Fever and ArthritisDz

ICD-9 Codes:

Definition:  The chapter considers conditions that manifest prominent fever and oligo- or polyarthritis. Polyarthritis is defined as inflammatory joint pain with swelling (synovial proliferation or effusion) affecting 4 or more joints. Oligoarthritis affects 3 or fewer joints and is usually asymmetric in distribution. Fever should be greater than 101 F, the duration of which depends on the condition.  The presence of fever is distinctive as most oligo- or polyarticular conditions do not manifest substantial or sustained fever. In these disorders, fever and pyrexia are manifestations of the host responses to exogenous pathogens (e.g, microbial infections) or endogenous pyrogens [e.g, interleukin-1  (IL-1), interferon-alpha (INF-α), tumor necrosis factor-alpha (TNF-a), interleukin-6 (IL-6)].

Etiology:  The pathogens and diseases responsible for a febrile articular disorder are easily considered according to the underlying pathologic process (see table):

1. Infections.  Infection as a cause of polyarthritis always should be considered in a patient who presents with acute onset musculoskeletal pain and fever.  The higher the fever and WBC count the more likely an infectious etiology.  Bacteria, viruses and atypical microorganisms may cause polyarthritis both directly as a pathogen or indirectly by an immune mediated response. Septic arthritis may develop as a result of hematogenous seeding of the synovial membrane due to bacteremia, direct or penetrating trauma (e.g., injury, animal bite or joint injection), or extension from a contiguous infection (e.g., cellulitis). Those at risk for septic arthritis include: the elderly, patients with diabetes, chronic renal or hepatic disease, gout, osteoarthritis, rheumatoid arthritis, prosthetic joints, intravenous drug abusers and those with a previous history of septic arthritis. The table below lists the range of organisms capable of causing such infectiions;  but among these, the most common are Neisseria gonnorhea, staphylococci, streptococci, and chlamydia (reactive arthritis). Several viruses have been linked to polyarthritis, and may manifest fever including parvovirus B19, mumps, rubella, hepatitis B and C viruses.  The arboviruses with polyarthritis. Severe cases of debilitating polyarthritis have been associated with the Chikungunya virus where human epidemics have been reported in Africa, Asian and certain parts of Europe. A detailed travel history may help guide specific testing for diseases endemic to the region. Although vigilance for infection is important to institute appropriate therapy, this should be balanced by thoughtful clinical assessment based on history and examination before extensive testing is ordered.
2. Autoimmune diseases. About a quarter of patients who present with inflammatory arthritis and fever eventually will be diagnosed with an autoimmune or autoinflammatory disease. These diseases arise from aberrant immune activation releasing an overabundance of endogenous pyrogens which consequentially drives fever and inflammation. Systemic lupus erythematosus, sarcoidosis, vasculitis, Behcet’s syndrome are some of the autoimmune diseases that may manifest with both polyarthritis and fever. Typically, patients will present with other clues to indicate that further testing are needed to verify the diagnosis. Patients with SLE may have a history of a photosensitive rash, Raynaud’s phenomenon, or serositis. RA can present with fever, but usually when vasculitis is present. In sarcoidosis, fever may accompany the triad of arthritis, erythema nodosum, and hilar adenopathy (Lofgren’s syndrome). Giant cell arteritis, granulomatosis with polyangitis, polyarteritis nodosa, Takayasu’s arteritis and vasculitides associated with other autoimmune diseases (e.g, cryoglobulinemia, SLE, RA) often present with fever, malaise, and weight loss along with musculoskeletal symptoms. In most autoimmune diseases as mentioned above, fever is low grade (e.g, < 38oC) and indolent. With autoimmune disorders the highest fevers are seen with AOSD, lupus (with vasculitis, hepatitis, pneumonitis or alveolar hemorrhage) or PMR/GCA and the other medium and large vessel vasculitides.
3. Autoinflammatory diseases.  are a group of rare but impressively febrile (e.g, >39oC) and recurrent disorders In contrast to the autoimmune diseases, high-titer autoantibodies and antigen-specific T cells are typically absent in autoinflammatory diseases. Familial Mediterranean Fever, TNF receptor–associated periodic syndrome (TRAPS), hyper-immunoglobulinemia D with periodic fever syndrome (HIDS), systemic-onset juvenile idiopathic arthritis (SoJIA), adult onset Still’s disease (AOSD), the syndrome of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) are but a few of the autoinflammatory diseases that have been described in the last decade. These diseases are characterized by unprovoked, recurrent episodes of fever, serositis, arthritis, and cutaneous inflammation resulting from specific genetic mutations affecting the innate immune system (11). In Cryopyrin-Associated Periodic Syndromes (CAPS) which