Makindo Medical Notes

🔥 Chronic inflammation is a long-standing host response (months–years) driven by persistent danger signals — infectious, autoimmune, metabolic, or environmental. Unlike acute inflammation (rapid, exudative, neutrophil-predominant), chronic inflammation features mononuclear infiltrates, ongoing tissue injury, and repair with fibrosis. The “failure to resolve” is as important as the initial trigger.

🧭 Why inflammation becomes chronic

• Persistent infections (PAMPs that don’t go away): e.g., Mycobacterium tuberculosis, H. pylori, chronic hepatitis B/C.
• Autoimmunity / autoinflammation (DAMPs from self-tissue): e.g., RA, SLE, multiple sclerosis, vasculitides; periodic fever syndromes.
• Inhaled/ingested irritants: crystalline silica (pneumoconiosis), asbestos (asbestosis/mesothelioma risk), smoking-related airway disease.
• Metabolic inflammation (“metaflammation”): obesity and insulin resistance — adipose macrophage “crown-like” structures, ↑ TNF-α/IL-6, ↓ adiponectin.
• Foreign bodies: sutures, prostheses, or urate/CPPD crystals (gout/pseudogout).

🧪 Core mechanisms (from trigger to chronicity)

• Pattern recognition: PRRs (TLRs, NLRs) detect PAMPs/DAMPs → NF-κB activation.
• Inflammasome: NLRP3 complex activates caspase-1 → maturation of IL-1β, IL-18 (key chronic amplifiers).
• Cellular players:
  • Macrophages (M1 pro-inflammatory vs M2 pro-repair): secrete TNF-α, IL-1, IL-6, TGF-β; present antigen to T cells.
  • Lymphocytes: Th1 (IFN-γ) → macrophage activation; Th17 (IL-17) → neutrophil recruitment and tissue damage; Tregs (IL-10, TGF-β) restrain responses.
  • Plasma cells: sustained antibody production (including pathogenic autoantibodies in RA/SLE).
  • Fibroblasts / myofibroblasts: ECM deposition under TGF-β → fibrosis.
• Angio- & lymphangiogenesis: VEGF-driven new vessels sustain leukocyte influx; lymphangiogenesis aids drainage yet can perpetuate antigen traffic.
• Matrix remodelling: MMPs vs TIMPs imbalance → architectural distortion, stiffness, and impaired function.
• Resolution failure: deficiency of specialised pro-resolving mediators (SPMs: resolvins, protectins, maresins) and ineffective efferocytosis perpetuate the loop.

🪵 Granulomatous inflammation (when the immune system “walls it off”)

• Granuloma = epithelioid macrophages ± Langhans giant cells, surrounded by lymphocytes ± fibrosis.
• Caseating: TB (cheese-like necrosis). Non-caseating: sarcoidosis, Crohn’s, berylliosis, foreign body granulomas.
• Driven by Th1–IFN-γ and TNF-α signals. Anti-TNF therapy can reactivate latent TB — hence mandatory TB screening beforehand.

🧬 Key mediators

• Pro-inflammatory: TNF-α, IL-1β, IL-6, IL-17, IFN-γ, chemokines (IL-8/CXCL8, CCL2).
• Pro-fibrotic: TGF-β, PDGF, CTGF.
• Anti-inflammatory / pro-resolving: IL-10, TGF-β (context-dependent), lipoxins, resolvins, protectins, maresins.

🩺 Clinical features & consequences

• Local: pain, stiffness, swelling; organ-specific dysfunction (e.g., ILD dyspnoea, IBD diarrhoea/PR bleeding, synovitis in RA).
• Systemic (acute-phase response): fever, malaise, anorexia, weight change, anaemia of chronic disease (hepcidin-mediated iron sequestration), thrombocytosis.
• Tissue damage → fibrosis: cirrhosis (chronic hepatitis), pulmonary fibrosis (post-inflammatory), CKD (glomerulosclerosis), strictures (Crohn’s).
• Atherothrombosis: endothelial dysfunction and plaque progression (IL-1/IL-6 axis).
• Cancer risk: HCC with HBV/HCV, cholangiocarcinoma with PSC, gastric adenocarcinoma with H. pylori; long-standing IBD → colorectal cancer.
• AA amyloidosis in sustained high SAA states (e.g., poorly controlled RA, chronic infections).
• Bone loss via RANKL-mediated osteoclast activation → osteoporosis and erosions (RA).

