Immunomodulatory drug methotrexate used to treat patients with chronic inflammatory rheumatisms post-chikungunya does not impair the synovial antiviral and bone repair responses

Abstract

Chikungunya virus (CHIKV) is a mosquito-transmitted RNA alphavirus causing major outbreaks of infectious chronic inflammatory rheumatisms (CIR). Recently, methotrexate (MTX), a disease modifying anti-rheumatic drug has been used successfully to treat patients suffering from rheumatoid-like arthritis post-CHIK but its immunomodulatory activity in the context of viral persistence has been a matter of concerns. We herein used a model of primary human synovial fibroblasts (HSF) and the synthetic molecule polyriboinosinic:polyribocytidylic acid (PIC) to mimic chronic infectious settings in the joints of CHIKV infected patients. The innate antiviral immune and inflammatory responses were investigated in response to MTX used at the therapeutic concentration of 1 μM. We found that MTX did not affect cellular viability as indicated by the LDH release assay. By quantitative RT-PCR, we observed that HSF responded robustly to PIC by increasing ISG15 and IFNβ mRNA levels. Furthermore, PIC upregulated the mRNA expression of two of the major pattern recognition receptors, RIG-I and MDA5 involved in the innate immune detection of viral RNA. MTX did not impact the antiviral response of PIC on ISG15, IFNβ, RIG-I and MDA5 mRNA expressions. MTX alone or combined with PIC did not affect the expression of proinflammatory CCL2 and CXCL8 chemokines. PIC strongly upregulated the mRNA and protein expression of osteoclastogenic factors (IL-6, GM-CSF but not RANKL). Critically, MTX treatment alone or combined with PIC did not affect the expression of all three tested osteoclastogenic cytokines. We found that MTX alone did not increase the capacity of CHIKV to infect and replicate in HSF. In conclusion, our study argues for a beneficial effect of MTX to treat CIR post-CHIKV given that it does not critically impact the antiviral, the proinflammatory and the bone tissue remodeling responses of synovial cells.

Rheumatic manifestations of chikungunya: emerging concepts and interventions

“…Alternatively, instead of IFNγ expression by T H 1 cells, TNF expression by CD4 cells might have an important function in promoting chikungunya arthropathy 135 . TNF-expressing CD4 cells have a potential pathogenic function in psoriatic arthritis 143 and are targeted by methotrexate in RA 144,145 ; notably, methotrexate has shown some benefit in treating chikungunya 146,147 .…”

“…Low-dose corticosteroids (with or without NSAIDs) seem to be effective in NSAID-refractory pat ients 35,113,146,171,175 , although the potential adverse effects of these drugs should be considered in risk-benefit assessments 31,176 . For patients with chronic chikungunya who are refractory to the aforementioned treatments, DMARDs have shown some efficacy 113,172 , and sulfasalazine and methotrexate have been suggested as first-line options 146,147 . However, chikungunya arthropathy is usually not overtly erosive 16,47 , and so DMARDs might seem hard to justify 177 unless an underlying destructive autoimmune disease is present.…”

Evaluation of mechanisms of action of re-purposed drugs for treatment of COVID-19

“…MTX, a disease modifying anti-rheumatic drug (DMARD), is used clinically for rheumatoid or psoriatic arthritis and systemic lupus erythematosis with good therapeutic results [91] , [92] , [93] . It is a folic acid analogue that is either used as a monotherapy or in combination with other synthetic DMARDs.…”

“…In addition to interfering with the synthesis of precursor nucleotides, MTX has been shown to exert an immunomodulatory role [91] . Recently, Municio et al [92] showed that long-term low-dose MTX treatment increased the expression of A20 in macrophages stimulated with TLR ligands or TNF-α ( Fig.…”

The Clinical Features, Pathogenesis and Methotrexate Therapy of Chronic Chikungunya Arthritis

“…A recent study revealed that MTX treatment is probably safe and does not affect the antiviral and inflammatory responses of primary human synovial fibroblasts (HSF). MTX alone did not increase the capacity of CHIKV to infect and replicate in HSF [82]. This fact is important because the immunomodulatory activity of MTX in the context of viral persistence has been of concern.…”