Inflammatory Arthritis

Etiology

Etiologies of inflammatory arthritis include:

Infectious or septic arthritis: Organisms causing infectious arthritis include Staphylococcus aureus, Streptococcal pneumoniae, Neisseria gonorrhea, anaerobic bacteria, mycobacteria species, brucellosis, Borrelia burgdorferi, sporotrichosis, coccidioidomycosis, viruses (Parvovirus, Enterovirus, and Rubella). Septic arthritis is usually monomicrobial. Polymicrobial infections are usually less common and occur in the setting of penetrating trauma involving joint space. Septic arthritis due to gram-negative bacteria is usually observed in the setting of trauma or intravenous drug abuse.[3][4]

Crystalline arthritis: Crystal-induced arthritis includes gout, pseudogout, and basic calcium phosphate (BCP) disease. Hyperuricemia leading to deposition of monosodium urate crystals in the joint space causes gout. Hyperuricemia is a predisposing factor of gout, although 80% of the hyperuricemic individuals never develop gout. Hyperuricemia can be caused by primary or secondary overproduction or underexcretion of uric acid, an end product of purine metabolism. Pseudogout is caused by synovial inflammation caused by deposited calcium pyrophosphate crystals in the cartilage. Most of the cases of calcium pyrophosphate deposition (CPPD) are idiopathic, but disorders of calcium, phosphorus, or magnesium metabolism, familial chondrocalcinosis, and hemochromatosis can be associated with the illness. Basic calcium phosphate disease is rare and can be seen in association with hypothyroidism and diabetes mellitus. 

Autoimmune inflammatory arthritis: This is a broad category that can be further divided into several categories:

• Rheumatoid arthritis - seropositive or seronegative.
• Juvenile idiopathic arthritis.
• Seronegative spondyloarthritis - This family of HLA-B27 associated arthropathies includes psoriatic arthritis, ankylosing spondylitis, reactive arthritis, arthritis associated with inflammatory bowel disease, and non-radiographic spondyloarthritis.[5]
• SAPHO syndrome - synovitis, acne, pustulosis, hyperostosis, and osteitis.
• Arthritis associated with underlying connective tissue or autoimmune diseases - arthritis is a common clinical manifestation of several rheumatic and autoimmune diseases such as:
  • Systemic lupus erythematosus
  • Drug-induced lupus
  • Sjogren syndrome
  • Mixed connective tissue disease
  • Systemic sclerosis
  • Inflammatory myopathies
  • Behcet's disease
  • Vasculitis: Henoch Schnolein Purpura, ANCA-associated vasculitis
  • Sarcoidosis
  • Relapsing polychondritis
• Arthritis associated with malignancy - Inflammatory arthritis can be a frequent paraneoplastic phenomenon associated with underlying malignancies. 
  • Palmar fasciitis and polyarthritis (PFPA) syndrome - frequently associated with ovarian cancer but can be seen in association with any malignancy.

Epidemiology

The annual incidence of early inflammatory arthritis ranges from 115 to 271 per 100,000 adults, and the incidence of undifferentiated inflammatory arthritis (UA) ranges from 41 to 149 per 100,000 adults. Out of which, 13% to 54% of patients with undifferentiated inflammatory arthritis will develop rheumatoid arthritis (RA), and in 21% to 87%, undifferentiated inflammatory arthritis will persist as such. A specific diagnosis can be made at the presentation in about 70% of such patients, the most common being rheumatoid arthritis.[6][7][8] Gout is the most common inflammatory arthritis, while rheumatoid arthritis is the most common autoimmune inflammatory arthritis.  While females are more likely than males to have most autoimmune inflammatory arthritis such as rheumatoid arthritis, systemic lupus erythematosus, and Sjogren syndrome, gout and seronegative spondyloarthritis are more common in males than in females.  Age of onset is variable, juvenile idiopathic arthritis usually presenting before 10 years of age, most autoimmune inflammatory arthropathies presenting in the early adulthood while late age of onset is not uncommon in autoimmune inflammatory arthropathies and paraneoplastic inflammatory arthritis.

