DOI: 10.5152/eurjrheum.2019.19145 Invited Review

Polyarthritis and its differential diagnosis Nilüfer Alpay-Kanıtez1 , Selda Çelik2 , Cemal Bes2 Abstract

Polyarthritis is a term used when at least five are affected with . Several different dis- eases ranging from to infection diseases can lead to polyarthritis. Anamnesis, physical examination, laboratory findings and imaging methods are important tools to differential diagnosis. Keywords: Polyarthritis, differential diagnosis, laboratory investigations

Introduction Polyarthritis refers to a disease that involves at least five joints. One or more signs of , including pain, movement restriction, swelling, warmth, and redness, are seen in the joints involved. 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 or . Imaging methods such as ultra- sonography and magnetic resonance may be helpful in differentiating from arthritis. Table 1 illustrates the diseases and their clinical characteristics that are frequently seen in clinical practice and cause non-inflammatory PJP.

In some cases, polyarthritis can be severe enough to necessitate the admission of patients to emergency services, or it can be asymptomatic and may remain undiagnosed for months. Several diseases ranging from rheumatic arthritis (RA) to infectious diseases can lead to polyarthritis. Anamnesis, physical exam- ination, laboratory findings, and imaging methods are the tools that support an accurate diagnosis. Herein, we aimed to underline the differential diagnosis of a patient with polyarthritis and in doing so, contribute to clinical practice.

Clues for differential diagnosis ORCID IDs of the authors: N.A.K. 0000-0003-1185-5816; S.Ç. 0000-0002-7919-6696; Demographic data: Age and gender itself may narrow the potential diagnostic options. For example, in C.B. 0000-0002-1730-2991. a young male patient, systemic lupus erythematous (SLE) is at the last position on the list of differential Cite this article as: Alpay-Kanıtez N, Çelik diagnoses of polyarthritis. The incidence of crystal is higher in older patients. The other dis- S, Bes C. Polyarthritis and its differential diagnosis. Eur J Rheumatol 2019; 6(4): eases of advanced age, such as polymyalgia rheumatica and giant-cell arthritis, can also be the causes 167-73. of polyarthritis. 1 Division of , Department of Internal Medicine, Koç University School of Medicine, İstanbul, Turkey History: Diseases associated with connective tissue disorders such as Raynaud’s phenomenon and xe- 2 Division of Rheumatology, Department rophthalmia, psoriasis, inflammatory back pain, symptoms of inflammatory bowel disease, viral infection, of Internal Medicine, University of Health Sciences Dr. Sadi Konuk Training and infectious diarrhea, and genitourinary infection should be checked in each patient. Chronology of the Research Hospital, İstanbul, Turkey onset of symptoms is crucially important in defining the problem. Address for Correspondence: Nilüfer Alpay-Kanıtez; Division of Rheumatology, Department of Internal Genetic susceptibility: Polyarthritis is not a common sign of auto-inflammatory diseases, the Mende- Medicine, Koç University School of Medicine, İstanbul, Turkey lian-inherited prototype of which is Familial Mediterranean Fever (FMF). Rather, Rheumatic diseases ac- E-mail: [email protected] companied by polyarthritis are associated with multifactorial susceptibility. Family history is can only be Submitted: July 29, 2019 a matter of fact in (AS) and (PsA). Accepted: August 13, 2019 Copyright@Author(s) - Available online at www.eurjrheumatol.org. Classification of polyarthritis: If polyarthritis limits itself in less than 6 weeks, it is defined as acute poly- Content of this journal is licensed under a Creative arthritis; if the symptoms last longer than 6 weeks, then chronic polyarthritis is suspected. While acute Commons Attribution-NonCommercial 4.0 International License. polyarthritis is frequently associated with viral infections, RA is one of the most likely diagnoses in chron- ic polyarthritis. The types of joints involved and their symmetric involvement can be considered as load- stars. It is defined as symmetric arthritis if at least half of the joints involved are symmetric. Involvement 167 Alpay-Kanıtez et al. Polyarthritis Eur J Rheumatol 2019; 6(4): 167-73

Table 1. Causes and clinical features of polyarticular joint pain. Sex Age Accompanying findings Laboratory Fibromyalgia F>>M 30-55 Fatigue and sleep disturbances, cognitive disturbances, None psychiatric symptoms, headache, paresthesia Osteoarthritis F>M >60 Pain is worse with joint use, bony swelling, joint deformity None uch as Heberden’s nodule Osteomalasia F=M nr Muscle weakness, spasms and cramps, difficulty walking, Increased ALP, PTH; reduced Ca, fracture P, 25-hydroxy vitamin D Thyroid dysfunction F>M 30-55 Palpitations, sweating, weight loss, hair loss Abnormalities of TSH, sT4 F>M >60 Weakness and fatigue, polyuria, polydipsia, osteoporosis Increased PTH, Ca; reduced P Hypermobility syndromes F>M <30 Recurrent joint subluxations, hyperextensible skin, bowel symptoms None Malignancies F=M nr Weight loss, fever, pain at rest and at night Hypercalcemia, increased LDH, cytopenia

