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Three Part Question

In [a patient undergoing any type of thoracic surgery] does [stopping methotrexate prior to surgery] have any effect on [reducing post-operative complications]?

Clinical Scenario

A 50-year-old male/female with a past medical history of rheumatoid arthritis attends pre-operative clinic prior to an elective right upper lobectomy. Amongst the regular medications is methotrexate. You wonder whether the patient should continue methotrexate to reduce risk of flare-up and problems with post-operative pain control or stop this medication prior to surgery due to concerns about immunosuppression and increased risk of post-operative complications; especially wound infections and air leaks. If you were to stop it, how long should it be discontinued for and when should it be re-started?

Search Strategy

Pubmed (Medline) 1965 - 2020 was searched for ((methotrexate) AND (thoracic surgery)) AND (complication).
Pubmed (Medline) 1965 - 2020 was also searched for (methotrexate) AND (postoperative complications), filtered for ‘English’ only and ‘Human’ studies only.
Pubmed (Medline) 1965 - 2020 was searched for ((methotrexate) AND (thoracic surgery)) AND (complication), and showed 126 results, but none of them were deemed relevant.
Pubmed (Medline) 1965 - 2020 was searched for (methotrexate) AND (postoperative complications), filtered for ‘English’ only and ‘Human’ studies only, and returned 328 results.

Search Outcome

Pubmed (Medline) 1965 - 2020 was searched for (methotrexate) AND (postoperative complications), filtered for ‘English’ only and ‘Human’ studies only. This returned 328 results. No papers were directly related to our question, but 5 were deemed somewhat relevant to our topic. These are listed in the table below. All relevant papers are summarised in the table below.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Grennan et al 2001 UK	388 patients with rheumatoid arthritis who were to undergo elective orthopaedic surgery. Group A (88 subjects) continued methotrexate. Group B (72 subjects) stopped methotrexate w weeks before operation and restarted 2 weeks after operation. Group C (228 subjects) was not on methotrexate.	Prospective randomised study	Postoperative complications occurring within 1 year. Complications were defined as wound morbidity, systemic infection, wound dehiscence, loosening of implants, or any complication requiring a secondary revision procedure and occurring within one year of surgery. Flare up of rheumatoid arthritis at 6 weeks.	Signs of infection or surgical complication occurred in 2% (n=2) of group A, 15% (n=11) in group B and 10.5% (n=24) in group C. The complication rate was less in group A than in group B or C. At 6 weeks after surgery there were no flare ups in group A, 8% (n=2.6) of flares in group B and 2.6% (n=6) flares in group C.	1 year follow up, so it does not take into account long term complications.
Sany et al 1993 France	64 patients with rheumatoid arthritis treated with methotrexate who underwent orthopaedic surgery. Group A (32 patients, 50 procedures) methotrexate was stopped 7 days prior to surgery. Group B (32 patients, 39 procedures) methotrexate was not stopped prior to surgery.	Randomised unblinded prospective study	Post-operative wound infection	No postoperative infection observed in either groups. Prolonged wound healing in 12% (n=6) of cases in group A and in 10% (n=4) of cases in group B.	Small patient cohort ( 64 patients only) study. No cases of post-operative infection, does not take into account other factors.
Sreekumar et al 2011 UK	Patients from a previous study (Grennan et al 2001) were followed up at 10 years. Of the 388 original patients, 193 were lost to follow up and 116 had died. 65 patients agreed. 31 were reviewed in clinic and 34 were reviewed through a telephone consultation.	Retrospective review	Surgical complication was defined as any condition requiring revision surgery other than infection. Clinical infection was defined as infection around the operation site or deep bone infection.	No incidence of late deep infection in any of the patient’s that were followed up. 1 patient required revision surgery in group A, but no evidence of a septic cause was found. Of the patients who had died, no evidence of sepsis contributed to their death.	193 patients lost to follow up, so many complications may have been found in this cohort. Only 65 out of the original 388 were followed up, so not a representative sample and bias could have played a part.
Murata et al 2006 Japan	122 patients with rheumatoid arthritis who had 201 orthopaedic procedures. Group A continued methotrexate (77 procedures), Group B discontinued methotrexate more than 1 week before surgery (21 procedures) and Group C who had no treatment with methotrexate.	Retrospective review	Post-operative infection (reddening of wound, discharge, administration of antibiotics. Poor wound healing (wound dehiscence after suture removal). Flare up of rheumatoid arthritis (increased pain in at least 2 joints, within 4 weeks of surgery).	Post-operative infections group A - 3.9% (n=3), group B - 4.8% (n=1), group C - 3.9% (n=4). Poor wounding healing group A - 1.3% (n=1), group B - 9.5% (n=2), Group C - 7.8% (n=8). Flare ups group A - 3.9% (n=3), group B - 14.3% (n=3), group C - 6.8% (n=7).	"Follow up was only for 1 year, longer follow up is required. Flare ups were only followed up for 4 weeks, longer follow up required. "
A.Steuer et al 1997 UK	200 randomly selected rheumatologists. 148 consultant rheumatologists responded. 200 randomly selected orthopaedic surgeons. 104 consultant orthopaedic consultants responded.	Survey	Concern over the use of methotrexate and post-operative complications. If and when methotrexate was stopped pre-operatively.	40% (n=59) of rheumatologists actually participated actively in peri-operative care. 35% (n=52) of rheumatologists and 46% (n=48) of orthopaedic surgeons were concerned that MTX may increase post-operative complications. 20% (n=30) of rheumatologists always stopped methotrexate prior to surgery, 17% (n=18) of orthopaedic surgeons always stopped it before surgery. 70% (177) of clinicians felt that national guidelines would be helpful on this matter.	A survey is a low level of evidence study type.

