Polyarthritis – Causes, Symptoms, Diagnosis, Treatment

Polyarthritis refers to a joint disease that involves at least five joints. One or more signs of inflammation, including pain, movement restriction, swelling, warmth, and redness, are seen in the involving joints. In the event that pain is the only symptom, it is difficult to differentiate polyarthritis from the causes of polyarticular joint pain (PJP), such as fibromyalgia or osteoarthritis. Polyarthritis can be caused by several inflammatories as well as non-inflammatory arthritides. The causes of inflammatory polyarthritis include rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, reactive arthritis, IBD-associated arthritis, juvenile idiopathic arthritis, undifferentiated spondyloarthritis, gout, pseudogout, and arthritis associated with underlying autoimmune diseases such as SLE and MCTD.

Causes of Polyarthritis

Infectious diseases

Numerous different bacteria, viruses, fungi, and parasites can cause polyarthritis. Infections may lead to polyarthritis over three different mechanisms;

• Direct invasion – A microbiological agent directly infects the synovial tissue. This is causes monoarthritis but may lead to polyarthritis in rare cases (e.g. Syphilis, leprosy).
• Immune-mediated inflammation – Antimicrobial antibodies lead to polyarthritis due to the similarities between microbiological antigens and autoantigens (e.g. ARF, Lyme disease).
• Reactive arthritis – Urogenital or gastrointestinal system infections can cause inflammatory joint diseases like spondyloarthritis, but the microbiological agent is not detected in the synovial fluid.
• Inflammatory rheumatic diseases – Rheumatoid arthritis psoriatic arthritis and other spondyloarthropathiesCrystal arthropathiesSystemic lupus erythematosusSjogren’s syndrome, scleroderma and other connective tissue disorders systemic vasculitis, sarcoidosis, Behcet’s disease, etc.
  • 1) Bacterial (Lyme disease, endocarditis, septic arthritis)
  • 2) Viral (hepatitis B and C, Epstein Barr virus, parvovirus, dengue, alphaviruses, rubella, human immunodeficiency virus, mumps, coxsackievirus)
  • 3) Collagen-vascular disease (rheumatoid arthritis, palindromic rheumatism, rheumatic fever, lupus, vasculitis, systemic sclerosis, myositis, ankylosing spondylitis, psoriatic arthritis, Behcet syndrome, relapsing polychondritis)
  • 4) Crystal-induced arthritis (uric acid deposition of gout, calcium pyrophosphate deposition of pseudogout)
  • 5) Post-infectious or reactive arthritis (post enteric infections, disseminated gonococcal infection)
  • 6) Familial Mediterranean fever

• Infective disorders – Invasive joint infections Viral infections (Chikungunya, HIV, HCV, HBV, human parvovirus B19, etc.) ii.II-Bacterial infections (staphylococcal, gonococcal, meningococcal, Brucella, Borrelia [Lyme arthritis], leprosy arthritis, etc.) Reactive arthritis (Infections without joint invasion)I-Sexually acquired (Chlamydia trachomatis, Ureaplasma)II-Enterocolitis (Campylobacter, Salmonella, Shigella, Yersinia)III-Others (Infective endocarditis, rheumatic fever, post-streptococcal reactive arthritis)
• Malignancies – Solid tumors (lung, breast, urinary bladder, prostate cancer, etc.)Hematologic malignancies (leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma)
• Drugs – Antimicrobials (tetracyclines, quinolones, rifampicin, voriconazole)Anti-diabetic DPP-4 inhibitors (sitagliptin, linagliptin, alogliptin) Chemotherapeutics [aromatase inhibitors (anastrozole, letrozole), taxanes (paclitaxel, docetaxel, and cabazitaxel)Immune checkpoint inhibitorsPsychotropic 5-HT2A antagonists (mianserin, mirtazapine, nefazodone)

Others Causes

A)

• Oligoarthritis need to exclude post-streptococcal reactive arthritis,
• Lyme arthritis,
• acute rheumatic fever,
• reactive arthritis,
• toxic synovitis,
• septic arthritis,
• pyomyositis,
• steroid-induced osteonecrosis,
• sickle cell disease,
• hemophilia,
• scurvy,
• osteomyelitis,
• chronic nonbacterial osteomyelitis (CNO),
• sports injury,
• non-accidental injury,
• pigmented villonodular synovitis (PVNS),
• osteoid osteoma,
• bone tumors,
• neuroblastoma,
• leukemia, and lymphoma.

