Inflammation & Tissue Healing

Recognising acute inflammation, chronic inflammation, and pathological inflammatory states.

Acute inflammation - clinical recognition:

• •The five cardinal signs at the injury site: redness, warmth, swelling, pain, loss of function.
• •Onset acute, typically within hours; peaks at 24-72 hours.
• •Course self-limiting - resolves over days as tissue transitions to repair.
• •Examination: localised swelling, warmth, tenderness, effusion, ecchymosis, reduced ROM.

When acute inflammation is appropriate and expected: post-injury (muscle tear, ligament sprain, fracture, contusion); post-operative (normal surgical healing); acute flare of a chronic condition (OA flare, gout flare).

When to suspect pathological/chronic inflammatory disease:

• •Prolonged morning stiffness over 30 minutes - hallmark of inflammatory joint disease (RA, psoriatic arthritis, AS); improves with activity.
• •Symmetrical polyarthritis with systemic features - think RA.
• •Enthesitis with inflammatory back pain, psoriasis, IBD, or uveitis - think spondyloarthropathy (NICE NG65).
• •Acute monoarthritis with intense erythema and rapid onset - crystal arthropathy or septic arthritis (the must-not-miss diagnosis).
• •Night pain or rest pain out of proportion - consider inflammatory or malignant pathology.
• •Raised inflammatory markers (CRP, ESR) with joint symptoms.

Differentiating mechanical vs inflammatory MSK pain:

• •Mechanical: morning stiffness under 30 minutes, improves with rest, worsens with activity, intermittent activity-related swelling, absent systemic features, normal inflammatory markers.
• •Inflammatory: morning stiffness over 30 minutes (often over 60), worsens with rest (gelling), improves with activity, persistent and often symmetrical swelling, possible systemic features, frequently raised inflammatory markers.

Investigations confirm the diagnosis, differentiate mechanical from inflammatory pathology, assess disease activity, monitor treatment, and exclude serious pathology.

Blood tests:

• •CRP: the most useful acute-phase marker. Rises within 6-12 hours, falls rapidly with resolution. Produced by the liver in response to IL-6. Useful for monitoring disease activity. Normal CRP reduces the likelihood of active inflammation but does not exclude inflammatory disease.
• •ESR: non-specific, rises and falls slowly - useful for chronic disease monitoring (PMR, GCA). Influenced by age, sex, anaemia, pregnancy.
• •FBC: raised WCC in infection or active inflammation; thrombocytosis in chronic inflammation; anaemia of chronic disease (RA).
• •RF and anti-CCP for suspected RA - anti-CCP more specific; seronegative RA exists.
• •HLA-B27 supports spondyloarthropathy (positive in ~8% of the general UK population - not diagnostic).
• •Serum urate (per NICE NG219): measure during the acute gout flare. If elevated (>=360 micromol/L), supports the diagnosis. If normal but gout is still suspected clinically, repeat 2-4 weeks after the flare (urate may redistribute during acute inflammation).
• •Bone profile, vitamin D, calcium for metabolic bone disease and osteoporosis; ferritin/transferrin saturation for haemochromatosis.

Joint aspiration is the gold standard for acute monoarthritis - essential when septic arthritis is suspected (same-day urgent aspiration; delay risks joint destruction). Send for cell count (WCC >50,000/mm3 with neutrophil predominance suggests septic arthritis, overlap with crystal disease exists), Gram stain and culture, and crystal analysis under polarised light microscopy.

Imaging:

• •Ultrasound: effusion, synovitis (power Doppler indicating active inflammation), tendon pathology, guides aspiration/injection. Increasingly used in UK MSK and rheumatology practice.
• •MRI: bone marrow oedema, synovitis, erosions, soft tissue inflammation; valuable for early sacroiliitis (NICE NG65). Normal X-rays do not exclude early inflammatory disease.
• •Plain radiographs: late changes in inflammatory arthritis (joint space narrowing, erosions, periarticular osteopenia); chondrocalcinosis (CPPD); fracture and OA features.

Managing inflammation requires distinguishing WHEN to allow it, WHEN to suppress it, and HOW suppression affects healing.

Acute post-injury inflammation - let the healing begin:

PEACE and LOVE framework (Dubois and Esculier, 2019):

• •PEACE (first 1-3 days): Protect (brief), Elevate, Avoid anti-inflammatories (avoid routine NSAID use early - clinical evidence is mixed and short-term pragmatic use remains common), Compress, Educate.
• •LOVE (from day 3-5): Load (early progressive loading), Optimism, Vascularisation, Exercise.

NSAIDs and tissue healing: NSAIDs inhibit COX-1 and COX-2, reduce prostaglandin synthesis, and reduce pain, swelling, and inflammation. Concern: prostaglandins also contribute to tissue repair (fibroblast activity, angiogenesis, bone healing). Mechanistic and animal data suggest that prolonged NSAID use may impair muscle healing, tendon remodelling, and bone repair; clinical evidence in humans is mixed but caution is appropriate. Paracetamol is often preferred during active fracture and stress injury healing. Best practice: lowest effective dose, shortest duration; co-prescribe gastroprotection (PPI) with oral NSAIDs.

Cryotherapy: short-term analgesia; effect on tissue healing is uncertain; pragmatic adjunct, not centrepiece.

