Systemic inflammatory diseases, especially autoimmune diseases, are present difficulties in family medicine practice, due to atypical clinical presentation from patient to patient. Knowledge of the specific factors that trigger autoimmune disease and their mode of action may also inform risk reduction in the individual patient. These factors are especially relevant for those at increased risk of autoimmune disease based on family history. Diagnosis is based on clinical assessment, supported by family medicine doctors and multidisciplinary approach. In those patients who present with a polyarthritis, at least five joints must be involved with the signs of inflammation, pain, swelling, warmth, movement restriction, and redness in the involved joints. The severity of polyarthritis can range from asymptomatic to life-threatening, and time duration may differ. When symptoms last for more than six weeks, polyarthritis is most likely chronic. Usually, in the background of the chronic polyarthritis, there is dysregulated immune response, lymphocytes react against self-antigens by producing autoantibodies and suppressing the normal immune function, caused by unrecognized rheumatoid arthritis (RA) [1]. The prevalence of RA ranges from 0.5–1%, with grater predisposition in middle-aged woman, with the biggest incidence in sixth decade [2],[3]. Even though the exact cause of RA is still unknown, genetic and environmental factors are considered important for the development of the disease [4]. A number of studies offered compelling evidence associating Proteus mirabilis caused urinary tract infections (UTIs) with the development of RA [5] as well as an association of hypogammaglobulinemia with RA development [6],[7],[8]. Pathophysiology includes systemic inflammatory response, T cell, B cell, and monocyte infiltration of the joints synovial membrane, leading to the formation of the pannus, bony, and cartilage degradation. There are many components involved in development of the inflammatory process, including interleukin-6, tumor necrosis factor, granulocyte-macrophage colony-stimulating factor, cytokines, chemokines, and many others [9]. Diagnostic approach and tools for RA involve severe of following criteria: the presence of inflammatory arthritis in three or more joints, with the symptoms of pain, morning stiffness, swelling, symmetrical joint involvement, elevated levels of CRP, or the high erythrocyte sedimentation rate and positive diagnostic markers [4][10],[11]. At the time, the most used diagnostic markers for the confirmation of RA are anti-cyclical citrullinated peptide and rheumatoid factor (RF). Unfortunately, these markers show great limitation regarding sensitivity and specificity, leading to severe difficulty in early diagnosis of RA. Recently, a study suggested new markers for the diagnosis isolated from synovial fluid as well as the importance of synovial fluid analysis [12]. Despite this, there is still lack of increasing forces to develop and register new biomarkers, and lack of government-led primary care to expand its role in prevention, early detection and control, and management within rare autoimmune disease such as RA.

A female patient, aged 50-years, presented to a family medicine doctor firstly in April 2019, with the symmetrical pain in knees, ankles, hips, and shoulders with muscle spasms in both legs. The patient described an annealing and pulsating sensation in the knees and ankles. Since then, the pain is constant especially during physical activity, with the stiffness presented in the knees, ankles, hands, and hips. Periodically she suffers from dizziness, and joint edema, especially in the knees. From family history her mother suffered from psoriatic arthritis, but without other rheumatological diseases or inflammatory bowel disease (IBD) in family history. From earlier the patient suffered from dyslipidemia and nicotinism. The patient was suggested to perform rheumatological lab test with radiology imaging. As her pain was worsening, rheumatologist was consulted and suggested immunological tests, imaging, spirometry, cervical, and urethral smear. Initially her lab results showed normal SE, CBC, and DBC, with low anti-CCP (<0.50 U/mL), low values of TSH (0,16 mIU/L), elevated cholesterol (7.1 mmol/L), and DLDL-H (5 mmol/L) levels, slightly elevated levels of angiotensin-converting enzyme (ACE) (68 U/L), and elevated vitamin D (93.9 nmol/L) and calcium (2.62 mmol/L) levels with consistent pathological urine analysis with leukocytes present, but with normal CRP. Serum protein electrophoresis revealed slightly higher albumin (69.7%) and Alfa 2 globulin (15.2%) shares and low values of beta globulin (3.9%) and gamma globulin (7.0%) shares. Rheumatoid factor and Waaler–Rose test were both negative. Cardiolipin antibodies of IgG and IgM class were negative. Anti-beta2-glycoprotein I, proliferating cell nuclear antigen (PCNA) antibodies, histone antibodies, anti-dsDNA, extractable nuclear antigen (ENA) screen, anti-SS-A/Ro, anti-SS-B/La, anti-Sm, anti-Sm/RNP, anti-Jo-1, anti-Scl-70, U1RNP, and PmScl antibodies were all negative, and complement total (CH50) test, C3, and C4 were normal. Synovial fluid analysis showed high WBC count, elevated IL-6, IL-8, and ACE.