B)

• Polyarthritis need to exclude post-streptococcal reactive arthritis,
• Lyme arthritis,
• acute rheumatic fever,
• reactive arthritis,
• scurvy,
• chronic nonbacterial osteomyelitis (CNO) or
• chronic recurrent multifocal osteomyelitis,
• non-accidental injury,
• systemic lupus erythematosus (SLE),
• Mixed connective tissue disease (MCTD),
• Sjögren syndrome,
• scleroderma, sarcoidosis,
• Blau syndrome,
• arthritis associated with inflammatory bowel diseases,
• Farber disease,
• benign hypermobility joint syndrome and amplified musculoskeletal pain syndromes) Systemic arthritis need to exclude infections (mycoplasma, cat scratch disease, bacterial endocarditis, Lyme disease),
• acute rheumatic fever, syndrome of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA syndrome),
• autoinflammatory syndromes, systemic vasculitis (polyarteritis nodosa, Kawasaki disease), inflammatory bowel disease, malignancy (leukemia, lymphoma, neuroblastoma),
• Castleman disease

C)

• Enthesitis-related arthritis. Apophysitis (especially Osgood-Schlatter, Sever disease), inflammatory bowel diseases (IBD),
• chronic recurrent multifocal osteomyelitis (CRMO), amplified musculoskeletal pain syndrome.

Symptoms of Polyarthritis

• Simple arthralgia – The main symptom is pain; no clinical features of inflammation in the joints or morning stiffness; history of intercurrent illness or viral infection
• Osteoarthritis – Pain is usually in large, weight-bearing joints, carpometacarpal joint of the thumb, or distal interphalangeal joints of the fingers; the presence of Heberden’s nodes, crepitus; lifestyle factors such as overweight, sedentary occupation, repetitive use of joints, and history of trauma to affected joints may be relevant
• Seronegative (non-rheumatoid) arthritis – Linked with psoriasis, bowel disease (ulcerative colitis, Crohn’s disease), bladder symptoms, and anterior uveitis. May occur after infections (streptococcal throat infection, chlamydial urethritis, or bowel infection with yersinia, salmonella, shigella). Mainly asymmetrical, large joint oligoarticular involvement; possible spinal involvement (sacroiliitis)
• Rheumatoid arthritis – At least four of these signs or symptoms for six weeks: pain and swelling in at least three joint areas; symmetrical presentation; early morning joint stiffness for more than one hour; involvement of metacarpophalangeal joints, proximal interphalangeal joints, and wrists; subcutaneous nodules; positive rheumatoid factor; radiological evidence of erosions
• Pain in multiple joints (polyarthralgia) – or inflammation of joints (arthritis) also occurs in the majority of affected individuals. Lupus-like skin inflammation in sun-exposed areas and hair loss are common, as are skin scarring changes on the fingers and face like those seen in scleroderma.
• Muscle weakness – due to inflammation (myositis) of proximal muscle groups can also occur. Additional frequent symptoms include hand swelling and fatigue.
• They are typically monoarticular arthritis of a large joint and come with constitutional symptoms and rarely come in a polyarticular form. M

Diagnosis of Polyarthritis

Physical examination

Physical examination would provide support to the diagnosis as per the following basic points:

• Classification of polyarthritis – In light of information obtained via anamnesis; classification of polyarthritis is completed by physical examination. Accompanying extra-articular musculoskeletal system involvement such as enthesitis and tenosynovitis can be determined as well. It can be said that enthesitis and tenosynovitis are seen more prominently than the SpA group or seronegative diseases.
• Accompanying findings – Detecting the systemic symptoms accompanying polyarthritis during a physical examination and evaluating them accurately is important. Meanwhile, information about the diseases that might be the extra-rheumatic causes of polyarthritis can be obtained as follows;
• Weakness, weight loss, fever – Severe polyarthritis may cause weakness and weight loss due to intensive inflammation. In the presence of accompanying weakness and weight loss, systemic rheumatic diseases such as SLE and systemic vasculitis, which may possibly involve the visceral organs, should be at the top of the list of differential diagnoses. Fever may occur along with this inflammation. Only the presence of fever would require frequent questioning, primarily to rule out infectious diseases, lymphoproliferative diseases, and malignancy.
• Skin and mucosa – The presence of specific skin lesions such as malar rash, vasculitis rash, and psoriasis are important in making the diagnosis. Raynaud’s phenomenon can be detected during physical examination. There may be specific cutaneous signs of infectious diseases, primarily in viral infections. Illustrates palmoplantar skin rash in a syphilis patient with polyarthritis. Inspection of the mucosa should be a part of the physical examination.