🧪 Diagnosis — putting pieces together

• History & exam: chronicity, pattern (migratory vs additive joints; extra-articular features), exposure (occupational silica, asbestos), infections, family/autoimmune history.
• Bloods:
  • CRP (fast kinetics) and ESR (influenced by anaemia/fibrinogen) — track activity.
  • FBC: anaemia of chronic disease, thrombocytosis; Ferritin (acute-phase), Albumin (negative acute-phase).
  • Autoantibodies when indicated: RF/anti-CCP (RA), ANA/dsDNA/ENA (SLE), ANCA (vasculitis).
  • Infection work-up: hepatitis B/C, HIV, TB IGRA; stool tests (calprotectin in IBD).
• Imaging:
  • Ultrasound (power Doppler) for active synovitis, effusions.
  • HRCT chest for interstitial lung disease patterning.
  • PET-CT for vasculitis/fever of unknown origin when needed.
  • MRI for marrow oedema/enthesitis (SpA), fistulae in Crohn’s.
• Biopsy (gold-standard when accessible):
  • Granulomas: caseating vs non-caseating; special stains (Ziehl–Neelsen for AFB, PAS/Grocott for fungi).
  • Vasculitis: vessel wall necrosis/inflammation (e.g., temporal artery).
  • Foreign material: polarised light for silica/asbestos birefringence.

🧪 Biomarkers & indices you’ll actually use

• CRP for day-to-day activity; ESR for chronicity/anaemia influence.
• NLR (neutrophil-to-lymphocyte ratio) as a crude systemic inflammation marker.
• Faecal calprotectin for intestinal mucosal inflammation (IBD vs IBS triage in primary/secondary care).
• Serum amyloid A when amyloidosis suspected.

🛠️ Management — principles (UK context)

• Treat the cause: eradicate infection (e.g., quadruple therapy for H. pylori), withdraw irritants (occupational health for silica/asbestos), remove foreign body.
• Immune-mediated disease:
  • Rapid symptom control: corticosteroids (lowest effective dose, shortest time; plan a taper).
  • Conventional DMARDs: methotrexate, sulfasalazine, hydroxychloroquine, leflunomide.
  • Biologics/targeted synthetics (after screening for TB/HBV; vaccines up-to-date):
    • Anti-TNF (adalimumab, etanercept, infliximab, golimumab),
    • Anti-IL-6R (tocilizumab), anti-IL-17/23 (SpA/psoriatic pathways),
    • B-cell depletion (rituximab), T-cell co-stimulation blockade (abatacept),
    • JAK inhibitors (tofacitinib, upadacitinib, baricitinib).
  • Organ-specific: IBD (5-ASA, steroids, biologics), ILD (multidisciplinary; consider antifibrotics in progressive fibrosis per specialist advice), vasculitis (steroid + cyclophosphamide/rituximab; prophylaxis for PCP when indicated).
• Risk reduction / monitoring:
  • Screen before biologics: TB (IGRA/CXR), HBV/HCV/HIV; baseline FBC, LFT, U&E, lipids; pregnancy plans.
  • Bone health: FRAX, calcium/vitamin D; bisphosphonates for glucocorticoid osteoporosis prevention when appropriate.
  • CV risk: manage BP, lipids; consider statin in high risk; encourage smoking cessation.
  • Infection prevention: influenza and pneumococcal vaccines; avoid live vaccines on biologics.
• Lifestyle & adjuncts:
  • Mediterranean-style diet, weight optimisation (reduces IL-6/TNF-α load; improves response to anti-TNF in RA/SpA).
  • Exercise: anti-inflammatory myokines; preserves function and bone density.
  • Sleep and stress: circadian dysregulation and stress hormones modulate cytokines.
  • Smoking cessation crucial (drives RA seropositivity; worsens Crohn’s; accelerates atherosclerosis).

🧠 Differentials & mimics to keep you honest

• Infection vs autoimmune flare on immunosuppression — check observations, cultures, CXR; don’t reflexively escalate steroids.
• Malignancy as a cause of raised inflammatory markers (lymphoma, myeloma, occult solid tumours).
• Drug-induced pneumonitis/hepatitis/serositis mimicking primary inflammation (e.g., methotrexate lung, nitrofurantoin ILD).

🧾 Quick comparisons (CRP vs ESR)

• CRP: rises within hours, short half-life → responsive to change; less influenced by anaemia.
• ESR: slower to change; rises with age, anaemia, high fibrinogen; useful for some vasculitides and myeloma.

📌 Summary

Chronic inflammation reflects a loop of persistent triggers + failed resolution. Hallmarks include mononuclear infiltrates, matrix remodelling/fibrosis, angiogenesis, and — in some settings — granulomas. Clinically, it underlies conditions from RA and IBD to ILD and atherosclerosis, with systemic consequences (anaemia, cachexia, CV risk, amyloidosis). Effective care blends cause-directed therapy, immune modulation, risk prevention, and lifestyle measures — always with vigilant screening and monitoring in line with UK practice.