies should be considered in those with sterile but inflammatory joint fluid (without crystals), including the following:

●The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentration are nonspecific indicators of inflammation; they tend to be elevated in the presence of infection, inflammatory states, and malignancy. These tests may be most useful in patients with an equivocal joint examination; in this setting, an elevated ESR or CRP makes an inflammatory arthritis more likely. (See "Acute phase reactants".)

●The antinuclear antibody (ANA) test has high sensitivity but low specificity for systemic lupus erythematosus (SLE). Thus, it may be appropriate to order an ANA, since a negative test essentially rules out a diagnosis of SLE. On the other hand, a positive ANA may occur in the absence of disease and may occur in many rheumatic and non-rheumatic illnesses; therefore, a patient with few or no clinical features of SLE is unlikely to have the disease, even in the presence of a positive ANA. (See "Measurement and clinical significance of antinuclear antibodies".)

●A serum rheumatoid factor (RF) and anticyclic citrullinated peptide (CCP) antibodies should be ordered when there is at least a moderate suspicion of rheumatoid arthritis; however, these tests must be interpreted in clinical context, particularly in the setting of a monoarthritis.

●Routine tests such as a complete blood count and liver function tests should be considered if a multisystem disease is suspected based upon the history and physical examination.

●Other tests such as human leukocyte antigen (HLA)-B27 and Lyme serologies should be ordered only when the clinical suspicion is high for a spondyloarthritis or Lyme infection, respectively.

Synovial biopsy — In rare instances, the correct diagnosis in a patient with monoarticular arthritis will depend upon a tissue biopsy. Indications for synovial biopsy include refractory monoarthritis, a high degree of suspicion for atypical infectious agents, or evaluation for intraarticular tumors. As an example, synovial biopsy may be useful in the diagnosis of a mycobacterial or fungal infection, or sarcoidosis.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Arthritis (Beyond the Basics)")

SUMMARY

●Causes of monoarthritis – Major causes of monoarthritis include osteoarthritis, Lyme disease, some systemic rheumatic diseases, infection, trauma, and internal derangement (table 1). The differential diagnosis of an acute monoarthritis can also overlap with that of polyarthritis since virtually any polyarthritis disorder can initially present as a monoarthritis (table 2). (See 'Etiology' above.)

●History and physical examination – The evaluation of the patient should begin with a detailed history and physical examination to help narrow the underlying possible causes of monoarticular pain. The most important objective of the physical examination is to establish the presence or absence of an effusion or synovitis. (See 'History' above and 'Physical examination' above.)

●Imaging – Patients with a history of significant trauma or focal bone pain should have plain radiographs of the affected joint to evaluate for fracture or tumor. (See 'Radiographs' above.)

●Joint aspiration – When an effusion or synovitis is present on physical examination and the cause is uncertain, an arthrocentesis with synovial fluid analysis (algorithm 1) should be strongly considered. The main purpose of the synovial fluid analysis is to narrow the differential diagnosis by categorizing the effusion as noninflammatory, inflammatory, hemorrhagic, or septic. (See 'Joint aspiration' above.)

•Interpretation of synovial fluid analysis – For hemorrhagic effusions, the clinician should consider trauma, mechanical derangement, or a coagulopathy as possible etiologies. The patient with hemorrhagic synovial fluid and no evidence of trauma should have a prothrombin (PT), partial tissue thromboplastin time (PTT), platelet count, and bleeding time. (See 'Interpretation of synovial fluid analysis' above.)

Non-hemorrhagic effusions should be classified as either inflammatory or noninflammatory. Inflammatory synovial fluid (eg, >2,000 white cells/mm³) should also be evaluated for crystals (monosodium urate crystals and calcium pyrophosphate dihydrate [CPPD] crystals) with a polarizing microscope to rule out crystal-induced arthritis. In cases of suspected septic arthritis, the fluid should also be sent for gram stain and culture, as the presence of crystals does not exclude infection. (See 'Interpretation of synovial fluid analysis' above.)

●Laboratory studies – A sterile inflammatory joint fluid that is also without crystals raises the suspicion of systemic rheumatic diseases; such patients should have further evaluation that may include a complete blood count, liver function tests, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), rheumatoid factor (RF), anticyclic citrullinated peptide (CCP), human leukocyte antigen (HLA)-B27 antibodies, antinuclear antibodies (ANA), or Lyme serologies. (See 'Laboratory studies' above.)