Dr . Stein ’ s Problem-Based Learning

Dr. Stein teaches problem-based clinical reasoning from a clinical case twice a year at the Department of General Medicine, Juntendo University Faculty of Medicine. Problem-based clinical reasoning is to organize clinical information such as medical history, physical examination and laboratory data, into practical problem lists and develop assessment for diagnosis and treatment. Here is the report of the recent case conference to learn problem-based clinical reasoning. A 36-year-old man admitted to our hospital because of fever, erythema and migratory polyarticular pain. In this case, the listed problems by Dr. Stein were as follows: fever, macular erythema on upper and lower extremities, arthritis of both feet, bilateral Achillesʼ tendon pains and enthesitis of ankle joints and Achilles tendons. Based on this problem list, reactive arthritis seemed as the most possible diagnosis. By asking the history of present illness repeatedly, he confessed that he had experienced diarrhea about 5 days before other symptoms started. Stool culture was performed and yielded Salmonella typhimurium (O:4, H:I), so we could conclude the final diagnosis as reactive arthritis after Salmonella infection. Dr. Stein pointed out the importance to distinguish arthritis from arthralgia for correct recognition of patientʼs illness and the effectiveness to return to the history after listing problems and possible diagnosis.


History of present illness
A 36-year-old man was admitted to our hospital with fever, lumbago, leg pain, and rash.He had been well until eight days before admission, when he began to have fever, with temperature as high as 38.0℃.His symptoms were partially relieved with over-the-counter cold medication.The patient developed rashes on his back and buttocks five days prior to admission.The next day, he felt pain in his back and legs, and loxoprofen temporarily improved this symptom.Three days before admission, he presented to the outpatient clinic with persistent fever (37.9℃), back and leg pains.He complained of lumbago, pains on the posterior surface of the knees bilaterally, and Achilles tendon pains.Although the rash on his back faded, the patient developed multiple new erythematous lesions on his forearms bilaterally as well as on his lower extremities and back.Two sets of blood cultures were taken, and he was instructed to return to the clinic three days later.The patient was prescribed acetaminophen for treatment of his symptoms.
Two days later, the patient began experiencing throbbing dorsal, plantar, and heel pains in his feet, as well as his left wrist.The feet pains were severe enough to prevent walking, though the previous lumbago and knees pains were alleviated.The patient returned to the clinic the following day and was admitted.

Past medical history, habits, social history and family history
The patient was diagnosed with Wolff-Parkinson-White (WPW) syndrome as a teenager.He did not smoke and only drank alcohol occasionally.He worked in a hospital office as an administrator.He had no history of allergy; his family history was not significant.

Review of systems (Figure-1)
Important positives: see history of present illness.Important negatives: no additional information from ROS.

Dr. Steinʼs comments 1
Polyarticular pain in adults is frequently encountered in clinical practice and potential causes include various self-limited illnesses.The diagnostic possibilities can be narrowed substantially depending upon whether arthritis is present or not.Arthritis is"inflammation of a joint" , which presents with redness, warmth, swelling, and pain of the affected joint.A distinction between"arthralgias" , painful joint without swelling, should be noted since this finding is usually non-specific.Because arthritis is frequently accompanied by synovitis, an important objective of the physical examination is to identify the presence or absence of synovitis.The hallmarks of synovitis include: soft tissue swelling, warmth over a joint, joint effusion, and loss of motion.Reduced active range of motion (ROM) can be seen with periarthritis, while reduced passive ROM is not seen with periarthritis.Reduced ROM in multiple directions suggests arthritis, while reduced ROM in a single direction suggests periarthritis.
A macular rash that disappears under pressure is considered as"macular erythema" , which may be related to varying causes, including viral infection, drug reaction, rheumatic fever, and other conditions.

Physical examination on admission
On admission, the patient was alert, body temperature was 37.4℃, heart rate was 92 beats per minute, blood pressure was 112/72 mmHg, and oxygen saturation 98% while breathing ambient air.There was no scleral icterus or conjuctival pallor.His oropharynx was clear and without erythema or exudates.The neck was supple.Heart rate was regular, with no murmurs, gallops, or rubs.The lungs were clear to auscultation.The abdomen was soft, without tenderness.Liver, spleen, cervical, axillary, and inguinal lymph nodes were not There was tenderness, swelling, and redness on the dorsal and plantar surfaces of both feet, as well as at the insertion of the Achilles tendons.Limited ROM of both ankles was also found.Tenderness was also found on the right 3 rd finger, left 4 th finger, and the lateral sides of both knees.

