Polyarticular Arthritis

Etiology

Osteoarthritis and fibromyalgia represent the most frequent causes of noninflammatory polyarticular arthritis and joint pain, particularly among older adults. These conditions often present with chronic symptoms and can significantly impact mobility and quality of life, although they lack the systemic inflammatory features seen in other arthritic conditions.

Inflammatory arthritis arises from a broad spectrum of underlying disorders, including:

• Bacterial etiologies (eg, Lyme disease, endocarditis, septic arthritis, disseminated gonococcal infection) [2]
• Viral etiologies(eg, hepatitis B and C, Epstein-Barr virus, parvovirus, dengue, alphaviruses, rubella, human immunodeficiency virus, mumps, coxsackievirus, Chikungunya) 
• Inflammatory arthritis (eg, rheumatoid arthritis, seronegative spondyloarthritis, reactive arthritis, psoriatic arthritis, ankylosing spondylitis, inflammatory bowel disease (IBD)-associated arthritis, juvenile idiopathic arthritis)
• Connective tissue diseases (eg, lupus, Sjögren syndrome, vasculitis, systemic sclerosis, dermatomyositis, Behcet syndrome, and relapsing polychondritis)
• Crystal-induced arthritis (eg, gout and calcium pyrophosphate deposition disease)
• Autoinflammatory diseases (eg, Still disease, familial Mediterranean fever)

 Each of these conditions follows a distinct etiopathogenic mechanism, which guides diagnosis and management.

Epidemiology

Data published by the Arthritis Foundation in 2015 suggests over 100 types of arthritis. Approximately 91.2 million adults either have a physician-diagnosed case of arthritis or report joint symptoms consistent with a diagnosis of arthritis.[3] From 2019 to 2021, approximately 53.2 million, or 21.2%, of US adults aged 18 and older had been diagnosed with arthritis.[4] After the age of 65, half of men and two-thirds of women have arthritis. Moreover, the incidence is rising, and others estimate that by 2040, almost half the population will have physician-confirmed arthritis.[5] Aging and obesity serve as risk factors for developing osteoarthritis and contribute to the rising rates of osteoarthritis.[6] One estimate put the total costs related to arthritis (eg, medical care, earning losses, and lost time) at 1% of the US gross domestic product ($304 billion) for the fiscal year 2013.[7] Among people with arthritis, 33% have depression or anxiety, 25% have cardiac problems, 20% have respiratory conditions, and 16% have diabetes. 

Pathophysiology

The pathophysiology of polyarticular arthritis depends on the underlying cause. A discussion for each etiology is beyond the scope of this review.

For the most common cause of polyarticular arthritis, osteoarthritis, several mechanisms play an important role.[8] The concept of "wear and tear" is outdated in the context of osteoarthritis, although the aging process undoubtedly contributes to its development. Instead, degradation of the extracellular matrix followed by bone remodeling leads to progressive joint damage and structural failure. Localized inflammation affecting the synovium leads to the production of cytokines, chemokines, and enzymes, which are pathologic to the joint tissue. Fibrosis of the synovial tissue contributes to joint stiffness and pain from osteoarthritis.[8]

For the other most common cause of polyarticular pain, fibromyalgia, the underlying etiology is from disordered pain regulation and central sensitization. Genetic, environmental, hormonal, and neurological mechanisms are factors also associated with fibromyalgia. Most compelling, however, is that patients with fibromyalgia have abnormal pain processing, and an imbalance between neurotransmitters that signal pain (eg, substance P) compared with those that modulate pain (eg, serotonin and endogenous opioids).[9]

The pathophysiology of inflammatory arthritis can be infectious, crystal-induced, reactive, or autoimmune in nature. Gout is the most common crystal-induced arthropathy. Hyperuricemia is the leading cause of gout, resulting from either overproduction or underexcretion of urate. Monosodium urate (MSU) crystals form in patients with gout, and intra-articular deposits of MSU crystals can trigger an acute gout flare when an MSU crystal interacts with a macrophage, prompting the NLRP3 inflammasome. The inflammasome leads to the influx of neutrophils and pro-inflammatory cytokines, promoting the marked inflammatory response characteristic of a gout flare.[10]