Corticosteroid injections (CSIs) and tissue healing: CSIs provide short-term relief but may inhibit long-term healing (reduced collagen synthesis, fibroblast viability). Effects are dose-, site-, and timing-dependent. Worse long-term outcomes for lateral elbow tendinopathy (NICE CKS advises against); generally avoided around the Achilles (rupture risk). For OA (NICE NG226): consider only when other pharmacological treatments are ineffective or to provide a window of relief to support exercise. Subacromial injection may be considered for rotator cuff disorders (NICE CKS). Injection without rehabilitation is unlikely to provide sustained benefit.

Factors that impair healing (modifiable where possible): smoking (impairs all phases), poorly controlled diabetes, malnutrition (protein, vitamin C, zinc), corticosteroid use, ageing, and prolonged immobilisation.

Pathological chronic inflammation - targeted treatment:

• •Rheumatoid arthritis (NICE NG100): early aggressive DMARD therapy with methotrexate first-line; biologic therapies (TNF, IL-6 inhibitors, JAK inhibitors) for inadequate response; treat-to-target strategy.
• •Spondyloarthropathy (NICE NG65): NSAIDs first-line for symptom relief (in contrast to acute injury where they are cautioned); biologic therapy (TNF, IL-17 inhibitors) for inadequate NSAID response.
• •Gout (NICE NG219): acute flare - colchicine, NSAIDs (not aspirin), oral corticosteroids, or intra-articular CSI depending on comorbidities. Long-term urate-lowering therapy (allopurinol first-line) targeting urate <360 micromol/L (<300 micromol/L for tophaceous gout). Serum urate during the flare with repeat at 2-4 weeks if initially normal but gout strongly suspected.
• •Septic arthritis: surgical emergency - urgent aspiration, IV antibiotics, orthopaedic review; do not delay treatment for imaging.

The distinction for management: acute post-injury inflammation is BENEFICIAL - allow it, load early, avoid unnecessary suppression. Chronic pathological inflammation (autoimmune, crystal) is HARMFUL - suppress it. Tissue destruction continues unless the inflammatory process is controlled.

Rehabilitation is the primary driver of optimal tissue healing in most MSK conditions - it works BY harnessing the healing biology.

Phase-matched rehabilitation:

Inflammatory phase (0-72 hours) - PROTECT but do not immobilise: brief protection (PEACE); avoid provocative loading; allow inflammation to proceed; gentle pain-free isometric activation can begin in many injuries. Avoid prolonged NSAID use; avoid forced stretching and deep tissue massage.

Proliferative phase (72 hours - 6 weeks) - LOAD the healing tissue: the critical window. New collagen is mechanosensitive and aligns along lines of stress. Progressive loading stimulates fibroblast activity, collagen synthesis, and organised tissue. Begin isotonic strengthening; progress load, ROM, complexity. Maintain cardiovascular fitness; address the kinetic chain; begin proprioceptive training. For tendons with sheaths, early controlled motion protocols reduce adhesions.

Remodelling phase (6 weeks - 12+ months) - CONTINUE and PROGRESS: Type III to Type I collagen replacement; cross-linking strengthens tissue. Rehabilitation must continue BEYOND symptom resolution - premature cessation is a leading cause of re-injury. Progress to functional, plyometric, and sport-specific loading; criteria-based return to sport.

Key rehabilitation principles rooted in healing biology:

• •Load tolerance, not pain elimination, is the goal - manageable pain during loading is acceptable (pragmatic 5/10 or less approach, settling within 24 hours).
• •Loading converts repair tissue into FUNCTIONAL tissue; rest alone produces inferior tissue.
• •Flare-ups are normal - temporary load reduction, not cessation.
• •Tissue-specific timelines must be respected (muscle weeks; tendon months; bone 6-12 weeks).
• •Pain does not equal damage, especially in chronic MSK conditions; central sensitisation may amplify pain beyond tissue pathology.
• •Adherence is one of the strongest predictors of outcome.
• •Biopsychosocial: fear-avoidance, catastrophising, and low self-efficacy impair outcomes regardless of tissue state.

• •PEACE and LOVE framework (Dubois and Esculier, BJSM 2019) - the modern approach to acute soft-tissue injury, emphasising early loading and education over passive rest.
• •NICE NG100 (Rheumatoid arthritis), NG65 (Spondyloarthritis), NG219 (Gout) - the disease-specific UK frameworks for pathological inflammatory MSK conditions.
• •NICE NG226 (Osteoarthritis), NG59 (Low back pain and sciatica), NG193 (Chronic pain in over 16s) - exercise as a core treatment across MSK conditions.
• •Cook and Purdam tendinopathy continuum - tendinopathy as failed healing rather than primary inflammation, framing progressive loading as the cornerstone of treatment.
• •Specialised pro-resolving mediators (Serhan) - active resolution of inflammation; explains why unnecessary suppression may impair the natural resolution cascade.

• •Cardinal signs: rubor, calor, tumor, dolor, functio laesa - inflammation is a NECESSARY first step in healing.
• •Three overlapping phases: inflammation, proliferation (Type III collagen), remodelling (Type I, months); Davis's law and Wolff's law drive aligned repair.
• •NSAIDs and corticosteroids may impair tissue healing - paracetamol often preferred during bone and active soft-tissue repair.
• •Mechanical vs inflammatory: morning stiffness under 30 min = mechanical (OA); over 30 min = inflammatory (RA, SpA).
• •Acute hot swollen joint with fever = septic arthritis until proven otherwise - same-day aspiration.
• •Gout (NICE NG219): measure serum urate DURING the flare; if normal, repeat 2-4 weeks later.