Revised problem list
#1. Fever #2.Macular erythema on upper and lower extremities #3.Arthritis of both feet #4.Bilateral Achillesʼ tendon pains #5.Enthesitis of ankle joints and Achilles tendons #6.Polyarticular pain of knees, as well as right 3 rd finger and left 4 th finger.

Dr. Steinʼs comment 2
Lower extremity pain was diagnosed as inflammation of joints or soft tissue.Physical findings, especially #2 and #3, allowed for alteration of the patientʼs subjective symptoms to"macular erythema"and"arthritis and enthesitis" .As differential diagnosis, we listed the following diseases (Table-2).
Because the patientʼs pain began in the lumbar region with arthralgia of the knee joints, and then migrated to the ankles and wrist, his arthritis was thought to be migratory.Because he had migratory arthritis, enthesitis, preceding fever, and macular erythema, reactive arthritis was considered as a potential diagnosis.Reactive arthritis is a form of arthritis associated with a coexisting or recent antecedent extra-articular infection.Pathogens that cause reactive arthritis are listed in Table-3.
The Jones criteria for rheumatic fever, which is similar to reactive arthritis, require manifestations  In general, when the symptoms of polyarthritis persist for more than six weeks, evaluation of anti-nuclear antigen and anti-cyclic citrullinated peptide antibody are required as part of evaluation for systemic rheumatic disease.When the duration of symptoms is less than six weeks, viral arthritis or early onset of systemic rheumatic disease may be considered, and careful observation is required, with evaluation of viral antigen/antibody, if needed.

Laboratory tests and imaging studies
Laboratory findings demonstrated a white blood cell (WBC) count of 14, 500 per mm 3 , with 80% neutrophils.The erythrocyte sedimentation rate (ESR) was 93 millimeter at one hour.C-reactive protein was 11.1 mg/dl.A basic metabolic panel, liver function tests, renal function tests, uric acid, and urinalysis were normal.Two sets of blood cultures and a pharyngeal culture were negative.Parvovirus B19 IgM antibody, rubella IgM antibody, hepatitis B and C virus antibodies, urinary gonococcal, and chlamydial polymerase chain reac-tions were all negative.Antistreptolysin and antistreptokinase were not elevated.Anti-nuclear antigen, anti-cyclic citrullinated peptide antibody, proteinase anti-neutrophil cytoplasmic antibody, and myeloperoxidase anti-neutrophil cytoplasmic antibody were negative.
Chest radiograph and electrocardiogram were without abnormalities.Cardiac ultrasonography showed no vegetation or valvular abnormalities.There was no evidence of malignancy on systemic contrast-enhanced computed tomography (CT).There was no evidence of synovitis or erosion of the bone on contrast-enhanced magnetic resonance imaging (MRI) of both hands.Joint radiography showed no intra-articular calcification.Arthrocentesis was not performed due to insufficient synovial fluid.

Dr. Steinʼs comment 3
Based on these findings, viral arthritis, and systemic rheumatic disease were considered unlikely.Generally, bacterial arthritis presents with monoarthritis and enthesitis is not a common symptom.Septic arthritis derived from infective endocarditis presents with polyarthritis, but this was considered unlikely due to the absence of systemic embolic symptoms, as well as negative blood cultures and lack of abnormal findings in cardiac ultrasonography.Ankylosing spondylitis is associated with lumbar pain lasting over three months along with limited ROM of the lumbar vertebrae.There were no symptoms of Crohnʼ s disease or ulcerative colitis that would indicate inflammatory bowel disease-associated spondyloarthritis.No characteristic rash suspicious of psoriatic arthritis was observed.Crystal-induced arthritis is diagnosed by the presence of crystals in the synovial fluid, but this could not be sampled in this case.Regardless of this, crystal-induced arthritis was considered unlikely because of the migratory arthritis seen in this case, rather than the monoarthritis commonly observed with this condition.Contrast-enhanced CT for ruling out paraneoplastic syndrome may not have been necessary or was performed too early in the disease process for evaluation.Negative Streptococcus pyogenes culture and antibody indicated that rheumatic fever was unlikely.Therefore, reactive arthritis was considered to be the most likely diagnosis.