The patient had also done a PAP smear test, which was normal, and a breast ultrasound which revealed bilateral cysts around 6.8 mm size. An endocrinologist performed a thyroid ultrasound, which was normal, showing no signs of cysts or nodes, and had suggested vitamin D supplement therapy. Cervical smear and urine antibiogram were negative, while urethral smear tested positive for P. mirabilis, after which antibiotic therapy was conducted. Six months later, urethral smear tested positive for Ureaplasma urealyticum. Spirometry, capacity of the lungs for carbon monoxide (DLCO) and chest X-ray scan were all normal and the quantiferon test was negative. Lumbosacral spine X-ray showed marginal osteophytosis and interface arthritis. Foot X-ray revealed degenerative changes of the first metatarsophalangeal joint.

Bone densitometry revealed a normal bone density of 92%, while also showing osteopenia of the neck of the femur. Magnetic resonance imaging (MRI) of the spine and sacroiliacal joints revealed no acute inflammatory changes, but noted mild subchondral sclerosation of sacroiliacal surfaces and a small zone of subchondral edema in the lower left third of the sacroiliacal joint. Capillaroscopy showed poorer skin transparency, noting a pericapillary edema.

The patient was treated with analgesic multiple drug combinations (Paracetamol + Naproxen) and sulfasalazine, but pain is still persistent.

Even though it is known that systemic inflammatory diseases are characterized by exacerbations and remissions, the biggest problem presents disability, which statistically around 40% of patients develop after 10 years, especially those who are not properly treated [13]. Still, early diagnosis is key to optimal management and therapeutic strategies, particularly in those patients with well-characterized risk factors for poor outcomes such as high disease activity, presence of autoantibodies, and early joint damage [9]. Previous reports suggested important role of familial associations for rheumatoid autoimmune diseases, but in some cases there is pathophysiological complexity of understanding of underlying autoimmune disease [14]. As many studies considered the principles of treat-to-target (T2T) and have been widely adopted in both multinational and regional guidelines for rheumatoid arthritis (RA), in many cases there is lack of evidences for final diagnose, and it presents difficulties in therapeutic strategies [15].

In this case report, there is some complexity, because we showed highly atypical RA presentation with negative citrullinated proteins, anticyclic antibodies and rheumatoid factor, which are considered standard diagnostic markers of RA.

Due to existing autoimmune disorder in the family, in the form of psoriatic arthritis, and recurrent UTIs that are well known to trigger autoimmune response, with typical clinical signs of RA, we believed that our patient was showing early signs of RA. Unfortunately, previous reports shown that awareness with guidelines is not synonymous with their actual practice [16]. As it is known that UTI can induce autoimmune response, Puntis and his team focused on etiology of UTIs in patients with rheumatoid arthritis, and concluded that RA was associated with a higher-than-expected incidence of UTI, particularly among older females [17]. Li et al. examined association of microbial infection and RA. Also, they confirmed new generation of neo-autoantigens, and mechanism of tolerance by molecular mimicry, and bystander activation of the immune system [18]. Ebringer and Rashid examined an association of RA and Proteus UTI, and focused on pathogenetic mechanism which involves stages triggered by cross-reactive autoantibodies. Also, they explained importance of proper and early treatment with anti-Proteus antibiotics as well as biological agents to avoid irreversible joint damages [19]. In our case, the patient was positive for P. mirabilis, but another UTI was described the patient was positive for U. urealyticum, and it is known that U. urealyticum protein might act as a cross-reactive antigen [20]. On the other hand, as our patient had complex clinical presentation, and due to nonspecific RA criteria, synovial fluid was analyzed, and confirmed presence of RA [21]. These findings indicate that synovial fluid might play a role in the earliest phases of RA development. As blood is easily accessible, and it represents a medium that might be ideal for diagnosis, activation of the immune system during RA development can be monitored via measuring serum proteins, such as cytokines and chemokines. There is important role of full comprehension of how RA develops over time.

Since the majority of consultations in the primary healthcare setting are for older patients with multimorbidity, primary care physicians are also in high demand, and there is important role in understanding pathogenesis of autoimmune disease and continuous education. Pathophysiological complexity of understanding could be due to the agent triggering autoimmune disease, so it is possible that UTI precipitated the onset of preexisting autoimmune disease, and synovial fluid interpretation confirmed diagnose. To conclude with, it is believed that therapy for rheumatoid arthritis (RA) is the most effective and beneficial within a short time frame around RA diagnosis. Also, there is important role of GPs in educating patients with confirmed RA to report any new worrisome symptom, because these could be a significant predictor of disease progression.

To conclude with, it is believed that therapy for rheumatoid arthritis (RA) is the most effective and beneficial within a short time frame around RA diagnosis. Also, there is important role of GPs in educating patients with confirmed RA to report any new worrisome symptom because these could be a significant predictor of disease progression.