Pathophysiology

Pathophysiology is distinct and different based on the underlying etiology of inflammatory arthritis.  External or self-antigen leading to an immune-mediated inflammatory response by an influx of inflammatory cells such as neutrophils, lymphocytes, and macrophages from the bloodstream into the synovial membrane and is associated with hyperplasia of synovial fibroblasts. In some cases, damage to the cartilage and bone can cause joint destruction. Direct invasion of the joint by an infectious organism resulting in the inflammation of the synovium is usually the underlying pathogenesis for most infectious arthritis.  Further, infectious agents such as hepatitis B, hepatitis C, parvovirus B19 may trigger an immune response leading to the onset of inflammatory arthritis.[9][10][11] In autoimmune inflammatory arthropathies, an interplay of environmental and genetic factors leads to activation of the immune system leading to inflammatory arthritis.  In crystalline arthropathies, the occurrence of crystals in the synovium acts as an antigen leading to a neutrophil-mediated inflammatory cascade.

History and Physical

While there is a significant overlap, most inflammatory arthropathies can be classified based on history and physical examination. The onset of symptoms is usually acute in infectious and crystalline arthropathies while subacute or insidious in most autoimmune inflammatory arthropathies. Infectious arthritis is usually monoarticular. Crystalline arthropathies can be monoarticular, oligoarticular, or polyarticular.  While most autoimmune inflammatory arthropathies are polyarticular, they may initially have an oligoarticular or a monoarticular presentation gradually evolving into a polyarticular pattern. Bacterial infectious arthritis is more common in previously damaged joints and lower extremities such as knees. Inflammatory arthritis in Lyme disease usually presents as acute onset monoarticular inflammation of the knee. 

Inflammatory arthritis secondary to viruses such as hepatitis B, hepatitis C, parvovirus B19 is usually polyarticular and may mimic rheumatoid arthritis. 50% of gout patients present with podagra, which is acute onset inflammatory arthritis of the 1st metatarsophalangeal joint in the foot. The 1st metatarsophalangeal joint is eventually involved in 90% of the patients with gout. Pseudogout is more common in the knees, wrists, and 2nd and 3rd metacarpophalangeal joints of the hands. Basic calcium phosphate disease more commonly involves the shoulders. Rheumatoid arthritis typically involves small joints of the upper and lower extremities but spares the spine (except C1-C2) and distal interphalangeal joints in the hands.  Patients with seronegative spondyloarthropathies may have axial involvement and peripheral inflammatory arthritis, these patients as a predilection for lower extremity joints. Enthesitis and dactylitis may be seen frequently in seronegative spondyloarthropathies.  Patients with inflammatory arthritis associated with other connective tissue diseases such as systemic lupus erythematosus usually have other systemic clinical features such as skin rashes in systemic lupus erythematosus, sclerodactyly in systemic sclerosis, keratoconjunctivitis sicca in Sjogren syndrome, etc.[12] 

Thus, knowledge about the onset of arthritis, number of joints involved, symmetry of involvement, distribution of involvement, and pattern of involvement can give clues about the potential underlying etiology of inflammatory arthritis in a patient.

Evaluation

Laboratories

Elevation in inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein are frequently seen in all inflammatory arthropathies. Thrombocytosis and anemia of chronic disease can be frequently seen. Leukocytosis usually accompanies infectious arthritis, while leukopenia might be a feature of infectious arthritis associated with underlying autoimmune diseases such as systemic lupus erythematosus. Renal function may be abnormal in patients with gout who are more likely to have associated chronic kidney disease. Hyperuricemia is frequently seen in patients with gout, although serum uric acid levels may be falsely low during an acute episode of gout. Patients with pseudogout secondary to underlying metabolic diseases such as hypercalcemia, hyperparathyroidism, hypomagnesemia, and hemochromatosis may have laboratory abnormalities associated with the underlying disorder. Specific serological workup should be pursued when autoimmune inflammatory arthritis is in the differential.  Patients with rheumatoid arthritis frequently have positive rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies. Patients with underlying connective tissue diseases such as systemic lupus erythematosus, Sjogren syndrome, mixed connective tissue disease, inflammatory myopathies, and systemic sclerosis may have associated autoantibodies such as antinuclear antibody and more specific autoantibodies such as anti-double-stranded DNA antibody, anti-Smith antibody, anti-Ro antibody, Anti-La antibody, etc. 

