|Ahead of print publication
Efficacy and safety of conventional synthetic, biologic and targeted synthetic DMARDs in RA-ILD: A narrative review
Richard Conway1, Elena Nikiphorou2
1 Department of Rheumatology, St. James's Hospital; Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland
2 Department of Rheumatology, King's College Hospital; Centre for Rheumatic Diseases, King's College London, London, England
|Date of Submission||19-Jul-2021|
|Date of Acceptance||15-Oct-2021|
|Date of Web Publication||10-May-2022|
Department of Rheumatology, St. James's Hospital, James Street, Dublin 8
Source of Support: None, Conflict of Interest: None
The range of therapeutic options available for rheumatoid arthritis (RA) is becoming increasingly diverse. Conventional synthetic disease-modifying antirheumatic drugs (DMARDs), biologic DMARDs, and targeted synthetic DMARDs offer the rheumatologist a far greater breadth of treatment options than before. When choosing a treatment in the individual patient, several important factors need to be considered, one of which is the safety in RA interstitial lung disease (RA-ILD). Rheumatologists frequently encounter RA patients with RA-ILD or other co-existing lung diseases. The pulmonary safety profile of our medications is difficult to ascertain and as they are generally infrequent, adverse events are rarely identified in the initial treatment trials. The concern for the safety of these treatments has largely emerged from real-world observational data and has often been based on small numbers of case studies or retrospective analyses of observational studies. The evidence has been controversial with many agents implicated both in the context of predisposing or worsening the risk of ILD and at the same time as potentially beneficial treatments in delaying the onset or progression of ILD. As a result, clear guidance on the treatment of RA-ILD is generally lacking. The purpose of this article, therefore, is to detail our current knowledge of the safety of DMARDs in RA-ILD.
Keywords: Biologic disease-modifying antirheumatic drugs, interstitial lung disease, JAK inhibitors, methotrexate, rheumatoid arthritis
| Introduction|| |
Rheumatoid arthritis (RA) is a systemic inflammatory disease affecting approximately 1% of the worldwide population. It typically causes symmetrical erosive arthritis, resulting in progressive disability. However, the systemic effects of RA can involve nearly all other major organs. Lung involvement is one of the more common extra-articular manifestations and is associated with high levels of morbidity and mortality. It is estimated that 3%–8% of RA patients develop clinically significant interstitial lung disease (ILD), but the true prevalence is still unclear.,, RA-ILD is one of the leading causes of death in RA with an associated mortality of 10%–20% and the literature suggests a mean survival of 5–8 years on the diagnosis.,
Early treatment of ILD is important to mitigate the associated morbidity and mortality. However, the therapeutic approach for RA-ILD is complicated by the potential disease-influencing role of disease-modifying antirheumatic drugs. While the development of RA-ILD is most likely largely driven by systemic inflammation in a genetically predisposed population our medications have been implicated in the development of pulmonary complications. RA treatments have been suggested as causative factors in pneumonitis, predisposition to lung infections, and ILD. However, it has also been shown that the treatment of RA with these medications can be beneficial to the pulmonary manifestations of RA.,,
The current European League Against Rheumatism recommendations and American College of Rheumatology (ACR) guidelines do not have specific guidance for RA-ILD suggesting management in a multidisciplinary setting; the ACR guidelines do recommend the use of methotrexate (MTX) in pulmonary disease., They also highlight the early and aggressive treatment of RA with DMARDs. This article aims to review the current pulmonary safety information of currently available DMARDs to provide insights into the treatment approach in RA-ILD. A summary of the evidence regarding currently used DMARDs in RA lung disease is shown in [Table 1] and [Figure 1]. We have proposed an algorithm for the treatment of RA in patients with ILD in [Figure 2].
