Answer:
Low dose, weekly, oral methotrexate is an immunodulatory and immunosuppressive, though clinically there are very few manifestations of immunosuppression. The exact mechanism of action is not clear with possibilities of serving as an anti-metabolite affecting immunocytes, inhibiting chemotaxis via adenosine receptors, reduction of translocation of NF-kB into the nucleus, blocking other transmethylation events, and modification of signaling by JAK and STAT pathways (1)
There are questions in the archives of Ask the Expert concerning this question. I do not believe there is any more recent information that would modify this response.
There is evidence that methotrexate, particularly when coupled with other immunsuppressive agents such as TNF inhibitors, impairs immune response (2,3). This has been recently discussed in relation to COVID-19 vaccination (4). Of course, this is not the same as modulating a pre-existing type 2 response but suggests that the methotrexate could modify the immune response to the allergen immunotherapy.
In summary, there is no contraindication of giving allergen immunotherapy to patients receiving methotrexate. Methotrexate may affect the immune response to the immunotherapy, but this does not rule out trying the therapy in the situation you describe.
1. Cronstein, Bruce N., and Thomas M. Aune. "Methotrexate and its mechanisms of action in inflammatory arthritis." Nature Reviews Rheumatology 16.3 (2020): 145-154.
2. Nived, Per, et al. "Methotrexate reduces circulating Th17 cells and impairs plasmablast and memory B cell expansions following pneumococcal conjugate immunization in RA patients." Scientific reports 11.1 (2021): 1-9.
3. Kapetanovic, Meliha C., et al. "Methotrexate reduces vaccine-specific immunoglobulin levels but not numbers of circulating antibody-producing B cells in rheumatoid arthritis after vaccination with a conjugate pneumococcal vaccine." Vaccine 35.6 (2017): 903-908.
4. Arnold, Jack, Kevin Winthrop, and Paul Emery. "COVID-19 vaccination and antirheumatic therapy." Rheumatology (2021).
I hope this information is of help to you and your practice.
All my best.
Dennis K. Ledford, MD, FAAAAI
Q: 10/7/2013: Effect of methotrexate with immunotherapy
A patient on IT for severe allergic rhinitis, asthma and eczema advised me that her dermatologist would like to give her a trial of methotrexate for eczema. Is there any contraindication continuing with allergy immunotherapy in this patient? It is unclear how long of a course of methotrexate this patient will be receiving.
Thank you for your inquiry.
A: Basically, there is no contraindication to the administration of immunotherapy in a patient taking methotrexate. The question is whether or not methotrexate would dampen the response to immunotherapy based on its known effects on immune response. We have dealt with this issue on our website on several occasions. The most recent entry is copied for you below. This will give more details.
Q: 10/31/2011 The effect of methotrexate on immunotherapy
I am following an 11 y.o. boy for severe seasonal allergic rhinoconjunctivitis. He also has psoriasis. At his last appointment, he and his mother decided they would like to go ahead and start allergen immunotherapy. Shortly after the appointment, his dermatologist at NYU decided to start him on Methotrexate. I am hesitant to start IT at the same time he is starting methotrexate. Apparently, he will be on an incremental dosing regimen that will have him on therapeutic doses in 6-8 weeks. Is there any information available about the safety and efficacy of allergen immunotherapy concurrent with methotrexate therapy? Thank you.
A: Very similar questions have been posed to our website previously. For your convenience, I have copied and pasted them below. They will give you references and more detail regarding our response should you wish to research it further.
Basically, we cannot give a definitive answer to your question regarding the potential effect of methotrexate on immunotherapy because no specific studies in this regard have been done. However, we do know that methotrexate can dampen the response immunization as you can see from the answers to the previous questions, and therefore could have a potential effect on the response to immunotherapy.
However, there is no specific contraindication to the administration of immunotherapy in a patient taking methotrexate, and therefore one can administer this form of treatment to a patient on this drug, but one cannot adequately assess the potential diminution in efficacy of immunotherapy in this setting. However, clearly there is a potential for a diminished response as noted above.
Thank you again for your inquiry and we hope this response is helpful to you.
Q: I have a patient who fulfills all the criteria and indications to get allergen immunotherapy. She is on Methotrexate 12.5mg weekly, and Humeira for Rheumatoid arthritis.
My question is: Will the immunotherapy be effective, meaning will she have an adequate immunologic response to the IT or will the Methotrexate suppress the immune response?
A: Although I am not aware of any study specifically related to the effect of methotrexate and anti-TNF agents on the response to allergen immunotherapy, studies have looked at the effect of these agents on standard immunizations. There are data which suggest that the combination of anti-TNF agents and methotrexate can diminish the response to immunizations.
Based on these data, one cannot rule out a possible effect of these agents on your patient's response to allergen immunotherapy. For your convenience, I have copied an abstract below of an article which explores this issue.