Rheumatoid arthritis is the most common inflammatory arthritis mediated through autoimmunity. Antibodies to anti-cyclic citrullinated peptide (CCP) and rheumatoid factor form immune complexes that bind complement, leading to inflammation and tissue damage.[11] Synovial inflammation is the hallmark of this disease, with B cells, dendritic cells, monocytes, mast cells, innate lymphoid cells, and T cells all being found within the tissue. Cytokines and chemokines released by these cells promote the recruitment of additional inflammatory cells, resulting in synovial tissue hypertrophy, osteoclast activation, and subsequent bony erosions. Cartilage is degraded by matrix metalloproteinases, leading to progressive joint damage.[11]

History and Physical

Clinical Presentation

Differentiating arthralgia from myalgia is the first step in the evaluation. Myalgia typically represents generalized muscle aches throughout the musculature. It may be poorly localized to the joints proper. Myalgias are discussed separately but tend to be caused by viral illnesses (eg, influenza), systemic infection, eg, endocarditis, certain medications (eg, statins, aromatase inhibitors), fibromyalgia, metabolic disease (eg, mitochondrial disorders), severe vitamin D deficiency (osteomalacia), hypothyroidism, and associated with underlying inflammatory arthritis or connective tissue disease (eg, systemic lupus erythematosus, rheumatoid arthritis).

Arthralgia is defined as joint pain. Further differentiating arthralgia as true joint versus periarticular process (eg, tendon, bursa, ligament-associated) is also important, especially for focal symptoms. Polyarticular arthralgia, in general, tends to involve the true joint in most cases.

Clinical presentations of polyarticular pain are best evaluated using a framework to assess clinical features of timing, pattern of pain or stiffness, location, and associated symptoms. 

Timing

Joint pain can be categorized based on duration into acute and chronic forms. Acute joint pain develops abruptly and typically persists from a few hours to several weeks. Common causes include trauma, infections, eg, septic arthritis and tenosynovitis, viral illnesses like influenza, post-infectious arthritis resulting from parvovirus or poststreptococcal reactions, rheumatic fever, and crystal-induced conditions like gout and calcium pyrophosphate deposition disease.

Chronic joint pain, by contrast, involves symptoms that extend beyond 3 months. This form often results from conditions, including osteoarthritis, various types of inflammatory arthritis (eg, rheumatoid arthritis, seronegative spondyloarthritis, psoriatic arthritis, ankylosing spondylitis, reactive arthritis, and inflammatory bowel disease-associated arthritis), as well as connective tissue diseases (eg, systemic lupus erythematosus, Sjögren syndrome, scleroderma, and dermatomyositis).

Pattern of pain or stiffness

Pain patterns and the timing of stiffness can offer important diagnostic clues. Articular joint pain with an inflammatory origin frequently presents with stiffness following periods of rest or immobility. Patients commonly report morning stiffness lasting 1 to 3 hours, which gradually improves with physical activity and continued movement.

In contrast, noninflammatory joint pain typically worsens with movement and improves with rest. Osteoarthritis and fibromyalgia account for most cases of chronic noninflammatory polyarticular pain, with symptoms often reflecting mechanical stress and muscle involvement rather than synovial inflammation.

Location

Evaluating the symmetry and number of joints involved provides valuable diagnostic insight. Pauciarticular arthritis typically affects 2 to 3 joints and often stems from conditions, eg, osteoarthritis, crystal-induced arthritis, seronegative spondyloarthritis, reactive arthritis, psoriatic arthritis, and arthritis associated with IBD. In contrast, polyarticular arthritis involves 3 or more joints and can arise from a broader range of etiologies, including osteoarthritis, rheumatoid arthritis, psoriatic arthritis, reactive arthritis, IBD-associated arthritis, systemic lupus erythematosus (SLE), scleroderma, dermatomyositis, and Sjögren syndrome.

Pain in the lower back accompanied by prolonged morning stiffness warrants evaluation for inflammatory back disease, which may reflect conditions, eg, ankylosing spondylitis or other axial spondyloarthropathies.