F: Female, M: Male, nr: Specific age range not reported, ALP: Alkaline phosphatase, PTH: Parathyroid hormone, TSH: Thyroid stimulating hormone, Ca: Calcium, P: Phosphorus, LDH: Lactate dehydrogenase

Table 2. Clinical features of common rheumatic diseases causing polyarthritis. Age Sex <40 40 -60 >60 Female Male Classification of polyarthritis Rheumatoid arthritis + +++ ++ ++ + Mainly affects small joints, symmetric, additive Psoriatic arthritis +++ +++ + ++ ++ Affects small, large, axial joints, asymmetrical, additive Ankylosing spondylitis +++ ++ + + ++ Mainly affect large joints, asymmetrical, additive +++ ++ + ++ ++ Mainly affects large joints, asymmetrical, migratory + ++ +++ ++ + Mainly affects small joints, asymmetrical, intermittent Systemic +++ ++ + ++++ + Mainly affects small joints, symmetrical, additive Systemic vasculitis ++ +++ ++ +++ ++ Mainly affects small joints, symmetric, additive.

of large joints such as knee and ankle accord Migratory: At the onset of arthritis, initially 3. Type of involvement: Symmetric or asym- more with (SpA), where- only one or more joints are involved, which metric? as symmetric involvement of small joints of they improve completely after several days. 4. Clinical pattern: Migratory, additive, or in- the hand is expected in RA or SLE. Detection Following this, another joint region is in- termittent? of axial system involvement is important, as volved, and in this way, polyarthritis occurs 5. Table 2 illustrates the characteristics of it narrows the differential diagnosis down to gradually. Acute (ARF) is a common rheumatic diseases presenting the SpA group. There are usually three major typical example of this pattern of arthritis. with polyarthritis. patterns of joint involvement. Additive: Joints become involved within days Physical examination or weeks. This may be a potential pattern for Physical examination would provide support Main Points PsA. to the diagnosis as per the following basic • Polyarthritis can be a clinical manifes- points: Intermittent: Polyarthritis attacks continue for tation of distinct disease processes and a while, following which complete improve- Classification of polyarthritis: In light of infor- the differential diagnosis is reasonably very broad. ment occurs. Polyarthritis recurs after a while mation obtained via anamnesis; classifica- and may progress in this way in adult patients tion of polyarthritis is completed by physical • Rheumatic diseases, which prototype is with adult Still’s disease (ASD). examination. Accompanying extra-articular rheumatoid arthritis, cause polyarthritis musculoskeletal system involvement such as well as non-rheumatic diseases such As a result, polyarthritis is classified according as enthesitis and tenosynovitis can be deter- as infectious diseases, malignancies and to the following parameters (1); mined as well. It can be said that enthesitis even some medications. and tenosynovitis are seen more prominently • A good anamnesis and physical exam- 1. Duration: Acute or chronic? than the SpA group or seronegative diseases. ination are the main pillar of the differ- 2. Type of affected joints: Large or small; with Any limitation in the range of motion and de- ential diagnosis of polyarthritis. axial involvement or not? tection of specific deformities is crucial. For 168 Eur J Rheumatol 2019; 6(4): 167-73 Alpay-Kanıtez et al. Polyarthritis example, irreducible swan neck deformity is The eye: It is important to identify the char- Cardiovascular system: ARF can be encoun- always a sign of RA. acteristics of uveitis determined during the tered in adulthood even though it is an un- ophthalmological examination. While anterior common cause of polyarthritis in this age Accompanying findings: Detecting the sys- uveitis accompanies SpA group diseases, pan group. In such a case, cardiac murmur that is temic symptoms accompanying polyarthritis uveitis or posterior uveitis can be the signs of detected on physical examination can be a during physical examination and evaluating Behçet’s Disease (2). Uveitis with granuloma- sign of cardiac valve involvement. Examina- them accurately is important. Meanwhile, in- tous features is significant in and tion of peripheral pulses is important to sus- formation about the diseases that might be sarcoidosis. Infectious etiology is likely to be pect