Clinical course after admission
On admission, the patient was treated with intravenous antimicrobial agents (cephazolin 2 gms every 8 hours) based on suspicion of cellulitis, arthritis, and enthesitis due to staphylococcal or streptococcal infection.Arthritis of the feet improved after several days, but arthritis of the wrist developed and fever persisted for three days.Therefore, the antimicrobial agents were discontinued because they were considered ineffective.Colonoscopy showed no abnormal findings.We repeatedly queried the patientʼs history given suspicion of reactive arthritis.On more detailed questioning, he denied any high risk sexual exposure.However he reported ingestion of motsunabe (a hot pot stew made with offal and vegetables) in Fukuoka, Japan, seven days before his symptoms started.He did experience slightly loose stool for a few days following the ingestion, but he did not identify this as problematic.A stool culture was obtained, and it yielded Salmonella typhimurium (O: 4, H: I).Because of the acute colitis history, acute arthritis with suspicion of septic arthritis, and the enteric pathogenic stool culture, the patient received levofloxacin, 500 mg daily for 5 days.Daily oral nonsteroidal anti-inflammatory agents (NSAIDs) were started.Subsequently, fever and rash resolved, his arthritis improved, and the patient was discharged 15 days after admission.Later his HLA B27 test was reported as negative.Nine months after discharge the patient remained arthritis free.Finally, this case was diagnosed as reactive arthritis due to Salmonella typhimurium foodborne illness.

Dr. Steinʼs comment 4
Patients with reactive arthritis typically present with an asymmetric oligoarthritis, usually one to four weeks following the inciting infection.The features of reactive arthritis include arthritis of small joints, enthesitis (inflammation of ligaments or tendons at the point of attachment to bone), dactylitis (sausage shaped digits), or axial arthritis of the spine at any level.The diagnosis of reactive arthritis is a clinical diagnosis, and there are no validated diagnostic criteria.The diagnosis can generally be made in patients with all three of the following: characteristic musculoskeletal findings, evidence of preceding extra-articular infection, and a lack of evidence for another more likely cause of oligoarthritis, monoarthritis, or enthesitis.Characteristic musculoskeletal findings may include arthritis, enthesitis, and dactylitis, often occurring asymmetrically in peripheral joints of the lower extremities, but affecting the upper extremities in half of cases.Enthesitis can occur in patients with other forms of spondyloarthritis.Swelling at the heels is one of the characteristic symptoms of enthesitis.Common sites of heel involvement are at the insertions of the Achilles tendon and of the plantar fascia on the calcaneus, as seen in this patient.Estimates of the frequency of enthesitis in patients with reactive arthritis have ranged from 20 to 90 percent 1) .Dactylitis typically presents as sausage shaped digits, but the frequency in reactive arthritis has not been reported.
Extra-articular manifestations include: conjunctivitis, anterior uveitis, genitourinary symptoms such as urethritis, oral mucosal ulcers, dermatologic symptoms such as keratoderma blennorrhagica, and erythema nodosum.Peripheral blood leukocytosis is often seen, but it is not specific.The prevalence of HLA-B27 is generally estimated at 30 to 50 percent in patients with reactive arthritis, although it was negative in this patient 2) .The prevalence of HLA B-27 in healthy Japanese is estimated at 0.2 percent 3) .
Laboratory tests such as stool cultures, urine and genital swab testing may be performed based on preceding symptoms, such as diarrhea or urethritis, and can sometimes detect antecedent or concomitant infection.However, approximately 50 percent of pathogens have been reported to be undetectable.In this case, because there was very mild preceding diarrhea, detection of Salmonella typhimurium from stool culture led to the diagnosis of reactive arthritis from foodborne illness.A recent study reported the incidence of 12 reactive arthritis cases per 1,000 cases of Salmonella infections 4) .
The principal form of treatment for reactive arthritis is NSAIDs.The use of antibiotics is controversial 5) .Intra-articular and/or systemic glucocorticoids may be administered in patients with disease resistant to NSAIDs.Treatment with disease-modifying antirheumatic drugs (DMARDs) is indicated in patients who do not respond to initial therapy for more than three months.Most patients improve within 6 to 12 months, but about 25 percent of patients have been reported to develop chronic arthritis 6) .

Summary: Learning points from Dr. Steinʼs conference
We learned from Dr. Stein that it is important to discover whether there is associated arthritis in patients with arthralgia.We should consider reactive arthritis if the patient has migratory arthritis, enthesitis involving the feet, and an episode of preceding infection.It is important to guide the differential diagnosis by the pattern of symptoms and to repeatedly assess the history based on the differential diagnosis (Table-4)(http: //plaza.ufl.edu/jerrydoc/) 7).

Figure- 2
Figure-2 Macular erythema on lower extremities erythema on upper and lower extremities #3 Bilateral arthritis of feet #4 Enthesitis of ankle joints and Achilles tendon #5 Polyarticular pain of knees, right 3 rd finger, and left 4 th finger #6 Leukocytosis with increased numbers of granulocytes #7 Elevation of ESR and C-reactive protein

Table - 2
Differential diagnosisof Streptococcus pyogenes infection.However, this patient was not within the age range associated with a high frequency of rheumatic fever and no symptoms or findings of pharyngitis or respiratory infection.

Table - 3
Causative pathogens of reactive arthritis