Synovial Fluid Analysis

Aspiration of the synovial fluid and detailed analysis is critical in the evaluation of inflammatory arthritis. Synovial fluid shall be analyzed for total cell counts and differential, polarized light microscopy, Gram stain and cultures, and fungal/AFB cultures when appropriate. Total cell counts are usually less than 2000 cells/mm3 in non-inflammatory arthritis and more than 5000 cells/mm^3 in inflammatory arthritis. A total cell count of more than 50,000 cells/mm^3 cells and/or more than 90% neutrophils have a strongly positive likelihood ratio of being associated with septic arthritis, although it can present in acute gout or pseudogout as well. Septic arthritis and crystalline arthropathies usually have neutrophilic predominance, while rheumatoid arthritis usually has lymphocytic predominance in the synovial fluid.  Monosodium urate crystals on polarized light microscopy are needle-shaped and strongly negatively birefringent. Calcium pyrophosphate crystals on polarized light microscopy or rhomboid-shaped and weakly positively birefringent. Basic calcium phosphate crystals are not visible on polarized light microscopy and need special staining for visualization.

Imaging

Plain radiographs may be initially normal in early inflammatory arthritis or may show periarticular osteopenia. As the disease progresses, periarticular erosions can be seen in inflammatory arthritis such as rheumatoid arthritis.[1][13][14] In comparison, gout erosions tend to be juxta-articular/rat-bite erosions with overhanging edges. Chondrocalcinosis or CPPD deposition can be easily visualized on plain radiographs. Entheseal calcifications can be seen in seronegative spondyloarthritis. Radiographs in early axial spondyloarthropathies are normal but can show bamboo spine and sacroiliac joint fusion and erosions later in the disease process. MRI can be a beneficial tool, especially if radiographs are nondiagnostic. MRI is more sensitive than plain film in evaluating synovitis, erosions, sacroiliitis, with a much higher sensitivity than X-rays. CT scan is usually not helpful in evaluating inflammatory arthropathies but can be used to detect chondrocalcinosis or bony erosions when not evident on plain radiographs. Musculoskeletal ultrasound is an extremely useful tool in evaluating peripheral inflammatory arthritis and can help assess the presence of synovitis, degree of synovitis, presence of erosions or chondrocalcinosis, and can be used to perform ultrasound-guided diagnostic aspirations. Nuclear medicine joint scan is usually not the preferred modality due to its high sensitivity but very poor specificity but can be used to evaluate the presence or absence of inflammation and to evaluate prosthetic joint infections.

Treatment / Management

Inflammation is generally reversible, while joint destruction is not. Early and appropriate treatment may prevent disease persistence/progression, joint damage, and disability.

Prompt diagnosis and treatment of septic arthritis are of utmost importance as untreated septic arthritis or delay in treatment invariably leads to permanent joint destruction and other complications such as sepsis. After the synovial fluid analysis is performed, intravenous antibiotics with broad coverage should be initiated, which can later be targeted based on sensitivity analysis from the synovial fluid analysis. Joint lavage and orthopedic evaluation may be necessary in some cases. Prosthetic joint infections can be difficult to manage. Removing hardware followed by a spacer and a long course of antibiotics before repeat surgery to replace the hardware is usually indicated in prosthetic joint infections.