aortitis. Polyarthritis can be encountered the extra-rheumatic causes of polyarthritis more important if retinitis is determined. It is rarely in Takayasu arteritis or in giant-cell arte- can be obtained as follows; less likely for episcleritis to accompany a sys- ritis (5). Infective endocarditis must be consid- temic disease, whereas scleritis can be a sign ered in the differential diagnosis in a polyar- Weakness, weight loss, fever: Severe polyar- detected concurrently with polyarthritis in thritis case with new-onset fever and cardiac thritis may cause weakness and weight loss patients with systemic vasculitis (3). Dry eye is murmur. Syphilis could be the cause of poly- due to intensive inflammation. In the pres- one of the diagnostic criteria of Sjogren’s syn- arthritis in a patient with advanced-stage aor- ence of accompanying weakness and weight drome, which is among the causes of polyar- tic insufficiency. Aortic dilatation and related loss, systemic rheumatic diseases such as SLE thritis. aortic insufficiency may develop in AS (6). and systemic vasculitis, which may possibly Pericardial effusion and myocarditis, the signs involve the visceral organs, should be at the Reticuloendothelial system: Peripheral lymph- that might accompany rheumatic diseases, top on the list of differential diagnoses. Fever adenopathy can be easily detected via phys- are suspected during physical examination. may occur along with this inflammation. Only ical examination. In such case, the possibility the presence of fever would require frequent of a lymphoma must be excluded. SLE, ASD, Gastrointestinal system: Dysphagia may be questioning, primarily to rule out infectious and Sjogren’s syndrome are the rheumatic suggestive of scleroderma or polymyositis. diseases, lymphoproliferative diseases, and diseases that cause lymphadenopathy. Hepa- Infectious diarrhea is one of the most import- malignancy. tosplenomegaly can be found in ASD or SLE; ant causes of reactive arthritis. Peritonitis can however, it is more likely to be an indicator be a sign of SLE or FMF. Diarrhea or perianal Skin and mucosa: Presence of specific skin of lymphoproliferative disorders than lymph- disease may be suggestive of inflammatory lesions such as malar rash, vasculitis rash, adenopathy. bowel disease. Signs of mesenteric ischemia and psoriasis are important in making the could be associated with systemic vasculitis, diagnosis. Raynaud’s phenomenon can be The lungs: In a patient with polyarthritis, pul- particularly in emergency clinics. Abdominal detected during physical examination. There monary findings can either be in the form of collaterals may be the signs of Budd Chiari may be specific cutaneous signs of the in- pulmonary involvement of systemic rheumat- syndrome in a patient with Behçet’s Disease. fectious diseases, primarily in viral infections. ic disease, associated with infectious disease, Figure 1 illustrates palmoplantar skin rash in or related to a malignancy. Pulmonary signs Urogenital system: In a polyarthritis patient a syphilis patient with polyarthritis. Inspec- likely to be seen in rheumatic diseases, such with accompanying , SLE and tion of the mucosa should be a part of the as pleuritis, pleural effusion, airway disease, systemic vasculitis would be at the top of the physical examination. For instance, presence lung nodules, interstitial lung disease, pul- list of differential diagnoses. Detection of pro- of an ulcer in the oral mucosa of a young monary hypertension, and pulmonary hem- teinuria and hematuria, which indicate glo- female with polyarthritis may support the orrhage, must be examined in detail both in merular involvement, is important. Urogenital diagnosis of SLE. Genital aphthae that ac- the physical examination and in the anamne- infections can be the causes of reactive arthri- company recurrent aphthous lesions may sis (4). Detection of lung nodules may require tis (7). Epididymitis and orchitis, which might be enough proof to make a diagnosis of Be- histopathological examination to exclude be the signs of systemic vasculitis, can be de- hçet’s Disease. malignancy from the differential diagnosis. tected on physical examination.

Figure 1. Palmoplantar skin rash in a syphilis patient with polyarthritis. 169 Alpay-Kanıtez et al. Polyarthritis Eur J Rheumatol 2019; 6(4): 167-73

