Methotrexate and Wound Healing: Surgical vs Chronic Wounds

 

Introduction

Methotrexate (MTX) is a folate antagonist used as a chemotherapy agent and, at lower doses, as an immunosuppressant for chronic conditions like rheumatoid arthritis and psoriasis. Given its anti-proliferative and anti-inflammatory actions, there is concern about how MTX might affect wound healing. Wound healing involves a coordinated sequence of inflammation, new blood vessel formation (angiogenesis), collagen deposition, and tissue remodeling. This report examines MTX’s impact on acute surgical wounds versus chronic wounds (e.g. diabetic ulcers), looking at clinical outcomes (healing time, infections, complications), underlying biological mechanisms, and any differences between these wound types. We also consider patient populations commonly encountering these scenarios (rheumatology patients on low-dose MTX vs. oncology patients on high-dose MTX).

Clinical Outcomes with Methotrexate and Wound Healing

Surgical (Acute) Wound Healing under MTX

Healing Time & Wound Closure: In patients on low-dose MTX (e.g. for rheumatoid arthritis), most clinical studies have found no significant delay in surgical wound healing. For example, multiple trials have shown that continuing low-dose MTX does not lengthen postoperative healing time or cause wound dehiscence compared to patients not on MTX (Effect of methotrexate on bone and wound healing - PubMed). Experimental models, however, suggest dose matters: in rats, very high-dose MTX caused a clear delay in wound closure at 1–3 weeks post-injury, whereas low-dose MTX caused only a mild delay at the 2-week mark (Effect of low- and high-dose methotrexate on wound healing in rats - PubMed) (Effect of low- and high-dose methotrexate on wound healing in rats - PubMed). In human surgical practice, the low weekly doses used for autoimmune disease typically do not visibly prolong incision healing.

Infection Rates & Complications: Clinical evidence indicates that low-dose MTX does not significantly increase the risk of postoperative wound complications (such as infections or poor scar formation). A comprehensive review noted that clinical studies show low-dose MTX is safe and does not increase the incidence of postoperative wound complications (Effect of methotrexate on bone and wound healing - PubMed). For instance, rheumatoid arthritis patients undergoing elective orthopedic surgeries had no higher rates of surgical-site infection or delayed wound healing when MTX was continued, compared to those who stopped MTX (Effect of methotrexate on bone and wound healing - PubMed). In fact, current perioperative guidelines for rheumatologic drugs advise that conventional DMARDs like MTX can be safely continued through surgery without interruption (Methotrexate wound healing - Search Results - PubMed). This practice avoids disease flares and, according to studies, does not worsen healing or infection rates. High-dose MTX in cancer chemotherapy (e.g. osteosarcoma treatment) is more immunosuppressive, and if given too close to surgery could increase infection risk or impair healing; thus oncologists usually schedule surgery at a safe interval from chemotherapy (though specific data on wound infection in these cases are limited). Overall, for acute surgical wounds in patients on chronic low-dose MTX, evidence points to normal healing times and complication rates comparable to other patients.

Key Postoperative Considerations: Because low-dose MTX has shown minimal impact on surgical wound outcomes, many clinicians do not suspend MTX before routine surgeries (Methotrexate wound healing - Search Results - PubMed). Close monitoring is still prudent, as MTX can rarely contribute to issues like mild wound-edge necrosis or slower epithelialization in some individuals. If a patient is on high-dose MTX (chemotherapy), wound healing can be more significantly impaired (similar to other chemotherapeutic agents) – these patients are managed by timing surgery appropriately and providing supportive care to mitigate infection risk.

Chronic Wound Healing under MTX (e.g. Diabetic Ulcers)

Healing Dynamics: Chronic wounds, such as diabetic foot ulcers or venous stasis ulcers, are wounds that fail to progress through normal healing stages. They often have persistent inflammation, poor angiogenesis, and impaired cell response even without additional medications. Methotrexate can potentially exacerbate these healing problems. Due to its antiproliferative effects, MTX may further slow the formation of granulation tissue and re-epithelialization in a chronic wound. There is scant direct clinical trial data on MTX’s effect in chronic ulcers (since diabetic patients are not typically on MTX, except if they have another condition like rheumatoid arthritis). However, by extrapolation, healing time is likely prolonged if a patient with a chronic wound is taking MTX. Any existing tissue repair may stall, given MTX’s tendency to suppress cell growth needed for closure. In an animal model, even low-dose MTX suppressed collagen deposition and new skin growth during the healing process (Effect of low- and high-dose methotrexate on wound healing in rats - PubMed), changes that would be deleterious in a chronic wound that is already slow to heal.