Lab Test

• Initial laboratory tests – should include CBC, ESR, CRP, ANA, RF, anti-cyclic citrullinated peptide antibodies (anti-CCP), and HLA-B27. The typical inflammatory markers are common, especially in oligoarthritis. A positive RF or anti-CCP provides a little value for the diagnosis but may indicate a poorer disease course and outcome. Ferritin, fibrinogen, AST, triglyceride are recommended when there is a concern of macrophage activation syndrome (MAS). Other tests for excluding other diseases may be considerations depending on the differential diagnosis.
• Complete blood count – Cytopenia is a supportive finding for SLE. However, polyarthritis can be one of the components of the clinical manifestation of leukemia and lymphoma that causes cytopenia. Lymphocytosis is a valuable finding for chronic lymphoproliferative disorders. Polycythemia and thrombosis raise doubts on myeloproliferative disease as well. The presence of eosinophilia can be a sign of Churg-Strauss vasculitis and hypereosinophilic syndrome with polyarthritis.
• Urinalysis – A simple urinalysis can be helpful for making several differential diagnoses. The presence of pyuria may indicate polyarthritis reactive to a urinary system infection. The presence of proteinuria and/or hematuria is quite valuable for SLE and systemic vasculitis, which has the potential to involve glomeruli and may require a renal biopsy to make the diagnosis.
• Rheumatological workup usually recommended includes – Rheumatic factor (RF) and anti-citrullinated peptide antibodies (CCP) for rheumatoid arthritis (RA), antinuclear antibody (ANA) for systemic lupus erythematosus and some other entities, anti-smith and anti-double-stranded DNA for confirmation of lupus, anti-Scl-70 for systemic sclerosis, anti-Ro (SSA) and anti-La (SSB) for Sjogren syndrome, anti-U1-RNP for mixed connective tissue disease, anti-neutrophilic cytoplasmic antibody (ANCA) for granulomatosis with polyangiitis (C form) and microscopic polyangiitis (P form), Anti-Jo-1 for myositis, anti-histone for drug-induced lupus erythematosus, cryoglobulin for vasculitis and hepatitis C.
• Erythrocyte sedimentation rate and C-reactive protein –  are non-specific markers of inflammation but usually helpful in ruling in a pathology causing significant inflammation and also monitoring its response to treatment.[rx]
• The synovial fluid examination – is one of the most important tests especially for the initial diagnosis of arthritis. Cell counts and differentials, crystal evaluation under polarized light microscopy, bacterial/acid-fast bacilli/fungal cultures and Lyme’s DNA PCR shall be performed on the synovial fluid as appropriate.  Degenerative arthritis is usually associated with cell counts of less than 2,000 cells/mm3 while in inflammatory arthritis, cell counts are usually more than 5,000 cells/mm3 and may be as high as 50,000 cells/mm3.  More than 50,000 cells/mm3 cells and/or more than 90% neutrophils in synovial fluid analysis shall raise suspicion of septic arthritis, although this can also be seen in the setting of acute gout or pseudogout.
• Uric acid – should be studied in every patient with suspected crystal arthropathy. Uric acid concentration can be normal in a small proportion of patients with gout arthritis or during an acute attack of gout. Liver and kidney function tests should be considered in every patient with polyarthritis. SLE and systemic vasculitis patients can present with acute kidney failure. Acute hepatitis or other viral agents can compromise hepatic function tests. Elevated lactate dehydrogenase (LDH) is suggestive of autoimmune hemolytic anemia, ASD, myositis, and malignancy. Elevated creatinine kinase should be evaluated in every patient with polyarthritis and may be a potential indicator of myositis.
• Biopsy – Biopsy many times have the final word; as is in most medicine. There are enough diagnostic modalities for polyarticular arthritis to render biopsy unnecessary, but still, biopsies are occasionally done to diagnose or confirm a clinical suspicion for different vasculitis, arthritis, infectious etiologies, or granulomatous diseases.
• Polarized microscopy – of synovial fluid can help with crystal arthritis diagnoses, such as gout and pseudo-gout. Clinicians also analyze synovial fluid for cell count, gram stain, and cultures. Synovial fluid leukocyte counts less than 200/mm are normal, between 200/mm and 2000/mm are associated with non-inflammatory arthritis and over 2000/mm with inflammatory arthritis. If the cell count is over 50000/mm, physicians should treat the fluid as infectious.[rx]
• Ultrasound – is readily available in clinics and hospitals and is has utility for a variety of functions, but it has a limited role in polyarticular arthritis for detecting erosions and synovitis. Clinicians can easily perform joint injections under the guidance of ultrasound.[rx][rx] Computed tomography has almost no role other than ruling out other etiologies, and the role of MRI is to pick very early joint inflammation or early bone/soft tissue infection.
• Autoantibodies – They are critical in the diagnosis of RA, SLE, other connective tissue diseases, and systemic vasculitis. Rheumatoid factor (RF), anti-CCP antibody, and antinuclear antibody (ANA) should be studied in each patient with polyarthritis. Based on accompanying symptoms, endonuclease antibody (ENA) panel and anti-neutrophil antibody (ANCA) can also be studied. RF may be positive in RA, in SLE or other connective tissue diseases, and in systemic vasculitis. RF may be positive in patients with infectious diseases and malignancies [rx]. It is important to establish anti-CCP positivity to make a diagnosis of RA. High-titer positivity has high specificity in diagnosing RA [rx].