Nervous system: Motor or sensorial loss can oc- not exclude the diagnosis of polyarthritis or Synovial fluid analysis: Synovial fluid analysis, cur due to peripheral nerve involvement. Ob- rheumatic disease. Very high ferritin levels which is critical in diagnosing , serving a drop foot due to mononeuritis multi- may be a supportive sign of ASD, but ferritin has a limited role in the differential diagno- plex as the patient walks into the examination is not increased in a small proportion of ASD sis of polyarthritis. Detecting crystals in the room suggests systemic vasculitis. Signs such patients (9). synovial fluid of the patients with crystal ar- as side weakness, increased deep tendon re- thropathy is diagnostic. Microscopic examina- flex, ataxia, and dysphagia due to central ner- Other biochemical tests: should tion and synovial fluid culture be necessary if vous system involvement can be detected on be studied in every patient with suspected polyarthritis is caused by the direct invasion physical examination. Neurological examina- crystal arthropathy. Uric acid concentration of an infectious agent, such as tuberculosis tion, in detail if necessary, should be a part of can be normal in a small proportion of pa- and leprosy. the general rheumatologic examination. tients with arthritis or during an acute attack of gout. Liver and kidney function Radiological methods Laboratory findings tests should be considered in every patient Radiography can make a substantial contri- Laboratory findings are the third most im- with polyarthritis. SLE and systemic vasculitis bution to the diagnosis of polyarthritis. Hand portant component of differential diagnosis patients can present with acute kidney fail- radiography is valuable in making a diagno- after a detailed anamnesis and physical exam- ure. Acute hepatitis or other viral agents can sis of RA and PsA. Erosion and lytic lesions ination. Even simple laboratory tests may give compromise hepatic function tests. Elevated can be diagnostic for RA. Presence of sacro- clues in making a differential diagnosis. lactate dehydrogenase (LDH) is suggestive iliitis can be demonstrated radiographically of autoimmune hemolytic anemia, ASD, my- by a suprapubic sacroiliac radiograph. Sac- Complete blood count: Cytopenia is a sup- ositis, and malignancy. Elevated creatinine roiliac magnetic resonance imaging (MRI) is portive finding for SLE. However, polyarthritis kinase should be evaluated in every patient performed in case of suspected sacroiliitis can be one of the components of the clini- with polyarthritis and may be a potential in- despite the availability of a normal X-ray. Lin- cal manifestation of leukemia and lymphoma dicator of myositis. ear calcifications of cartilage detected in the that causes cytopenia. Lymphocytosis is a knee radiography can support the diagnosis valuable finding for chronic lymphoprolifer- Autoantibodies: They are critical in the diag- of pseudogout. No doubt, lung radiography ative disorders. Polycythemia and thrombosis nosis of RA, SLE, other connective tissue dis- must be performed in patients with respi- raise doubts on myeloproliferative disease as eases, and systemic vasculitis. Rheumatoid ratory system symptoms. Ultrasound, MRI, well. Presence of eosinophilia can be a sign factor (RF), anti-CCP antibody, and antinucle- X-ray, CT, and PET-CT are potential radiologi- of Churg-Strauss vasculitis and hyper eosino- ar antibody (ANA) should be studied in each cal methods of diagnosis. philic syndrome with polyarthritis. patient with polyarthritis. Based on accom- panying symptoms, endonuclear antibody Ultrasonography (US) can be used to evaluate Urinalysis: A simple urinalysis can be helpful (ENA) panel and anti-neutrophil antibody the severity and make the differential diagno- for making several differential diagnoses. The (ANCA) can also be studied. RF may be pos- sis of arthritis. Detecting enthesopathy and presence of pyuria may indicate polyarthritis itive in RA, in SLE or other connective tissue tendinopathy via US is significant for SpA (14). reactive to a urinary system infection. The diseases, and in systemic vasculitis. RF may be Starry sky appearance in the joints of patients presence of proteinuria and/or hematuria is positive in patients with infectious diseases with crystal arthropathy is helpful in making quite valuable for SLE and systemic vasculitis, and malignancies (10). It is important to es- which has the potential to involve glomeruli tablish anti-CCP positivity to make a diagnosis the diagnosis. Use of US also a valuable tool and may require a renal biopsy to make the of RA. High-titer positivity has high specificity in clinical follow-up to monitor treatment ef- diagnosis. in diagnosing RA (11). Accurate interpretation ficacy. Temporal artery doppler US findings of the result of ANA testing is also important, can help with differential diagnosis in case of Acute phase reactants (APR): These are the pro- where attention needs to be paid to the titer clinical suspicion. teins whose serum concentrations increase and pattern. Low-titer ANA positivity can be due to inflammation and tissue injury. C-re- seen in about 30% of healthy females. ANA Contribution of computed tomography (CT) active protein (CRP) is one of the most com- can also be positive in other autoimmune and MRI to the diagnosis of polyarthritis is mon APRs. Erythrocyte sedimentation rate diseases or malignancy (12). If ANA is positive, limited, except for SpA. However, they can be (ESR) is an indirect method to measure APR ENA panel, anti-DNA antibody, and comple- used for the differential diagnosis of accom- and is frequently used in clinical practice (8). ment testing can be performed. Sensitivity of panying system involvements. For example, Serum amyloid A, complement components, anti-DNA ranged from 27.7% to 100%, while thoracic CT findings are quite valuable in in- alpha-1 antitrypsin, fibrinogen, hepcidin, fer- its specificity ranged from 13% to 89.1% (13). terstitial lung disease. In addition, if arthritis is ritin, and haptoglobin are the other APRs. In- In a polyarthritis case with negative ANA test- suspected, MRI may be helpful in demonstrat- creased APR is not always a sign of rheumatic ing, there is usually no need to study further ing synovitis. disease. Infectious diseases and malignancies tests including ENA panel, anti-DNA antibody, (rarely) can increase APRs. The inflammation and its complement. PET-CT is helpful in making a differential di- in SLE is not expected to elevate CRP, except agnosis in cases with suspected malignancy. in some exceptional cases. Although APRs are Viral and bacterial serology: It is not a routine Recently, it was understood that PET-CT con- usually elevated in patients with rheumatic examination in polyarthritis patients but can tributes to the differential diagnosis of large disease-related polyarthritis, they sometimes be studied to support the diagnosis in case of vessel vasculitis. Large vessel vasculitis is a are within the normal limits. Normal APRs do clinical suspicion. rare cause of polyarthritis (5). 170 Eur J Rheumatol 2019; 6(4): 167-73 Alpay-Kanıtez et al. Polyarthritis