Infection Risk & Complications: Chronic wounds are very prone to infection due to prolonged exposure and often poor circulation (as in diabetes). MTX’s immunosuppressive action can heighten this risk – the body’s ability to fight bacteria in the wound is reduced. Clinically, one would expect higher infection rates or prolonged ulceration in an immunosuppressed patient. Indeed, immunosuppressive treatments (including MTX, corticosteroids, etc.) are recognized as factors that inhibit wound healing (The Effect of Comorbidities on Wound Healing - PubMed). Patients on MTX might experience more frequent wound infections or require longer antibiotic courses for chronic ulcers. Another potential complication is that MTX can cause systemic effects (e.g. liver toxicity or marrow suppression) that indirectly worsen wound healing by impairing overall patient health.

Special Cases: Not all chronic wounds would fare worse with MTX – if the chronic wound is driven by an autoimmune process, MTX could paradoxically help by controlling the underlying disease. For example, pyoderma gangrenosum (an ulcerative inflammatory condition) or rheumatoid vasculitic ulcers sometimes are treated with MTX to reduce pathologic inflammation, which can lead to wound improvement. These are specific scenarios where the anti-inflammatory benefit of MTX aids healing of a chronic immunologic ulcer. In contrast, a diabetic ulcer does not stem from an overactive immune response; it requires new tissue growth and infection control, both of which MTX may impede. In summary, for typical chronic wounds like diabetic ulcers, MTX is generally considered detrimental to healing and is often avoided or used with caution in patients with non-healing wounds.

Biological Mechanisms: How MTX Influences Wound Healing

Methotrexate interferes with several fundamental processes in wound repair. Its effects on inflammatory cells, blood vessel formation, and connective tissue synthesis can explain the clinical observations:

• Inflammatory Response: MTX is anti-inflammatory – it suppresses the early immune cell influx and cytokine release in wounds. Studies show MTX-treated wounds have lower levels of pro-inflammatory cytokines like TNF-α in the early healing phase (Effect of low- and high-dose methotrexate on wound healing in rats - PubMed). Methotrexate increases adenosine, which dampens neutrophil and macrophage activity. This can reduce excessive inflammation (potentially beneficial in chronic inflammatory wounds), but it may also delay the necessary initial inflammation that cleans debris and fights infection in an acute wound. In rats, MTX administration led to significantly decreased infiltration of inflammatory cells and reduced TNF-α expression at wound sites (Effect of low- and high-dose methotrexate on wound healing in rats - PubMed).

• Angiogenesis (New Blood Vessels): Wound healing requires growth of new capillaries to supply regenerating tissue. MTX impairs cell proliferation, including that of endothelial cells that form blood vessels. Experimental data confirm that MTX dose-dependently decreases angiogenesis in wounds (Effect of low- and high-dose methotrexate on wound healing in rats - PubMed). Treated wounds show reduced expression of factors like VEGF (vascular endothelial growth factor) and fewer new vessels. This antiangiogenic effect means the wound may receive less blood flow, oxygen, and nutrients, slowing the healing especially in the proliferative phase.

• Collagen Synthesis and Fibroblast Function: Fibroblasts in the wound lay down collagen, providing the scaffold for new tissue. Methotrexate’s antifolate mechanism hinders DNA synthesis in rapidly dividing cells, directly inhibiting fibroblast proliferation and collagen production. In MTX-treated animal wounds, the collagen content (measured by hydroxyproline levels) was significantly lower than normal (Effect of low- and high-dose methotrexate on wound healing in rats - PubMed). MTX also reduced type I collagen expression in healing tissue (Effect of low- and high-dose methotrexate on wound healing in rats - PubMed). The result is an antifibrotic effect: wounds under MTX form weaker granulation tissue and may take longer to build tensile strength. (Notably, in contexts of fibrosis or keloid scars, this effect might be beneficial, but in normal wounds it represents impaired healing.)

