Table 2.

List of existing and potential new therapies for treating arthrofibrosis, with a summary of the associated benefits and risks

Therapies	Benefits/risks
Dietary approaches
Omega 3 fatty acids in fish or supplements	Necessary for the production of SPMs vital for resolution of inflammation. Thins the blood, but typically no risks are associated within recommended daily limits.
Capsaicin (in peppers) and sulphoraphane (in cruciferous vegetables)	May reverse differentiation of myofibroblasts, sulphoraphane may prevent fibroblast differentiation. No risks are associated within recommended daily limits.
Resistant fibre	Gut bacteria produce short-chain fatty acids which counter inflammation. No risks are associated within recommended daily limits.
Low-sugar intake	Reduces inflammation. Typically no associated risks.
Soy products	Contains anti-inflammatory compounds. Reduced levels of TGF-β and lung fibrosis in rats. Benefits not established for treating fibrosis. Typically no risks are associated within recommended daily limits.
Potassium	May help prevent fibrosis, negative correlation between high levels of serum K+ and liver fibrosis. Typically no risks are associated within recommended daily limits.
Intermittent fasting	Protective against fibrosis of organs, suppresses inflammation, IL-1, IL-6 and TNF-α and inflammasomes. Typically no risks are associated. May be difficult to follow.
Pharmaceuticals
Oral and injected corticosteroids	Downregulates inflammation and possibly TGF-β. Increased risk of infections, suppressed adrenal gland hormone production, can cause high-blood pressure and liver damage etc if long-term.
TGF-β antibodies?	Several TGF-β neutralising antibodies and receptor blocking antibodies are in clinical trials. May prove to be effective therapies for arthrofibrosis.
IL-1 antibodies and IL-1 receptor antagonists	Have been successfully used to prevent post-operative arthrofibrosis in small studies. Shown effective at reducing lung fibrosis in animals (Gasse et al. 2007). Efficacy in the treatment of existing arthrofibrosis not known.
Halofuginone?	Inhibits Smad3 signalling by TGF-β. Suppresses collagen type I, fibroblasts and Th17 cells. Causes GI bleeding, enteric coated capsules recommended. Benefits and risks not established for treating fibrosis.
Low dose aspirin?	Induces production of SMPs. Can cause GI symptoms in some, enteric coated capsules recommended. Blood thinner.
TNF-α antibodies?	Reduces pain, inflammation, fibrosis and serum TGF-β in animals. Increased risk of infections. Benefits and risks not established for treating fibrosis.
Pirfenidone	Therapy for lung fibrosis, anti-fibrotic and anti-inflammatory, downregulates fibroblasts, collagen, alpha smooth muscle cell actin. Diarrhoea, photosensitivity, GI symptoms and liver toxicity in some.
Nintedanib	Therapy for lung fibrosis, anti-fibrotic, downregulates collagen. Diarrhoea, GI symptoms and liver toxicity in some.
Ketotifen?	Used to treat asthma, modifies mast cell activity. Results of small trial for elbow arthrofibrosis shows no effect.
Metformin?	Used to treat type II diabetes. Reduces TGF-β production, interferes with TGF-β signalling, reduces collagen deposition and proliferation of fibroblasts. Reduces fibrosis of organs.
Collagenase	May damage articular cartilage, ligaments and tendons, but trials show no negative effect on these structures. Repeated injections needed, increases ROM in shoulder arthrofibrosis. More trials are needed.
Substance P antagonists?	Used to alleviate nausea. In animal studies downregulates pro-fibrotic genes in joints and reduces fibrosis and inflammation of the colon.
Interferon β therapy?	Downregulates NLRP3 inflammasomes. Benefits and risks not established for treating fibrosis.
Epigenetic drugs?	May reverse myofibroblast differentiation and DNA and histone modifications that cause persistent fibrosis. Benefits and risks not established for treating fibrosis.
Surgical approaches
Arthroscopic lysis and debridement of ECM	Removal of adhesions and ECM can increase long-term ROM. Risk of adverse outcomes from the inflammatory response and worsening fibrosis. Infection, blood clots. No method to determine how individual patients will respond.
Manipulation under anaesthesia	Disruption of adhesions can increase long-term ROM. Risk of adverse outcomes from the inflammatory response and worse fibrosis. Risks include heterotrophic ossification, bone fracture, damage to prosthesis, ligament rupture and blood clots.
Open surgery	Removal of adhesions and ECM can increase long-term ROM. Risk of adverse outcomes from the inflammatory response and worse fibrosis. No method to determine how individual patients will respond.
Physical therapies
Bracing	May be needed for healing. Risk of adhesions forming due to lack of movement.
Exercise, physical rehabilitation therapy	Increases strength and ROM. Intensity should be adapted according to resulting inflammation in individuals. Risk of increasing inflammation and fibrosis when limits are exceeded.
Continuous passive motion	Remains controversial. May help to avoid MUA, likely more beneficial for patients with arthrofibrosis than for those without. Must be well controlled to prevent damage to tendons and ligaments from forced over-bending.
Other
Mesenchymal stem cells?	Modulate the immune system, inhibit the production of inflammatory cytokines. Age and origin may affect the outcome. May differentiate into fibroblasts. Can encourage tumours. Benefits and risks not well established for treating fibrosis.

For other potential therapies, including those that inhibit TGF-β signalling, see main text. Patients should always receive medical advice before adopting new treatments or diets and before altering treatment as this may alter current treatments or comorbidities. Some of these approaches are not well established for treating fibrosis, but are known to reduce inflammation. SPMs special pro-resolving lipid mediators, RDI recommended daily intake, ROM range of motion, ? a pharmaceutical therapy that is currently used to other conditions, which has potential for treating arthrofibrosis