|Table 1: Level of evidence of pulmonary efficacy and harm of disease-modifying antirheumatic drugs|
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|Figure 1: Overall weight of evidence on pulmonary safety of disease-modifying antirheumatic drugs|
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|Figure 2: Suggested management algorithm for rheumatoid arthritis with coexisting rheumatoid arthritis interstitial lung disease|
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| Conventional Synthetic Disease-Modifying Antirheumatic Drugs|| |
MTX is the first-line medication for the treatment of RA and one of the most effective. It also has the worst reputation of the DMARDs for its association with pulmonary adverse effects. It has been associated with acute hypersensitivity pneumonitis and chronic ILD. However, in contrast, recent data suggest beneficial effects in delaying the onset and progression of RA-ILD.,
The diagnosis of MTX-pneumonitis can be difficult to make both due to its clinical presentation and lack of proven diagnostic criteria. The presentation of MTX-pneumonitis can be clinically indistinct from a severe respiratory infection or worsening of existing respiratory pathology. Even the histology shares features common to RA-ILD (cellular interstitial infiltrates, diffuse alveolar damage, tissue eosinophils, and granuloma). A systematic literature review of 3463 patients with RA on MTX showed that 2% of patients had an element of lung toxicity. On review, only 15 (0.43%) of these patients were felt to be definitive cases of MTX-pneumonitis. Prespecified adverse event analysis of the randomized double-blind Cardiovascular Inflammation Reduction Trial (CIRT) of MTX to prevent cardiovascular disease demonstrated that 0.3% of MTX-treated patients compared to 0.1% of placebo-treated patients developed pneumonitis., These findings are complemented by meta-analyses of randomized controlled trials (RCTs). A meta-analysis of 22 RCTs involving 8584 patients with RA showed no association between MTX and noninfectious respiratory adverse events. It did show an increased risk of infectious respiratory complications and MTX (relative risk [RR] 1.11, 95% confidence interval [CI] 1.02–1.21). When the specific adverse event of pneumonitis was looked at this was found to be increased in MTX treated patients with an RR of 7.81 (95% CI 1.76–34.72), a similar RR to that reported from the CIRT study., A meta-analysis of MTX in 1630 non-RA patients was performed to avoid the potential confounding factor of the misdiagnosis of RA-ILD as MTX-pneumonitis. This demonstrated no increase in infectious (RR 1.02, 95%CI 0.88–1.19) or noninfectious (RR 1.07, 95%CI 0.58–1.96) pulmonary complications with MTX, and only a single case of possible MTX-pneumonitis. A combined meta-analysis of the 29 studies with 10,214 participants (5362 receiving MTX and 4852 comparator agents) included in these two meta-analyses was also performed. This showed that MTX was associated with an increase in total respiratory adverse events (RR 1.09, 95% CI 1.02–1.16) and infectious respiratory adverse events (RR 1.09, 95% CI 1.01–1.17), but not with noninfectious respiratory adverse events (RR 1.02, 95% CI: 0.73–1.44) or pulmonary death (RR 1.53, 95% CI: 0.46–5.01).
Recently, the previously assumed association between MTX and RA-ILD has been challenged. Ibfelt et al. used the Danish national registry, to examine 30,512 RA patients of whom 60% had received MTX. These patients were then compared to the RA patients who had never received MTX. There was no significant difference in incident ILD between the two groups, HR 1.00 (95% CI 0.78, 1.27). The standardized incidence ratio for ILD was 3–4 fold higher in people with RA compared to the general population, but MTX use did not increase this further. A prospective study of 128 patients compared respiratory outcomes using pulmonary function tests (PFTs) and high-resolution computed tomography (HRCTs) in those prescribed and not prescribed MTX. Over 2 years, they demonstrated no significant difference in outcomes between the MTX and non-MTX patients or between MTX and non-MTX patients with proven ILD on HRCT at baseline. A multivariate analysis of two prospective cohort studies (the early RA study (ERAS) and the early RA network (ERAN)) examined rates of ILD in newly diagnosed RA patients exposed and nonexposed to MTX. MTX exposure was associated with both a significantly reduced risk of incident RA-ILD (odds ratio [OR] 0.48, 95% CI 0.3–0.79) and a longer time to ILD diagnosis (OR 0.41, 95% CI 0.23–0.75). A retrospective multinational case–control study examined the association between MTX exposure and ILD in 410 RA patients with and 673 RA patients without ILD. There was an inverse relationship between MTX exposure and RA-ILD (OR 0.43 (95% CI 0.26–0.69)) and a delay in ILD detection in MTX users (11.4 ± 10.4 years vs. 4.0 ± 7.4 years, P < 0.001).
In summary, the evidence suggests that MTX may rarely be associated with pneumonitis., Recent studies have suggested that MTX may be protective in delaying the onset and progression of RA-ILD., Analysis of the literature shows a low incidence rate for MTX-associated hypersensitivity. MTX does appear to cause a small increased risk of respiratory infections. As the first-line medication in the treatment of RA and one of the keystones, this is reassuring as it shows the relative safety of MTX in ILD patients. There is little evidence to suggest the necessity of avoiding MTX when indicated due to respiratory concerns. The one caveat to this is that MTX is probably best avoided in patients who have the insufficient pulmonary reserve to survive the rare complication of MTX-pneumonitis., Those with the poor pulmonary reserve are also vulnerable to the increased risk of infectious pulmonary adverse events with MTX; this risk is shared with all other DMARDs.
Leflunomide has been associated with hypersensitivity pneumonitis and worsening or new-onset ILD. This association initially emerged in case reports from Japanese populations., A systematic literature review of this data suggested that leflunomide was associated with ILD, however, this was vulnerable to the same potential confounding factors as the original case series. A nested case–control study of 62,734 people with RA in the United States found an increased risk of ILD with leflunomide use (RR 1.9, 95% CI 1.1–3.6). However, among patients who had not received MTX and had no history of ILD the risk was not increased (RR 1.2, 95%CI 0.4–3.1), suggesting that this finding was likely due to channeling bias. A meta-analysis of eight RCTs found no increase in total respiratory adverse events (RR 0.90, 95% CI 0.81–1.01) or infectious respiratory adverse events (RR 0.96, 95% CI 0.84–1.10) with leflunomide. Leflunomide was associated with a decrease in noninfectious respiratory adverse events (RR 0.64, 95% CI 0.41–0.97), and with no cases of pneumonitis compared to six cases in comparators.