Comment(s)

The initial search did not deliver any papers that answered our original question of whether methotrexate should be stopped prior to thoracic surgery to decrease post-operative complications. Air leaks from chest drains are not uncommon after thoracic surgery, which can result in longer placements of intercostal chest drains and hospital stay, as well as a longer recovery for patients. Wound infection is a concern after any surgery. Following thoracic surgery there is the added risk that this, especially in the presence of a chest drain, could increase the risk of empyema (given possible associated immuno-suppression). There was no evidence related to methotrexate in the context of thoracic surgery. Hence the search was extended to other surgical specialties. The main specialty that had researched the effect of methotrexate in post-operative complications was orthopaedic surgery. This is understandable given the methotrexate is a common therapeutic agent for the management of rheumatoid arthritis, a condition often requiring orthopaedic interventions. The research by Grennan et al showed that patients who continued methotrexate during the peri-operative period actually had less postoperative complications (2%, n=2), than those that stopped methotrexate (15%, n=11) or even those who were not on methotrexate (10.5%, n=24). This study had small numbers and may not have been sufficient powered to detect the risk. Sreekumar et al, then followed this same cohort of patients up at 10 years. There was no late complication in any of the patients followed up at 10 years, indicating methotrexate would be safe in the long term to continue during the peri-operative period, however the majority of the subjects in the initial study were lost to follow up or had died, negating the accuracy of this study. In thoracic surgery, once the wounds had healed well primarily, long-term wound issues are rare. A randomised unblinded prospective study conducted by Sany et al, seemed to agree with previous studies as no post-operative infections occurred in both patients taking and not taking methotrexate during their operation. Murata et al not only showed that there was no real difference in post-operative complications depending on the continuation of methotrexate, but actually showed that rheumatic flare ups are lower if methotrexate is stopped pre-operatively (3.9%, n=3), compared to if it is stopped (14.3%, n=3). Post-operative analgesia is a concern after thoracic surgery. This could be exacerbated if flare-ups occur whilst the patient is recovering from thoracic surgery. A relatively old survey of practice by Steuer et al showed that clinicians have concern over the continuation of methotrexate and post-operative complications and practice was varied. 70% of clinicians thought national guidelines would be useful on the topic. If methotrexate is being discontinued, the other pertinent question would be when to stop it and when to re-start it. Through our search we found no papers that answered this question. Further research is needed to establish if methotrexate should be omitted prior to thoracic surgery; with guidance on when to stop and restart it. The evidence from orthopaedic studies appears to show that there is no evidence to stop methotrexate in the peri-operative period for patients undergoing surgery, but in fact may be beneficial to continue in terms of their rheumatic management. This may be applied to thoracic surgery practice, but specific research is needed to address these concerns. The which also included thoracic surgery related complications such as air leaks and the length until recovery.

Clinical Bottom Line

More research is required to assess the post-operative effects of methotrexate (and/or other immune-suppressant drugs) in patients undergoing thoracic surgery. Randomised studies may be difficult to undertake in sufficient numbers, given the paucity of such patient. Thus, we may need to rely on evidence from large databases. There is no clear evidence to support discontinuation of such drugs, including the duration for which it should be discontinued, prior to thoracic surgery. Evidence from other specialties indicate that there is no real evidence in the need to stop methotrexate prior to thoracic surgery. An individualised approach may be required taking into consideration factors including quality of lung tissue (presence/degree of emphysema or fibrosis), extent/type of thoracic procedure, nutritional status (low BMI, severe weight loss, low albumin), concurrent use of other immune-suppressant drugs (eg steroids), and infection risk (eg presence of bronchiectasis).

References

1. Grennan et al Methotrexate and early postoperative complications in patients with rheumatoid arthritis undergoing elective orthopaedic surgery Ann Rheum Dis 2001; 214-7
2. Sany et al Influence of methotrexate on the frequency of postoperative infectious complications in patients with rheumatoid arthritis J Rheumatol 1993;
3. Sreekumar et al Methotrexate and post operative complications in patients with rheumatoid arthritis undergoing elective orthopaedic surgery--a ten year follow-up Acta Orthop Belg 2011
4. Murata et al Lack of increase in postoperative complications with low-dose methotrexate therapy in patients with rheumatoid arthritis undergoing elective orthopedic surgery Mod Rheumatol 2006
5. A. Steuer et al Perioperative use of methotrexate - A survey of clinical practice in the UK British journal of Rheumatology 1997