Figure 2. Symmetrical enlargement of wrists and proximal interphalangeal joints. Her percutaneous synovial biopsy with amyloid deposits con- firmed by Congo red staining. Hematoxylin-eosin staining; original magnification 640.

Table 3. Causes of polyarthritis. Inflammatory rheumatic diseases Rheumatoid arthritis Psoriatic arthritis and other Crystal Systemic lupus erythematosus Sjogren's syndrome, scleroderma and other connective tissue disorders Systemic vasculitis, sarcoidosis, Behcet's disease etc. Infective disorders Invasive joint infections I-Viral infections (, 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, poststreptococcal 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 check point inhibitors Psychotropic 5-HT2A antagonists (mianserin, mirtazapine, nefazodone)

Histopathology diagnosis of accompanying symptoms or in These possibilities make the internal medicine Synovial histopathology is infrequently re- evaluating visceral organ involvement. perspective even more important in the evalua- quired in polyarthritis. Figure 2 demonstrates a tion of patients with polyarthritis (Table 3). polyarthritis case diagnosed with primary am- Extra-rheumatic causes of polyarthritis yloidosis via synovial biopsy. Histopathology Whether acute or chronic, polyarthritis can have Infectious diseases: Numerous different bac- is rather important for making the differential different causes other than rheumatic diseases. teria, viruses, fungi, and parasites can cause 171 Alpay-Kanıtez et al. Polyarthritis Eur J Rheumatol 2019; 6(4): 167-73

polyarthritis. Infections may lead to polyar- Remitting seronegative symmetrical synovitis Conflict of Interest: The authors have no conflict of thritis over three different mechanisms (15); with pitting edema (RS3PE): It is a form of poly- interest to declare. arthritis that occurs in the elderly. It is char- 1. Direct invasion: A microbiological agent acterized by the symmetrical involvement of Financial Disclosure: The authors declared that this directly infects the synovial tissue. This small joints and marked pitting edema on the study has received no financial support. is causes monoarthritis but may lead to dorsum of the hands and feet, a sudden in- polyarthritis in rare cases (e.g. Syphilis, flammatory onset, RF negativity, and an over- References leprosy). all excellent prognosis. Prevalence of malig- 1. Singh S, Mehra S. Approach to polyarthritis. Indian J Pediatr 2010; 77: 1005-10. [CrossRef] 2. Immune-mediated inflammation: Anti- nancy is increased in RS3PE, thus, the patients 2. Cunningham ET, Tugal-Tutkun I, Khairallah M, microbial antibodies lead to polyarthritis diagnosed with RS3PE need to be evaluated Okada AA, Bodaghi B, Zierhut M. Behçet Uveitis. due to the similarities between microbi- for malignancy. Ocul Immunol Inflamm 2017; 25: 2-6.[ CrossRef] ological antigens and autoantigens (e.g. 3. Tugal-Tutkun I. Systemic vasculitis and the eye. ARF, Lyme disease). Drugs and polyarthritis: Polyarthritis patients Curr Opin Rheumatol 2017; 29: 24-32. [CrossRef] 3. Reactive arthritis: Urogenital or gastro- should be questioned in detail about the 4. Doyle TJ, Dellaripa PF. Lung Manifestations intestinal system infections can cause medications they have been receiving. There in the Rheumatic Diseases. Chest 2017; 152: inflammatory joint diseases like spondy- has been an increasing amount of data in 1283-95. 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