Imaging Studies

Imaging is a costly proposition and has a low diagnostic yield. There are usually no positive findings in the cases of acute polyarthritis. There is also no need to do imaging of every single joint involved. Some joints are “high yield” and provide information essential for diagnosis and treatment; some other joints are not.

• X-rays – are helpful in showing fractures, dislocations, and osteomyelitis. In advanced osteoarthritis, the x-rays are useful and show erosion, sclerosis, joint space narrowing, osteophyte formation; but usually by the time these changes are present, the disease is well advanced and easily recognizable from history and physical. Also, many aging patients have x-rays compatible with osteoarthritis without having clinical symptoms; therefore, the correlation can be tricky. Although hand, wrist, and metacarpal x-rays are unnecessary for a diagnosis of RA, they occasionally do help, and the response to treatment is at times monitored based on findings on x-rays. Cervical X-rays (specifically the C1-2) are essential during follow-up of RA to look for damages and help prevent a pathologic fracture of the joint which would be devastating.[rx] X-rays also easily show the disposition of calcium pyrophosphate in joints, such as a knee, and make the diagnosis of pseudo-gout. X-rays can show sacroiliac joint involvement of seronegative spondyloarthropathy although magnetic resonance imaging (MRI) is more sensitive.
• Magnetic resonance imaging (MRI) – is the modality gold standard for the study of JIA. All joints interested in pathological inflammatory phenomena can be easily examined in all possible plans and with an excellent contrast resolution of bone and soft tissues.  It is the most sensitive imaging technique detecting synovitis. The standard MR imaging protocol needs to include: T1 spin-echo (SE) sequence, fat-suppressed sequence (classic T2 fat-sat; short tau inversion recovery – STIR; DIXON fat-suppression sequence); T1 fat-suppressed sequence precontrast and postcontrast. MRI is the only modality able to objective bone marrow edema and the most sensitive to detect bone erosions.[rx]
• Radionuclide scans – are rarely done but have specific purposes. Picking up metastases, Paget disease of the bone, and osteomyelitis represent several of these indications.
• Computed tomography (CT) – to the diagnosis of polyarthritis is limited, except for SpA. However, they can be used for the differential diagnosis of accompanying system involvements. For example, thoracic CT findings are quite valuable in interstitial lung disease. In addition, if arthritis is suspected, MRI may be helpful in demonstrating synovitis.
• PET-CT – is helpful in making a differential diagnosis in cases with suspected malignancy. Recently, it was understood that PET-CT contributes to the differential diagnosis of large vessel vasculitis. Large vessel vasculitis is a rare cause of polyarthritis[rx].

Treatment of Polyarthritis