include: Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome (MWS), Neonatal-Onset Multisystem Inflammatory Disease (NOMID), mutations in the NLRP3 gene have affected components of the inflammasomes (e.g, cryopyrin) which are important in recognizing microbial products and endogenous danger signals (11). Interestingly, recent evidence suggests that genes in the same NLR family as the cryopyrinopathies may be implicated in gout and other crystalline arthritis (12). Gout and crystalline diseases. Patients with gout and pseudogout can manifest high fevers during acute attacks. In fact it can be very difficult to distinguish between acute septic arthritis and acute gout as they have similar presentations and may even coexist. Up to 50% of gout patients will have a normal serum uric acid level during the acute attack and both will have high acute phase reactants and fever. In a study of hospitalized gout patients, fever was found in 50% of patients who presented with polyarticular disease and 20% in monoarticular disease where infection had been excluded (13). Patients who present with crowned dens syndrome (CDS) related to calcium pyrophosphate dihydrate (CPPD) or calcium hydroxyapatite crystals deposition in the peri-odontoid ligaments of the atlas will present with high fever, severe occipital headache and neck stiffness. These patients are typically misdiagnosed with aseptic meningitis and given inappropriate antibiotics (14). Uncommonly, crystalline diseases may co-exist with other diseases, including septic arthritis. A high index of suspicion should be maintained for infection in any patient who present with monoarticular joint pain and effusion.
4. Malignancy. Neoplastic proliferative diseases may present with indolent arthritis and fever.  Paraneoplastic syndromes often present with rheumatologic features.  Interestingly, these paraneoplastic manifestations seldom respond to standard antirheumatic doses of steroids or disease modifying agents, but will resolve only as the underlying cancer is treated.  Lupus-like syndromes (photosensivity, polyserositis, Raynaud’s, arthritis, fever) has been associated with ovarian cancer, breast cancer, and hairy cell leukemia. Dermatomyositis may present with fever and polyarthritis and occasionally be accompanied by an occult malignancy. Symptoms mimicking polymyalgia rheumatica with shoulder and hip girdle pain and elevated ESR have been described in patients with multiple myeloma, colon, lung, and renal cell carcinoma. Carcinomatous polyarthritis can be confused with rheumatoid arthritis, but generally has an explosive onset and asymmetric disease pattern. The presence of fasciitis may be a clue for an underlying malignancy (e.g., pancreatic, lung, breast, colon, CLL, myelodysplasia, etc).  The urgency to distinguish rheumatic condition from malignancy is paramount in children. Seventy five percent of children acute lymphoblastic leukemia (ALL) will present with musculoskeletal pain before blasts appear in the peripheral smear; hence, identifying malignancy from other causes of arthritis can be challenging (16). One retrospective case control study examined the predictive factors for malignancies vs. juvenile idiopathic arthritis (JIA) based on clinical and laboratory data in children with musculoskeletal pain (17). The most predictive factors for malignancy were elevated lactate dehydrogenase (LDH), anemia, and neutropenia. An increase in LDH of greater than two-fold was found exclusively in children with malignancies. Musculoskeletal pain was observed at similar frequencies in children with JIA and neoplasia, though fever tended to be recurrent in those with malignancy. Patients with systemic autoimmune diseases are also at risk for developing de novo malignancies. The risk for lymphoma is increased in patients with rheumatoid arthritis and Sjogren’s disease, solid tumors have been associated with dermatomyositis and giant cell arteritis, and myelodysplasias have been seen in patients with GPA. Also, secondary malignancies have been attributed to cytotoxic medications (e.g, cyclophosphomide, azathioprine, cyclosporine, methotrexate, and tumor necrosis factor-inhibitors) used to treat the underlying autoimmune disease. Due to the complexity of patients with rheumatic diseases, vigilance and knowledge of typical and atypical manifestations of these diseases are important when trying to distinguish between disease flare and a co-existing malignancy. Prompt recognition is important so as to institute prompt treatment for the malignancy, but extensive searches for an occult malignancy in most rheumatic syndromes is not advised unless accompanied by suggestive findings
5. Drug Induced Syndromes. Few medication will manifest musculoskeletal adverse effects and mimick a primary rheumatologic disease. Best characterized are the agents that give rise to drug-induced lupus as: hydralazine, procainamide, isoniazid, propylthiouracil, sulfonamides, quninidine, tumor necrosis factor inhibitors, and minocycline.  Other agents are known for their ability to induce serum sickness (penicillin, sulfa, antithymocyte globulin, rituximab). Drug induced vasculitis