Current Opinion in Rheumatology:
May 2008 - Volume 20 - Issue 3 - p 295-299
doi: 10.1097/BOR.0b013e3282ffdeca
Clinical therapeutics: Edited by Gerd Burmester and Thomas Dorner
Immunization of patients with rheumatoid arthritis with antitumor necrosis factor[alpha] therapy and methotrexate
Brezinschek, Hans-Petera; Hofstaetter, Thomasa; Leeb, Burkhard Fb; Haindl, Piab; Graninger, Winfried Ba
Abstract
Purpose of review: The aim of this study is to highlight the recent findings on the use of methotrexate and/or TNFá-blockers in adult patients with rheumatoid arthritis and their effects on the immune response to various vaccines.
Recent findings: Regarding influenza vaccination, methotrexate monotherapy is not associated with a decreased response, whereas the use of etanercept and infliximab in combination with methotrexate may cause lower titers and lower response rates. Concerning pneumococcal vaccination, methotrexate seems to impair responsiveness. The concomitant use of adalimumab and methotrexate is also associated with decreased response, whereas the concomitant use of etanercept or infliximab seems not to have an effect on response rates. As immunological pathways seem to play a major role, T-cell-dependent pneumococcal vaccines are designed to achieve higher response rates and protective titers.
Summary: Patients with rheumatic disorders are more likely to develop preventable infectious diseases, which underlines the importance of adequate immunoprotective titers. Several studies have shown that the combination of methotrexate and certain TNFá-blockers are affecting the responsiveness to vaccines. Further findings indicate that the response also depends on what type of vaccine is used.
Effect of Methotrexate on Antibody Production
Q: Is methotrexate known to impair the specific antibody response to vaccine (i.e. Pneumovax? (I have an adult patient with leukocytoclastic vasculitis requiring methotrexate, Enbrel (aka etanercept), and intermittent prednisone. She has a h/o chronic rhinosinusitis and an essentially zero response to Pneumovax, which is a vaccine that theoretically invovles only B-cell stimulation b/c it is a polysaccharide antigen) I know prednisone is known to decrease the specific Ab response to vaccines such as Pneumovax, but I was wondering if methotrexate is also known to impair the humoral immune response. (Etanacerpt is a TNF-antagonist so theoretically would not affect B-cell stimulation and antibody production.)
A: Unfortunately, we cannot answer your question definitively in spite of studies dealing with this issue. As you can see from the abstracts below, there is clearcut evidence in vitro and in vivo in animals that methotrexate can suppress antibody synthesis and immunization responses. In humans, studies of methotrexate on response to immunization give somewhat conflicting results. Therefore, I cannot tell you with any confidence whether or not the methotrexate administration is directly responsible for the suppression of the immune response to Pneumovax as seen in your patient. We do know that high dose prednisone can suppress immune response, however, and certainly it is possible that the methotrexate in combination with the prednisone could suppress the response to Pneumovax.
The Effect of Methotrexate on the Production of Antibodies against Attenuated Distemper Virus in the Dog1E. Donnall Thomas et al The Journal of Immunology February 1, 1963 vol. 90 no. 2 324-328
Summary
Methotrexate is a potent inhibitor of antibody production in the dog at dose levels that are not in themselves productive of serious toxicity. In the absence of antibody production inoculation with the attenuated virus of distemper vaccine causes a fatal illness. The production of a fatal illness by this usually benign vaccine virus illustrates the heightened hazard of infection in subjects whose immunologic responsiveness is reduced by chemotherapy.
Antiproliferative effects of methotrexate on peripheral blood mononuclear cells
Arthritis & Rheumatism
Volume 32, Issue 4, pages 378–385, April 1989
Nancy J. Olsen MD,
Lisa M. Murray BS
Abstract
Methotrexate was added to cultured mononuclear cells from the peripheral blood of normal individuals and patients with rheumatoid arthritis (RA) to study the drug's effects on mononuclear cell proliferation and antibody synthesis. In the presence of methotrexate, marked antiproliferative effects (to levels <15% of baseline) were seen with 3H-deoxyuridine, but not with 3H-thymidine, as the marker of cell division. This difference was not due to altered kinetics of proliferation or the presence of salvage nucleotides in the culture medium. The absence of suppression of antibody production preactivated by pokeweed mitogen in vitro and the low levels of suppression of spontaneous IgM rheumatoid factor production by blood mononuclear cells from RA patients suggested a relative resistance of activated cells to the effects of methotrexate. The effects of methotrexate on both cell proliferation and antibody synthesis were completely reversed by the addition of high concentrations of exogenous folinic acid. The results suggest that methotrexate has effects on immuno-competent cells that may contribute to the efficacy of this drug in the treatment of RA and other autoimmune diseases.
J Immunol. 1988 Jul 15;141(2):410-6.
Suppression of B cell function by methotrexate and trimetrexate. Evidence for inhibition of purine biosynthesis as a major mechanism of action.
Rosenthal GJ, Weigand GW, Germolec DR, Blank JA, Luster MI.