• Re-epithelialization (Skin Regrowth): Closing a wound requires epithelial cells to migrate and cover the defect. Methotrexate has been shown to suppress epithelialization during wound healing (Effect of low- and high-dose methotrexate on wound healing in rats - PubMed). By slowing the division of keratinocytes at the wound edges, MTX delays the resurfacing of the wound with new skin. This aligns with clinical observations that ulcers in MTX-treated patients can have persistent open areas longer than expected.

• Immune Cell Function and Infection Defense: MTX broadly suppresses the immune system, including lymphocyte activity. While neutrophils are less affected by low-dose MTX, some impairment in overall immune surveillance occurs. This can translate to a reduced ability to clear wound bacteria, increasing infection susceptibility. Chronic MTX therapy is associated with higher infection risk in general, so in wounds there is concern for poor infection control (The Effect of Comorbidities on Wound Healing - PubMed). Moreover, MTX-induced reductions in inflammation can mask typical signs of infection, potentially delaying diagnosis of wound complications.

In summary, MTX exerts anti-healing effects: it is antiproliferative, antiangiogenic, anti-inflammatory, and antifibrotic in the wound milieu (Effect of low- and high-dose methotrexate on wound healing in rats - PubMed) (Effect of low- and high-dose methotrexate on wound healing in rats - PubMed). These mechanism insights explain why high doses of MTX can markedly impair healing. At the same time, low doses modulate inflammation without completely halting cell growth, which is likely why low-dose MTX has a relatively modest impact on acute wound healing in practice.

Surgical vs. Chronic Wounds under Methotrexate: A Comparison

The table below contrasts the impact of methotrexate on acute surgical wounds versus chronic non-healing wounds, highlighting key differences in outcomes and considerations:

Aspect	Surgical Wounds (Acute, on MTX)	Chronic Wounds (e.g. Diabetic Ulcers, on MTX)
Healing Time	– Usually not significantly delayed with low-dose MTX in RA patients (Effect of methotrexate on bone and wound healing - PubMed). – Wounds generally close on normal timetable; high-dose (chemo) MTX may delay closure if given perioperatively.	– Likely prolonged healing; chronic ulcers may remain open longer under MTX due to impaired cell proliferation. – Any existing slow-healing trend is exacerbated, leading to extended wound duration before closure.
Infection Risk	– No major increase in surgical-site infections observed with MTX continuation (low-dose) (Effect of methotrexate on bone and wound healing - PubMed). – Standard preventive measures suffice; immunosuppression is mild at anti-rheumatic doses.	– Higher infection susceptibility; immunosuppression can allow bacterial overgrowth in chronic wounds (The Effect of Comorbidities on Wound Healing - PubMed). – Patients may experience more frequent or severe wound infections, complicating ulcer management.
Collagen & Tissue Repair	– Minimal impact on final scar strength at low dose. Collagen deposition proceeds adequately in surgical incisions. – High-dose MTX (chemo levels) can reduce collagen, but such doses are usually avoided during the immediate post-surgery period.	– Reduced granulation tissue formation; MTX’s antifibrotic effect means less collagen in the ulcer bed (Effect of low- and high-dose methotrexate on wound healing in rats - PubMed). – Wound edges show poor matrix buildup, potentially preventing the wound from closing or sustaining closure.
Angiogenesis	– Little to no noticeable effect on angiogenesis for routine surgical patients on MTX. – Incisional wounds heal with sufficient blood supply in low-dose contexts (animal studies show angiogenesis only depressed at high doses (Effect of low- and high-dose methotrexate on wound healing in rats - PubMed)).	– Compromised angiogenesis in the wound. MTX can further impair blood vessel growth in tissues already poorly perfused (as in diabetic limbs), limiting oxygenation of the ulcer site.
Inflammatory Response	– Blunted early inflammation but not enough to derail healing. MTX may reduce postoperative swelling and erythema slightly. – No strong detriment; inflammatory phase still occurs albeit subdued, which may even reduce pain or excessive scarring.	– Dampened chronic inflammation, which is double-edged: it might reduce damaging proteases and cytokines, but also weakens immune defense (Effect of low- and high-dose methotrexate on wound healing in rats - PubMed). – Overall, the wound may lack the inflammatory stimulus needed to kick-start healing, remaining in a stalled state.
Clinical Guidance	– Continue low-dose MTX during surgery in most cases (Methotrexate wound healing - Search Results - PubMed). Guidelines support no interruption, as benefits (avoiding disease flare) outweigh risks. – Ensure adequate nutrition and prophylactic antibiotics if needed, as usual best practices for wound healing.	– Re-evaluate MTX therapy if a patient has a non-healing ulcer. Weigh the necessity of MTX for the underlying disease against its hindrance to wound healing. – Often, clinicians hold or reduce MTX until the chronic wound shows progress, unless MTX is crucial (case-by-case decision).