 Cardinal Findings
—HAV: Transient arthralgias may occur in acute infection. A transient serum sickness-like syndrome uncommonly occurs.
—HBV: The most common rheumatic syndrome in acute HBV infection is abrupt onset of a severe, symmetric polyarthritis in the prodromal phase. Simultaneous joint involvement is the usual pattern; occasionally a migratory or additive pattern is observed. The arthritis and rash are often short-lived and typically disappear with the onset of jaundice. Urticaria, petechiae, and maculopapular eruptions commonly accompany the arthritis. A similar syndrome, after HBV vaccination, has been reported. In 1% of cases of chronic HBV infection, PAN may occur with necrotizing vasculitis, mononeuritis multiplex, and fever. HBV-associated glomerulonephritis is a variant of this condition.
—HCV: As many as one-third of patients with chronic HCV will have rheumatic complaints that may include an acute arthritis (rare), chronic RA-like arthritis affecting small joints and associated with lowtiter positive RF and ESR elevations, and an intermittent mono/oligoarthritis (usually with cryoglobulins) of large and medium-sized joints. RA-like arthritis is typically nonerosive. Mixed cryoglobulinemia (type II cryoglobulins) has been strongly associated with chronic HCV infection (30%–90%) with associated membranoproliferative glomerulonephritis. Chronic HCV infection has been associated with Sjögren syndrome, psoriasis, or psoriatic arthritis, with sporadic reports occurring after interferon treatment.

Diagnostic Tests:

1. The diagnosis of polyarthritis and fever is made clinically with the history and physical exam; nevertheless, laboratory tests and radiographic imaging may aid in diagnosis, guide treatment and predict outcome.
2. Routine labs are helpful to confirm the diagnosis.  While the ESR and C-reactive protein (CRP) provide surrogate measures of inflammation, they do not discriminate well between infection, rheumatologic diseases or malignancy.  Other laboratory measures are often used to identify inflammation and suggest the diagnosis.  Patients with systemic onset JIA or AOSD often have high ferritin levels and abnormal liver function tests.  SLE may manifest with hypocomplementemia, lymphopenia, and thrombocytopenia; a low haptoglobin with elevated LDH in this disease may suggest immune mediated hemolysis.   But high elevations in LDH should be investigated further and malignancy excluded particularly in children or patients with concomitant weight loss, fever, lymphadenopathy.  High serum uric acid may point to gout, but the test may be normal in up to half of patients during an acute attack.  Along with routine labs, specialize testing should be judiciously ordered based on patient history and symptoms.
3. Serologies– Autoantibodies have been used to guide the diagnosis of various autoimmune diseases.  Testing for serologic markers may add significant diagnostic and prognostic value to the evaluation of inflammatory polyarthritis.  The presence of RF and ANA are nonspecific and can be found in patients with infection, malignancy, and rheumatologic diseases.  These autoantibodies can be present in other diseases as well, including: viral hepatitis, SLE, cryoglobulinemia, Sjogren’s syndrome, paraproteinemias, bacterial endocarditis, mycobacterial diseases, syphilis, leprosy, chronic interstitial lung diseases, parasitic infections, and lymphoproliferative  disorders.
4. Other serologic markers offer better specificity and have more use in diagnosing rheumatic diseases.  The anti-citrullinated peptide antibodies (anti-CCP) carry the same sensitivity as RF for RA, but with better specificity (>90%).   When present with the RF, the anti-CCP has a positive predictive value for RA >99% (18).  The cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) is also highly specific; its presence indicates GPA; similarly, the anti-double-stranded DNA (dsDNA) and anti-Smith antibodies are specific for SLE.  Antibodies against microbial antigens should be obtained when suspicion is high for infection based on contact or travel history.  Relevant assays available to evaluate for infection as a cause of fever and polyarthritis include serologies to parvovirus-B19, cytomegalovirus, hepatitis B and C, streptolysin O, borrelia, and brucella .  Further information about testing for these infections is covered in other chapters.
5. Synovial fluid analysis—One of the most important evaluation in a patient with fever and arthritis is synovial fluid analysis. Arthrocentesis is a useful adjunct to diagnosing patients and relieving symptoms.  Evaluation of synovial fluid should include: cell count, crystal analysis, and gram stain/cultures for routine and atypical (e.g, acid fast bacilli, fungi, spirochetes, gonococci) microorganisms.  Synovial fluid from an inflamed joint is typically yellow and turbulent with inflammatory cells; white blood cell counts are typically >10,000 cells/mm (ranges 5000-50,000), with a predominance in neutrophils.  In the presence of infection or gout, WBC may exceed 50,000 cells/mm.  Patients who are infected (eg, septic arthritis) and those with gout generally have a much higher percentage of neutrophils (>85%) in the synovial fluid when compared to other inflammatory arthropathies.  Prompt evaluation under polarized microscopy will maximize the yield for crystal identification.

Differential Diagnosis

—Acute arthritis: Because arthritis occurs in the prodromal preicteric phase of hepatitis, clues to the correct diagnosis are few. Serum transaminases are frequently elevated, but the diagnosis is often made retrospectively, after jaundice develops. Nonetheless, acute polyarthritis, especially when accompanied by a serum sickness-like syndrome, should raise suspicion of acute viral hepatitis. Other viral infections presenting in a similar manner include rubella, mumps, Parvovirus B19, herpesviruses, HIV, enteroviruses, and a variety of arboviruses. At the outset, acute HBV infection may be mistaken for RA, SLE, rheumatic fever, Still’s disease, or gonococcal or reactive arthritis.
—Cryoglobulinemia: Detection of cryoglobulins should prompt testing for viral hepatitis (HBV, HCV). Other causes of cryoglobulinemia include connective tissue diseases and myeloproliferative and lymphoproliferative disorders.
—PAN: Ten to 25% of cases of classic PAN are associated with chronic HBV or HCV infection.

Keys to Diagnosis: The eventual diagnosis of polyarthritis and fever will depend on key historic features, after considering the chronology of symptoms (onset, evolution, pattern of joint involvement), background history, and physical findings. Figure 2 is a helpful algorithm in the evaluation of these symptoms. Over-reliance on laboratory testing to establish a diagnosis is ill-advised as such tests are poorly predictive when used indiscriminately or as part of broad batteries of “arthritis screening” tests. The strength of laboratory testing and imaging is greatly enhanced when they are used to confirm a reasonably strong clinical suspicion garnered from the history and examination

BIBLIOGRAPHY

Cush, JJ and Dao, K. Polyarthritis. Kelley’s Textbook of Rheumatology Ninth Edition. Philadelphia, Elsevier Saunders, 2013

Cush JJ. Autoinflammatory syndromes. Dermatol Clin. 2013;31:471-80. PMID: 23827249