Systemic Toxicology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Abstract
Methotrexate (MTX) is a widely used drug in the treatment of a variety of human neoplasms. Trimetrexate (TMQ) is a lipid-soluble quinazoline derivate of MTX that, unlike MTX, is not dependent upon membrane folate transport for cellular entry. A number of studies have demonstrated that MTX and, more recently, TMQ possess potent immunosuppressive properties. To examine the cellular events associated with the immunomodulatory effects of anti-folates on humoral immunity, a murine B cell maturation model was used. In vitro, MTX and TMQ reduced the number of antibody-forming cells to SRBC, as well as IgM production. B cells stimulated with anti-Ig demonstrated a dose-related suppression in [3H]UdR incorporation after addition of either drug, suggestive of a decrease in de novo DNA synthesis. B cell activation events preceding S phase were also suppressed by both anti-folates, as evidenced by inhibition of RNA synthesis. However, neither drug affected surface expression of Ia Ag nor inositol phosphate accumulation. Addition of TdR caused a slight non-significant increase in the antibody-forming cell response in the presence of 10(-7) M MTX. However, addition of hypoxanthine or adenine, but not guanine, resulted in complete restoration. Timed addition revealed that the ability of MTX to suppress antibody responses was diminished if added after 48 h of culture, similar to the reversal of this suppression mediated by hypoxanthine. Cell cycle analysis of LPS-stimulated B lymphocytes demonstrated that both drugs modulated events preceding, as well as during, the S phase. The present studies suggest that although drug-induced impairments in dTMP biosynthesis may be responsible for deficient lymphoid proliferation, anti-folate-induced impairment in purine biosynthesis is a major mechanism in anti-folate-induced suppression of humoral immunity.
Response to pneumococcal vaccine in patients with early rheumatoid arthritis receiving infliximab plus methotrexate or methotrexate alone. Sudha Visvanathan, et al
The Journal of Rheumatology May 1, 2007 vol. 34 no. 5 952-957
Abstract
Objective: We assessed whether the addition of anti-tumor necrosis factor (TNF) agent to methotrexate (MTX) therapy might alter the response of patients with rheumatoid arthritis (RA) to pneumococcal vaccination. METHODS: Seventy patients with early RA (n = 20, 36, and 14 in the infliximab 3 mg/kg plus MTX, infliximab 6 mg/kg plus MTX, and placebo plus MTX groups, respectively) were included in an analysis of patients enrolled in an ASPIRE substudy. Patients received 0.5 ml pneumococcal vaccine (Pneumovax) 34 weeks after initiation of study treatment; patient sera were collected 4 weeks later (week 38). Antibody responses were tested using enzyme immunoassay methods for reactivity to a panel of 12 serotypes of the pneumococcal vaccine.
Results: No significant difference in response to Pneumovax was observed between the infliximab plus MTX and placebo plus MTX groups. Roughly 80%-85% of patients responded to at least one serotype; however, only 20%-25% of patients in the different treatment groups responded to at least 6 different serotypes. Comparable proportions of patients in the 3 treatment groups responded to an increasing number (> or = 1 to > or = 6) of different serotypes. Patients < 45 years of age and those receiving oral corticosteroids generally appeared to respond better than those age 45 to 65 years and those not receiving oral corticosteroids.
Conclusion: All treatment groups in this study had lower responses to vaccine than would be expected in the normal population. However, the addition of the anti-TNF agent infliximab to MTX therapy did not appear to affect the response of patients with RA to pneumococcal vaccination.
Influence of methotrexate, TNF blockers and prednisolone on antibody responses to pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis
M. C. Kapetanovic et al Rheumatology (January 2006) 45 (1): 106-111
Objective: To compare antibody responses to 23-valent pneumococcal vaccine (Pneumovax®) in controls and patients with established rheumatoid arthritis (RA) treated with TNF blockers, methotrexate (MTX) or a combination of both.
Methods: Patients with RA (n = 149) and healthy controls (n = 47) were vaccinated. Treatment with TNF blockers (etanercept or infliximab) and MTX was given to 50 patients, and 62 patients were treated with TNF blockers alone or with other DMARDs. MTX alone was given to 37 patients. Concentrations of immunoglobulin G (IgG) antibodies against pneumococcal capsular polysaccharides 23F and 6B were measured by enzyme-linked immunoassay before and 4–6 weeks after vaccination. An immune response was defined as a twofold or higher increase in antibody concentration following vaccination.
Results: Prevaccination antibody levels for both 23F and 6B were similar in the patient groups. Antibody concentrations after vaccination increased significantly in all groups. Patients treated with TNF blockers without MTX showed better immune responses than those treated with TNF blockers in combination with MTX (P = 0.037 for 23F and P = 0.004 for 6B) or MTX alone (P<0.001 for both 23F and 6B). RA patients given MTX alone had the lowest immune responses. Prednisolone treatment did not influence the responses.
Conclusions: Patients treated with TNF blockers and controls showed similar responses to vaccination. In contrast, patients treated with MTX had reduced responses regardless of anti-TNF treatment. The findings do not argue against the use of pneumococcal vaccination in RA patients undergoing treatment with TNF blockers.
Sincerely,
Phil Lieberman, M.D.