What is the recommended treatment algorithm for enthesitis, including first‑line nonsteroidal anti‑inflammatory drugs, local glucocorticoid injection, physiotherapy, conventional disease‑modifying antirheumatic drugs such as sulfasalazine, and biologic agents like tumor necrosis factor inhibitors or interleukin‑17 inhibitors?

Treatment of Enthesitis

For enthesitis that persists despite NSAIDs, biologic therapy with a TNF inhibitor or IL-17 inhibitor should be initiated, as these agents directly target the inflammatory pathways driving entheseal inflammation and have demonstrated efficacy in multiple high-quality guidelines. 1

First-Line Treatment: NSAIDs

• NSAIDs are the initial pharmacological treatment for enthesitis, used at maximum tolerated doses to control pain and inflammation 1
• Continuous NSAID use is preferred over on-demand dosing in patients who respond well and remain symptomatic 1
• For patients with stable disease, on-demand treatment is strongly recommended over continuous treatment 1
• No particular NSAID is preferred over another; selection should be based on cardiovascular and gastrointestinal risk profiles 1, 2
• COX-2 selective inhibitors reduce gastrointestinal complications by 50-90% in high-risk patients 2

Important caveat: NSAIDs carry significant risks including gastrointestinal bleeding (RR 5.36) and cardiovascular events, requiring careful risk assessment before prescribing 2

Local Glucocorticoid Injections

• Local glucocorticoid injections directed at the entheseal site are conditionally recommended for enthesitis inadequately controlled by NSAIDs 1
• These injections provide more effective short-term pain relief than oral NSAIDs for localized inflammation 2
• Critical warning: Peritendinous injections of Achilles, patellar, and quadriceps tendons must be avoided due to high rupture risk 1, 2
• Injections directly into tendon substance can weaken tissue and predispose to spontaneous rupture 2
• Limit the number of injections due to cumulative risk of tendon weakening 2

Physical Therapy

• Physical therapy is strongly recommended and should be initiated alongside pharmacological treatment 1
• Active supervised exercise interventions are preferred over passive modalities (massage, ultrasound, heat) 1
• Land-based physical therapy is conditionally recommended over aquatic therapy 1
• Eccentric strengthening exercises can reverse degenerative changes in entheseal tissue 2

Biologic Disease-Modifying Agents

When to Initiate Biologics

Biologic therapy should be started when enthesitis remains active despite adequate trials of NSAIDs and local glucocorticoid injections 1

First Biologic Choice

• TNF inhibitors are the current standard first-line biologic for enthesitis refractory to conventional treatment 1
• IL-17 inhibitors (secukinumab, ixekizumab) are strongly recommended as alternative first-line biologics, particularly when concomitant severe psoriasis is present 1
• IL-12/23 inhibitors may be preferred when concomitant inflammatory bowel disease is present 1

After First Biologic Failure

Primary non-response (failure to respond to first biologic):

• Switch to a biologic with a different mechanism of action (e.g., TNF inhibitor to IL-17 inhibitor, or vice versa) 1
• JAK inhibitors are strongly recommended when biologics are contraindicated or unavailable 1

Secondary non-response (initial response followed by loss of efficacy):

• Switching to another TNF inhibitor is conditionally recommended 1
• Alternatively, switch to IL-17 inhibitor or JAK inhibitor 1

Conventional Synthetic DMARDs

• Sulfasalazine and methotrexate are NOT recommended for isolated enthesitis without peripheral arthritis 1
• Sulfasalazine may be considered only when active peripheral arthritis coexists with enthesitis 1
• There is no evidence supporting csDMARDs for purely entheseal inflammation 1

Analgesics for Residual Pain

• Paracetamol (acetaminophen) and opioid-like drugs may be considered for residual pain when NSAIDs have failed, are contraindicated, or poorly tolerated 1, 2
• Paracetamol has acceptable gastrointestinal safety compared to NSAIDs 2
• These are adjunctive measures and do not address underlying inflammation 1

Systemic Glucocorticoids

• Long-term systemic glucocorticoids are strongly recommended against for enthesitis management 1
• Short-term systemic glucocorticoids may be used with caution at the lowest effective dose in specific situations 1

Treatment Algorithm Summary

1. Initiate NSAIDs at maximum tolerated dose + physical therapy with supervised active exercises 1
2. Add local glucocorticoid injections to specific entheseal sites if inadequate response (avoiding Achilles, patellar, quadriceps tendons) 1, 2
3. Escalate to biologic therapy (TNF inhibitor or IL-17 inhibitor) if enthesitis persists despite steps 1-2 1
4. Switch biologic mechanism if primary non-response, or consider another agent in same class if secondary non-response 1
5. Consider JAK inhibitor if biologics fail or are contraindicated 1

Common pitfall: Attempting to treat isolated enthesitis with sulfasalazine or methotrexate—these agents lack efficacy for purely entheseal disease and delay appropriate biologic therapy 1