Notes: Acute surgical wounds tend to heal efficiently even under MTX, especially at the doses used for immunosuppression (Effect of methotrexate on bone and wound healing - PubMed). Chronic wounds, conversely, require robust regenerative processes that MTX can stifle. Also, patient context matters: a rheumatoid arthritis patient on MTX who undergoes surgery can usually heal well, whereas a diabetic patient on MTX (if, say, they are on it for psoriasis) with a foot ulcer may struggle to heal the ulcer. In cancer patients on chemotherapy doses of MTX, both surgical wound healing and any chronic wound would be markedly impaired, so timing and supportive care are critical.

Conclusion

Methotrexate’s impact on wound healing is complex and dose-dependent. High-dose MTX (as in chemotherapy) clearly impairs healing – causing delayed wound closure, reduced collagen and blood vessel formation, and greater risk of infection. Low-dose MTX, as used in chronic inflammatory diseases, has a much more subtle effect: evidence indicates that surgical incisions generally heal normally in patients on low-dose MTX, with no significant increase in infections or complications (Effect of methotrexate on bone and wound healing - PubMed). Thus, for acute wounds like surgical sites, MTX can often be safely continued. On the other hand, chronic wounds such as diabetic ulcers represent a scenario where any drug that suppresses inflammation or cell growth can further hinder healing. While direct studies are limited, it is biologically plausible and clinically suspected that MTX may prolong the course of chronic wounds and heighten infection risk (The Effect of Comorbidities on Wound Healing - PubMed). Careful clinical judgment is required – in patients with difficult non-healing wounds, temporary discontinuation of methotrexate might be considered to allow better immune function and tissue regeneration, unless MTX is absolutely needed for life-threatening autoimmune control.

In summary, methotrexate modestly influences acute wound healing (often safely continued in surgery) but can significantly affect chronic wound repair due to its anti-proliferative and immunosuppressive actions. Ongoing research, including recent animal studies, continues to shed light on MTX’s tissue-level effects (Effect of low- and high-dose methotrexate on wound healing in rats - PubMed) (Effect of low- and high-dose methotrexate on wound healing in rats - PubMed). Clinicians should remain vigilant for wound-healing issues in patients on methotrexate, tailoring management (such as optimizing nutrition, local wound care, and adjusting MTX dosage) to promote the best healing outcomes while still treating the underlying disease.

Sources: Peer-reviewed articles and reviews were consulted, including Expert Opinion on Drug Safety (Pountos & Giannoudis 2017) which reviewed MTX effects on bone and wound healing (Effect of methotrexate on bone and wound healing - PubMed), clinical studies in The Journal of Rheumatology and Modern Rheumatology on surgical outcomes with MTX, a 2020 review of comorbidities affecting wound healing (The Effect of Comorbidities on Wound Healing - PubMed), current perioperative guidelines for rheumatic patients (Methotrexate wound healing - Search Results - PubMed), and a 2025 experimental study in Acta Cirúrgica Brasileira investigating MTX in wound-healing phases (Effect of low- and high-dose methotrexate on wound healing in rats - PubMed) (Effect of low- and high-dose methotrexate on wound healing in rats - PubMed). These sources collectively inform the understanding of how methotrexate alters healing physiology and patient outcomes in both acute and chronic wound settings.