Associated symptoms

The presence of systemic symptoms, eg, fever, weight loss, fatigue, and malaise, often indicates an underlying systemic inflammatory arthritis, connective tissue disease, infection, or malignancy. Dermatologic findings can further support specific diagnoses; for example, skin rashes may indicate conditions, eg, psoriasis, systemic lupus erythematosus, dermatomyositis, or sarcoidosis. Alopecia commonly appears in association with SLE and may serve as an additional diagnostic clue. Many connective tissue diseases also present with evidence of cardiopulmonary, renal, or neurologic involvement, reinforcing the need for a thorough systemic evaluation.

Physical Examination

A thorough physical examination serves to distinguish articular from extraarticular sources of pain, determine the number and distribution of affected joints, and, most importantly, evaluate for signs of inflammation. Careful inspection and palpation of each joint, along with assessment of range of motion, provide essential diagnostic clues.

Assessment of both active and passive range of motion (ROM) helps differentiate between articular and periarticular causes of pain. When pain occurs during active ROM but not during passive ROM, a tendon or bursa disorder becomes more likely. Palpation further refines the diagnosis: bursitis typically presents with a localized tender area that remains unchanged with movement, while tendinitis causes tenderness that worsens with joint motion. Articular diseases typically produce both reduced active and passive ROM.[12]  Each joint should be evaluated for swelling, warmth, and erythema—classic signs of inflammation. Swelling combined with joint line tenderness strongly suggests synovitis, a defining feature of inflammatory arthritis.

Bony enlargement and tenderness within the joints often indicate osteoarthritis. The presence of crepitus during both passive and active ROM reflects damage to the articular cartilage. When systemic inflammatory or connective tissue disease is suspected, a comprehensive physical examination should be conducted to identify subtle clinical findings, eg, rashes, oral ulcers, or organ involvement, that may support a specific diagnosis.

Evaluation

Laboratory Studies

The laboratory evaluation of polyarthritis can be extensive. A thorough history and physical exam are necessary to guide appropriate test selection, as not all of the following tests should be ordered for every patient presenting with polyarticular pain. 

In general, a complete blood count (CBC) and comprehensive metabolic panel (CMP) will help identify the presence of any systemic disorders contributing to the presentation. The clinical assessment should guide the selection of other tests and may include a urinalysis to screen for occult renal disease, thyroid-stimulating hormone (TSH) levels, serum 25-OH vitamin D levels, and viral serologies, eg, hepatitis B, hepatitis C, HIV, and parvovirus. A serum uric acid level may help support a diagnosis of gout, but it can be falsely low during a flare.

Testing for specific inflammatory arthritis or connective tissue disease is aided by the presence of laboratory assessment (see Table 1. Laboratory Tests for Inflammatory Arthritis or Connective Tissue Disease).

Table 1. Laboratory Tests for Inflammatory Arthritis or Connective Tissue Disease

Erythrocyte sedimentation rate and C-reactive protein are nonspecific markers of inflammation. However, they are usually helpful in excluding pathologies that cause significant inflammation and in monitoring treatment response.[21] The laboratory evaluation can also be used to test for other infections, including Lyme disease, bacterial infections with blood cultures, or other serologic viral testing if supported by clinical evaluation. 

Synovial fluid analysis

For patients with swollen joints and a clear effusion, a synovial fluid aspirate may help narrow the differential diagnosis. Synovial fluid should be sent for cell count, gram stain, cultures, and crystal analysis. Synovial fluid leukocyte counts <200/mm is considered a normal finding, between 200/mm and 2000/mm is associated with noninflammatory arthritis, and a finding of >2000/mm indicates inflammatory arthritis. Physicians should treat the fluid as infectious (septic) if the cell count is >50,000/mm.[22]

Imaging Studies 

Imaging of joints may not be necessary if the exam reveals clear signs of osteoarthritis (bony enlargement, crepitus, and swelling) or inflammatory arthritis (synovitis or swollen, tender joints). 

X-ray imaging can reveal fractures, unexpected bony lesions, and advanced arthritic changes. In osteoarthritis, x-ray imaging will show sclerosis, joint space narrowing, and osteophyte formation. Inflammatory arthritis, such as rheumatoid arthritis, psoriatic arthritis, or gout, will not show any specific x-ray features if the disease is early in its course. Late findings for inflammatory arthritis include marginal erosions, severe joint space narrowing, cystic changes, and ankylosis of joints. X-rays can also be used to monitor response to treatment in some cases.

