What are the differential diagnoses and clinical patterns for a 23‑year‑old man with a 2‑year history of diffuse musculoskeletal pain, joint pain, mood swings, impaired concentration, difficulty falling asleep, normal complete blood count, negative Rhesus factor, negative antinuclear antibody profile, negative anti‑cyclic citrullinated peptide, negative human leukocyte antigen B27, and stool examination showing pus cells and mucus?

Differential Diagnosis and Clinical Patterns

Primary Working Diagnosis: Inflammatory Bowel Disease with Type 2 Peripheral Arthropathy

The most likely diagnosis is inflammatory bowel disease (IBD) with extra-intestinal manifestations, specifically Type 2 peripheral arthropathy, given the 2-year history of polyarticular joint pain, neuropsychiatric symptoms, sleep disturbance, and stool examination showing pus cells and mucus despite negative serological markers. 1

Key Diagnostic Features Supporting IBD-Associated Arthropathy

• Type 2 peripheral arthritis affects more than five joints with symmetrical distribution, persists for months to years independent of bowel disease activity, and remains seronegative for RF, anti-CCP, and HLA-B27 1
• The presence of pus cells and mucus in stool examination strongly suggests active intestinal inflammation, which occurs in 5-20% of IBD patients who develop peripheral arthritis 1
• Mood swings, loss of focus and concentration, and sleep disturbance are common systemic manifestations of chronic inflammatory disease, with acute psychological stress shown to increase systemic inflammatory responses including TNF-alpha production by 54% and IL-6 by 11% in IBD patients 2

Critical Next Steps in Diagnostic Workup

• Obtain fecal calprotectin immediately—a level <100 μg/g supports functional bowel disorder, while elevated levels confirm intestinal inflammation and necessitate colonoscopy 3
• Measure inflammatory markers (ESR and CRP) together, as up to 50% of patients with active inflammatory disease may have normal CRP at baseline, and ESR elevation alone indicates active inflammation 4
• Colonoscopy with biopsies is essential to confirm IBD diagnosis, as microscopic gut inflammation occurs in up to 70% of patients with spondyloarthropathy, though only 7% develop clinically apparent Crohn's disease 1

Secondary Differential Diagnoses

1. Seronegative Spondyloarthropathy (SpA) Without IBD

• Consider axial SpA if inflammatory back pain develops, though HLA-B27 negativity reduces the likelihood—HLA-B27 has 90% sensitivity for axial SpA with a positive likelihood ratio of 9 4
• Peripheral SpA can present with asymmetric oligoarthritis affecting large joints, but this patient's polyarticular pattern and stool findings favor IBD-associated arthropathy 1, 5
• MRI of sacroiliac joints should be ordered if inflammatory back pain emerges, as plain radiographs miss most early lesions and may lag >7 years behind clinical onset 4

2. Reactive Arthritis

• Reactive arthritis typically presents with asymmetric oligoarthritis affecting large joints (knees, ankles, wrists) following gastrointestinal or genitourinary infection, often with conjunctivitis or urethritis 1
• The 2-year chronic course and polyarticular pattern make classic reactive arthritis less likely, though post-infectious arthritis can trigger IBD-associated joint disease 1

3. Fibromyalgia with Concurrent Functional Bowel Disorder

• Between 20-50% of fibromyalgia patients have IBS, with lifetime rates reaching 77%, and fibromyalgia comorbidity predicts more severe IBS and associated psychiatric disorder 3
• However, the presence of pus cells and mucus in stool examination indicates organic intestinal pathology rather than functional IBS 3
• Fibromyalgia does not explain objective stool abnormalities and should be considered only after excluding inflammatory disease 5

4. Hepatitis B-Associated Arthropathy (Less Likely)

• RF positivity occurs in 18.7-34.4% of hepatitis B patients, but anti-CCP positivity is rare (only 1-20.5% in HBV), making this diagnosis unlikely with negative anti-CCP 6, 7
• Screen for hepatitis B and C if risk factors present, as chronic viral hepatitis can mimic rheumatic diseases 7

Clinical Pattern Recognition

Distinguishing IBD-Associated Arthropathy from Rheumatoid Arthritis

• IBD peripheral arthritis is inflammatory but generally non-erosive, unlike rheumatoid arthritis which causes progressive joint damage 1
• Negative RF and anti-CCP effectively exclude rheumatoid arthritis, as anti-CCP has 65-72% positivity in RA but remains negative in most IBD patients 6, 7
• Order hand radiographs to confirm absence of erosive changes—SpA shows joint inflammation without erosive changes, differentiating it from RA 4

Recognizing Extra-Intestinal Manifestations

• Peripheral arthritis onset may precede bowel symptoms in up to 27-28% of IBD cases, though it usually coincides with or follows intestinal disease 1
• Enthesitis (tendon insertion inflammation) and dactylitis (sausage digits) occur in 2-4% of IBD patients and indicate spondyloarthropathy pattern 1
• Examine for enthesitis at Achilles tendon, plantar fascia, and patellar tendon insertions 1

Immediate Management Algorithm

Step 1: Confirm Intestinal Inflammation (Within 1 Week)

• Fecal calprotectin measurement 3
• ESR and CRP (repeat together, as discordance is common) 4
• Comprehensive metabolic panel and liver function tests
• Hepatitis B and C serologies if not previously tested 7

Step 2: Gastroenterology Referral for Colonoscopy (Within 2-4 Weeks)

• Colonoscopy with multiple biopsies from terminal ileum and all colonic segments is mandatory to diagnose IBD and differentiate Crohn's disease from ulcerative colitis 1, 8
• Look for characteristic features: Type 1 arthritis correlates with IBD flares and affects <5 large joints, while Type 2 affects >5 joints independent of bowel activity 1

Step 3: Initiate Symptomatic Treatment Immediately

• Start continuous full-dose NSAIDs (not as-needed) for 4-6 weeks with gastroprotection—response to NSAIDs is a diagnostic feature of inflammatory arthritis 4
• Begin structured physical therapy immediately, as it is as important as pharmacologic treatment and should not be delayed until "failing" medications 4
• Address sleep disturbance with sleep hygiene counseling and consider short-term low-dose amitriptyline (10-25 mg at bedtime) for both sleep and pain modulation

Step 4: Rheumatology Referral (Within 3 Months)

• Refer to rheumatology within 3 months if symptoms persist despite optimal NSAID therapy, or earlier if moderate-to-high disease activity remains after 4-6 weeks 4
• If peripheral arthritis persists after 4-6 weeks of continuous NSAIDs, methotrexate is recommended for peripheral disease, though it is ineffective for axial disease 4

Critical Pitfalls to Avoid

• Do not dismiss inflammatory disease based on normal CRP alone—ESR elevation indicates active inflammation, and up to 50% of patients with active disease have normal baseline CRP 4
• Do not attribute all symptoms to fibromyalgia or functional disorder when objective findings (pus cells, mucus in stool) indicate organic pathology 3
• Do not order serial radiographs for monitoring, as structural changes occur slowly and radiographs do not assess disease activity 4
• Do not use NSAIDs "as needed"—continuous dosing is required to suppress inflammation and assess therapeutic response 4
• Do not delay colonoscopy based on age—IBD can present at any age, and the combination of joint pain with abnormal stool examination mandates endoscopic evaluation 1, 8

Monitoring Strategy

• Calculate ASDAS (using ESR) and BASDAI scores at baseline and every 4-6 weeks until remission, then every 3-6 months 4
• Repeat ESR/CRP every 1-3 months during active disease 4
• Assess response to NSAIDs at 4-6 weeks and initiate DMARD therapy if inadequate response 4