A systematic review of inflammatory cells and markers in human tendinopathy

Key points

1. 0139 of 53 included studies found signs of inflammation (inflammatory cells or elevated markers) in tendinopathic tendons
2. 02Macrophages were the most commonly identified inflammatory cell type, found in 16 studies; mast cells in 8, granulocytes in 3, lymphocytes in 2
3. 03Studies using immunohistochemistry (IHC) detected inflammatory cells in 23-100% of specimens (mean 88%), whereas haematoxylin and eosin (H&E) staining detected them in only 0-100% (mean 16%) - suggesting H&E substantially underdetects inflammation
4. 04All 22 studies that measured inflammatory markers detected elevated levels of at least one marker (including IL-1, IL-6, IL-8, IL-10, IL-17, IL-33, COX-1, COX-2, TGF-b, TNF-a, FGF)
5. 05Anti-inflammatory drugs (NSAIDs and corticosteroids) may suppress pain short-term but potentially hinder tendon healing and cause long-term problems by suppressing inflammation needed for tissue remodelling

How it was conducted

Design

Systematic review following PRISMA guidelines

Databases searched

PubMed, Scopus, Web of Science, Embase (searched November 2017 and updated December 2018)

Studies included

53 studies from 1431 initially identified

Specimens assessed

2306 tendinopathic tendon specimens across multiple anatomical locations (Achilles, patellar, rotator cuff, biceps, extensor tendons)

Study types

Cross-sectional, case-control, prospective observational studies, RCTs, and in vitro studies using tendinopathic tissue

Quality assessment

CASP appraisal tool; 50/53 studies scored 6 or higher out of 11; all included studies were evidence level 3 per OCEBM

What they found

• 39/53 studies (74%) showed signs of inflammation in tendinopathic tendons
• 25 studies reported presence of inflammatory cells; 14 reported absence
• With H&E staining, inflammatory cells were detected in 0-100% of specimens across studies (mean 16%)
• With IHC staining, inflammatory cells were detected in 23-100% of specimens across studies (mean 88%)
• Macrophages found in 16 studies, mast cells in 8, granulocytes in 3, lymphocytes in 2
• All 22 studies measuring inflammatory markers detected elevated levels of at least one marker
• 7 of the 25 studies supporting inflammatory cell presence did not specify cell types
• 12 studies included patients who had received corticosteroid injections; inflammation was observed regardless of prior corticosteroid treatment

Limitations

• Extreme heterogeneity in tendinopathy presentations (from chronic pain to acute rupture), anatomical locations, and disease stages makes studies incomparable and meta-analysis impossible
• Detection method variability - particularly the insensitivity of H&E versus IHC - is a major source of conflicting conclusions across studies
• Control specimens were suboptimal in many studies: macroscopically healthy areas of diseased tendons and contralateral tendons may themselves be subclinically affected, inflating or deflating apparent differences
• Inconsistent documentation of confounders such as activity level, NSAID or corticosteroid use history, and metabolic comorbidities limits interpretation of results

Why it matters

For patients

People with chronic tendon pain should know that inflammation may be present even in long-standing tendinopathy, and that anti-inflammatory drugs provide only short-term relief and may not address the underlying cause.

For clinicians

Clinicians should use IHC rather than H&E when assessing tissue samples for inflammation, recognise that chronic inflammation is likely present in many tendinopathy cases, and reconsider reliance on NSAIDs and corticosteroids as sole long-term treatments given their potential to impair tendon healing.

For readers

This review highlights that the longstanding view of tendinopathy as a purely degenerative, non-inflammatory condition is not well supported by evidence, and that identifying specific inflammatory subtypes and their triggers is a priority for future research.