In cases where more clarity is needed to determine whether an inflammatory process is occurring, musculoskeletal ultrasound (MSUS) is a frequently used modality for identifying and localizing the source of inflammation.[23] MSUS can identify synovitis, tenosynovitis, effusions, enthesitis, and bony erosions, and help differentiate noninflammatory from inflammatory pain that is not evident by examination. The advantages of MSUS include its easy accessibility, low cost, and sensitivity; however, technique and interpretation remain operator-dependent. Magnetic resonance imaging (MRI) is also used to differentiate inflammatory features in the soft tissue structures of joints; however, it remains a costly procedure.

Treatment / Management

Polyarticular Arthritis Management

The management of polyarticular arthritis depends largely on the underlying etiology. In cases of osteoarthritis, general treatment strategies focus on reducing mechanical stress and preserving joint function. Recommended interventions include weight loss, minimizing joint overuse, applying heat for symptomatic relief, and engaging in range-of-motion and strengthening exercises. Nonsteroidal anti-inflammatory drugs (NSAIDs), administered either orally or topically, offer symptomatic relief, while corticosteroid injections may help control localized inflammation. Joint replacement surgery often becomes necessary for larger, weight-bearing joints when conservative measures fail to maintain adequate function or relieve pain.

Inflammatory arthritis requires a different approach, centered on disease-modifying antirheumatic drugs (DMARDs). These include traditional oral agents, eg, methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine—as well as biologic therapies. Early initiation of aggressive DMARD therapy helps prevent irreversible joint damage and preserve long-term function. Biologic DMARDs used in rheumatoid arthritis management include tumor necrosis factor (TNF) inhibitors like etanercept, adalimumab, certolizumab, golimumab, and infliximab. Additional agents, eg, the interleukin-6 (IL-6) inhibitors tocilizumab and sarilumab, the CTLA-4 inhibitor abatacept, and the anti-CD20 monoclonal antibody rituximab, also play a vital role in managing disease progression. For seronegative spondyloarthropathies, including ankylosing spondylitis and psoriatic arthritis, anti-IL-23 and anti-IL-17 antibodies are commonly used, in addition to TNF inhibitors, to control inflammation and improve symptoms.

Gout management focuses on controlling uric acid levels through urate-lowering therapies. Common medications include allopurinol, febuxostat, probenecid, and pegloticase, which help prevent recurrent attacks and long-term joint damage by reducing serum urate concentrations.

Differential Diagnosis

The differential diagnosis for polyarticular arthritis and pain is broad, including:

• Degenerative
  • Osteoarthritis
• Fibromyalgia
• Bacterial
  • Lyme disease
  • Septic arthritis
  • Disseminated gonococcal infection
• Viral
  • Hepatitis B
  • Hepatitis C
  • Epstein-Barr virus
  • Parvovirus
  • Chikungunya
  • HIV
• Inflammatory arthritis
  • Rheumatoid arthritis
  • Seronegative spondyloarthritis
  • Reactive arthritis
  • Psoriatic arthritis
  • Ankylosing spondylitis
  • IBD-associated arthritis
  • Juvenile idiopathic arthritis
  • Polymyalgia rheumatica
• Connective tissue disease
  • SLE
  • Sjogren syndrome
  • Vasculitis
  • Systemic sclerosis
  • Dermatomyositis
  • Behcet syndrome
  • Relapsing polychondritis
• Crystal-induced arthritis
  • Gout
  • Calcium pyrophosphate deposition disease
• Autoinflammatory disease
  • Still disease
  • Familial Mediterranean fever
• Malignancy

Prognosis

The prognosis of polyarticular arthritis varies widely depending on the underlying cause, the timeliness of diagnosis, and the appropriateness of treatment, as well as the duration of symptoms, age at onset, presence of obesity, the number of joints involved, lower limb involvement, and severity of inflammation. Noninflammatory and self-limiting causes, such as viral arthritis or soft tissue conditions, generally have a favorable prognosis and often resolve without long-term effects.

In contrast, chronic inflammatory conditions like rheumatoid arthritis or systemic lupus erythematosus can lead to joint destruction, functional impairment, and systemic complications if not promptly and effectively treated. Early recognition, guided by detailed clinical evaluation, and the use of targeted therapies—including biologics for autoimmune diseases—can significantly improve outcomes and help prevent permanent joint and organ damage.