Gout and pseudogout can mimic septic arthritis. In patients with acute monoarthritis, once septic arthritis has been ruled out by synovial fluid analysis, and the diagnosis of gout or pseudogout has been confirmed by synovial fluid analysis, treatment with anti-inflammatory agents such as oral, systemic or intra-articular corticosteroids, NSAIDs, or colchicine shall be pursued. The choice of agent depends on the severity of inflammatory arthritis as well as patient comorbidities.[15] In patients with recurrent acute attacks of gout, or patients with gout who have chronic kidney disease, tophi, or erosions, treatment with urate-lowering therapy shall be considered as well.

In patients with autoimmune inflammatory arthritis, early treatment to suppress inflammation and prevent recurrent inflammation, disease progression, and joint damage are crucial. The choice of treatment depends on the underlying etiology. Conventional disease-modifying antirheumatic drugs such as methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine are usually first-line agents, and if lack of response, treatment with biologic disease-modifying antirheumatic drugs shall be pursued as appropriate.[16] Close monitoring with baseline and serial laboratories is indicated in patients being treated with disease-modifying antirheumatic drugs. The initial therapeutic goal is to achieve significant clinical improvement within 3 months, which may be defined as at least a 50% reduction in disease activity.[7][17][18] Combination therapies of conventional disease-modifying antirheumatic drugs with other conventional or biologic disease-modifying antirheumatic drugs are more effective and often needed to control the disease. Combination therapies of biologic disease-modifying antirheumatic drugs are not recommended due to the increased risk of infections. Long-term use of corticosteroids is usually not recommended, especially at moderate to high doses due to concerns regarding adverse effects. The role of corticosteroids in managing chronic autoimmune inflammatory arthritis should ideally be limited in managing flares with has needed corticosteroid dose-tapers.(A1)

Surgery is rarely needed in the early stages of inflammatory arthritis but can be considered in patients with chronic deformities due to underlying chronic autoimmune inflammatory arthropathies such as rheumatoid arthritis. An interprofessional team approach, including patient education, physical and occupational therapy, diet, and lifestyle modification, can significantly improve patient outcomes.

Differential Diagnosis

It is of importance to differentiate inflammatory from noninflammatory arthritis. The most common form of non-inflammatory arthritis is osteoarthritis which usually has an insidious onset and gradually worsens. Typical joints involved in primary osteoarthritis include the knees, hips, lumbar spine, 1st metatarsophalangeal joints in the feet, proximal and distal interphalangeal joints in the hands, and 1st carpometacarpal joint in the wrist. Repetitive use or injuries can lead to the involvement of other joints as well, such as the shoulders, elbows, ankles, and wrists. It can be symmetric or non-symmetric. Bony hypertrophy changes can be palpable on the exam, especially in the hands and feet. The joint can be tender and swollen, but erythema or warmth is usually absent. Synovial fluid analysis reveals noninflammatory fluid. Radiographs can show characteristic osteoarthritic changes with loss of joint space and osteophytes. Erosions are rare, but central "gull-wing" erosions can be seen in erosive osteoarthritis of the hands involving the proximal and distal interphalangeal joints.

Prognosis

Prognosis depends on the cause of arthritis. If treated early and appropriately, acute inflammatory arthropathies such as septic arthritis or crystal-induced arthritis have an excellent prognosis. Delay in treatment or misdiagnosis can lead to erosions and permanent joint damage, which can be aggressive, especially in septic arthritis. In patients with rheumatoid arthritis or seronegative spondyloarthritis, early and aggressive treatment can prevent long-term complications such as erosions and joint deformities. The prognosis of inflammatory arthritis associated with underlying connective tissue disorders depends on the underlying disorder.[19]

Complications

Complications in septic arthritis arise from delay in treatment or mass diagnosis, possibly leading to aggressive and permanent joint damage. Chronic gout, rheumatoid arthritis, and seronegative spondyloarthritis can be associated with erosive changes and joint damage, which can interfere with daily function.