In a 36‑year‑old woman with one month of fatigue after starting night‑shift work, intermittent elbow and knee pain, low mean corpuscular hemoglobin, mild monocytosis, elevated C‑reactive protein, normal erythrocyte sedimentation rate, negative anti‑cyclic citrullinated peptide antibodies and rheumatoid factor, and a soft grade 1/6 systolic flow murmur, what is the most likely diagnosis and what next steps should be taken?

Diagnostic Assessment: Likely Undifferentiated Peripheral Inflammatory Arthritis with Need for Urgent Rheumatology Referral

This 36-year-old woman does not meet criteria for rheumatoid arthritis and most likely has undifferentiated peripheral inflammatory arthritis (UPIA) or an alternative diagnosis requiring systematic evaluation. The negative RF, anti-CCP, and ESR combined with only mildly elevated CRP (10.5 mg/L) and normal joint examination make RA unlikely at this time 1.

Why This Is NOT Rheumatoid Arthritis

The laboratory profile argues strongly against RA:

• Seronegative RA accounts for only 20-30% of cases, but this patient lacks the clinical synovitis required for diagnosis 1
• Normal ESR and RF together occur in only 15-14% of RA patients at presentation, making RA statistically unlikely 2
• The 2010 ACR/EULAR criteria require ≥6/10 points for definite RA classification. This patient scores only 2-3 points maximum: 1 point for abnormal CRP, 0 points for negative serology, and insufficient joint involvement documented 1
• Anti-CCP negativity has 90% specificity for excluding RA, particularly when combined with negative RF 1, 3

Most Likely Diagnosis: Undifferentiated Peripheral Inflammatory Arthritis (UPIA)

The clinical picture fits UPIA:

• Intermittent joint pain since childhood with no documented pathology suggests a non-inflammatory or functional pain syndrome 1
• Recent onset of elbow and knee pain (11 days) is too brief to meet the ≥6 weeks duration criterion for RA classification 1
• Mildly elevated CRP (10.5 mg/L) with normal ESR creates diagnostic uncertainty—this discordance can occur when inflammation is resolving or when CRP elevation reflects non-rheumatic causes 4
• The grade 1/6 flow murmur is likely a benign finding (innocent murmur) but requires echocardiography to exclude structural heart disease 5

Critical Alternative Diagnoses to Exclude

1. Shift-Work Sleep Disorder with Secondary Fatigue

• Night-shift work starting 1 month ago directly correlates with symptom onset 6
• Sleep loss exacerbates fatigue, depression, and pain perception in susceptible individuals, and can amplify pre-existing pain syndromes 6
• Fatigue is multifactorial and sleep deprivation is a common, reversible cause that must be addressed before attributing symptoms to inflammatory disease 5, 7

2. Psoriatic Arthritis

• Can present with polyarticular involvement, elevated CRP, and negative RF/anti-CCP 1
• Examine skin carefully for psoriatic plaques, scalp involvement, nail pitting, or onycholysis 1

3. Reactive Arthritis

• Recent conjunctivitis, urethritis, or GI/GU infection should be specifically queried 1
• HLA-B27 testing is indicated if axial symptoms, enthesitis, or asymmetric lower-extremity arthritis develop 1

4. Viral Arthritis

• Parvovirus B19, hepatitis B/C, or EBV can cause transient polyarthralgia with elevated inflammatory markers 1
• Symptoms resolving within 6 weeks favor viral arthritis; persistence beyond 6 weeks suggests true inflammatory arthritis 1

5. Polymyalgia Rheumatica (PMR)

• Age <50 years makes PMR unlikely, but proximal muscle pain without true weakness and markedly elevated ESR/CRP would support this diagnosis 4
• This patient's normal ESR effectively excludes PMR 4

Immediate Next Steps

1. Complete the Diagnostic Work-Up Before Labeling as RA

Order these tests immediately:

• Anti-CCP antibodies (if not already done)—the most specific test for RA with 90% specificity 1, 3
• Complete blood count with differential to assess for cytopenias and calculate disease activity scores 1
• Comprehensive metabolic panel including liver enzymes, creatinine, glucose, and urate to establish baseline before potential DMARD therapy 1
• Repeat CRP and ESR in 2-4 weeks to determine if elevation is persistent or transitory 1
• HLA-B27 if any features of spondyloarthropathy emerge (inflammatory back pain, enthesitis, asymmetric arthritis) 1
• ANA with reflex to ENA panel to screen for SLE or other connective tissue diseases 1

2. Obtain Baseline Imaging

• Bilateral hand, wrist, and foot X-rays to assess for erosions, which are highly predictive of RA diagnosis and disease persistence 1
• If X-rays are normal but clinical suspicion remains high, consider ultrasound with Power Doppler or MRI to detect subclinical synovitis 1
• Echocardiography to evaluate the grade 1/6 murmur and exclude structural heart disease 5

3. Perform a Detailed 28-Joint Examination

Document the following:

• Tender and swollen joint counts in PIPs, MCPs, wrists, elbows, shoulders, and knees 1
• Squeeze test of MCPs and MTPs to assess for clinical synovitis 1
• Morning stiffness duration—≥30 minutes (ideally ≥1 hour) strongly suggests inflammatory arthritis 1
• Skin examination for psoriatic plaques, nail changes, rheumatoid nodules, or vasculitic lesions 1

4. Urgent Rheumatology Referral Within 6 Weeks

Refer to rheumatology within 6 weeks of symptom onset because early DMARD therapy prevents irreversible joint damage if inflammatory arthritis is confirmed 1, 8. However, do not start DMARDs empirically until RF and anti-CCP confirm RA diagnosis 4.

Management of Contributing Factors

Address Sleep Deprivation First

• Counsel the patient on sleep hygiene and consider temporary adjustment of work schedule if feasible 6
• Sleep loss exacerbates fatigue, depression, anxiety, and pain in patients with inflammatory arthritis, and addressing this may significantly improve symptoms 6
• Fatigue in rheumatic diseases is multifactorial, encompassing physiological, psychological, and social factors 7

Symptomatic Pain Management

• Continue orphenadrine citrate + paracetamol 50/650 mg as prescribed for intermittent pain 1
• NSAIDs may be added if pain is persistent, but they are usually insufficient for true inflammatory arthritis 4
• Avoid starting corticosteroids until inflammatory arthritis is confirmed, as they can mask symptoms and delay accurate diagnosis 1

Monitor for Disease Evolution

• Repeat clinical assessment with inflammatory markers (CRP and ESR) every 4-6 weeks to detect disease progression 1
• UPIA is an exclusion diagnosis that should be constantly rethought, as patients may develop features of a specific diagnosis over time 1

Critical Pitfalls to Avoid

• Do not diagnose RA based on a single positive RF alone—RF positivity occurs in ~15% of first-degree relatives of RA patients and up to 25% of healthy individuals 1
• Do not dismiss the diagnosis based on normal ESR/CRP—35-45% of RA patients have normal inflammatory markers at presentation 2
• Do not delay rheumatology referral waiting for complete serologic work-up—the priority is getting the patient evaluated within 6 weeks 8
• Do not attribute all symptoms to RA without excluding sleep deprivation, viral arthritis, and other reversible causes 6
• Do not start methotrexate or other DMARDs empirically—wait for rheumatology assessment and confirmation of inflammatory arthritis 1

Prognosis and Follow-Up

• If inflammatory arthritis is confirmed, early DMARD therapy (methotrexate 15-25 mg weekly) improves long-term outcomes 1
• If symptoms resolve within 6 weeks, viral arthritis or transient synovitis is more likely 1
• If symptoms persist beyond 6 weeks with documented synovitis, the likelihood of evolving into definite RA or another inflammatory arthritis increases 1