There is no clear evidence of a causal relationship between leflunomide and ILD. Similar to MTX, there appears to be a rare possibility of pneumonitis, and caution is probably warranted in those with poor baseline pulmonary function.
Azathioprine, sulfasalazine, and hydroxychloroquine
There is little in the published literature showing a significant link between the above medications and the worsening of ILD. The PANTHER-IPF trial raised concerns regarding the pulmonary safety of azathioprine. In this trial in idiopathic pulmonary fibrosis (IPF) the combination of prednisolone, azathioprine, and N-acetylcysteine was associated with increased mortality and severe respiratory adverse events in the patients on the combination therapy. Of course, the question remained as to which component of the combination treatment was responsible, with prednisolone perhaps the most likely culprit. Reassuringly, a retrospective cohort analysis demonstrated no increase in respiratory adverse events with azathioprine compared to mycophenolate mofetil. There is a documented association between sulphasalazine and eosinophilic pneumonitis which generally recovers once sulfasalazine is ceased.,, There is no evidence suggesting a link between sulphasalazine and ILD. Cases of possible drug-induced pneumonitis with hydroxychloroquine have also been reported. Despite these reported idiosyncratic types of lung toxicity reactions, controlled studies have not convincingly demonstrated safety concerns or benefits of hydroxychloroquine or sulfasalazine in the context of ILD.
Cyclophosphamide has been commonly used in connective tissue disease-associated ILD, particularly in systemic sclerosis. Extrapolating from this data, cyclophosphamide has been used in RA-ILD. Evidence supporting this is limited to retrospective case series.,, Given the limited supporting data, and the increased adverse events observed with cyclophosphamide compared to other DMARDs, we would suggest being cautious in its use in RA-ILD.,
| Biologic Disease-Modifying Antirheumatic Drugs|| |
Tumour necrosis factor inhibitors
There are currently five tumor necrosis factor inhibitors (TNFi) licensed for the treatment of RA. Three monoclonal antibodies (adalimumab, golimumab, infliximab) a recombinant soluble TNF receptor (etanercept), and the pegylated monoclonal antibody, certolizumab. TNFi are the most frequently used biologic DMARDs in RA and are often prescribed in conjunction with MTX. TNFi have known significant adverse effects and patients are monitored closely while using them. Concern has been raised over the long-term respiratory effects of these medications as TNF exhibits both profibrotic and antifibrotic effects and so there is biologic plausibility for an effect on ILD.,
It was hypothesized that TNFi may have a role in stabilizing ILD due to the presence of TNF alpha in IPF. However successive trials, while many were underpowered, have not demonstrated this. The initial RCTs that demonstrated the efficacy of TNFi in RA reported no excess of ILD compared to placebo., However, RCTs are both underpowered to identify rare complications and of too short a duration to identify adverse events with long latencies. RCTs of TNFi in RA have generally excluded patients with RA-ILD from recruitment. A salutary lesson was learned from the postapproval identification of the increased risk of tuberculosis in TNFi-treated patients. Several case reports and series have reported new onset or progressive ILD coincident with the commencement of TNFi.,,, A case-control study of 163 RA patients from Japan found TNFi was associated with an increased risk of progression of RA-ILD, new-onset ILD and mortality. A retrospective study of 100 RA-ILD patients from Korea reported a 25% mortality in those treated with TNFi, frequently in the early stages of treatment. A Spanish multicenter prospective observational study explored the association between different biologic DMARDs and outcomes in 69 patients with RA-ILD. They found that non anti-TNF biologic were associated with reduced worsening of ILD in multivariate analysis with an OR of 0.102 (95%CI, 0.015–0.686).
There were also several early case reports documenting the improvement of RA-ILD with TNFi treatment., A US cohort study of 8417 people with autoimmune diseases found no association between TNFi use and incident ILD over an average follow-up of 3 years, adjusted hazard ratio 1.03 (95% CI 0.51–2.07). Detorakis et al., in a progressive study design, demonstrated stable ILD scores in patients on TNFi with no significant new incidences. As TNFi are prescribed in more advanced forms of RA, which are more likely to develop ILD, this may be the cause of the increased incidence of RA-ILD. A British Society for Rheumatology Biologics Register study looked at 367 RA-ILD patients. They found that patients on a TNFi had a higher proportion of death from RA-ILD when compared to those on a conventional DMARD (21% vs. 7%). However, there was no difference between all causes of mortality between the two groups. The authors hypothesized that the difference in deaths attributed to RA-ILD was due to the TNFi cohort having more severe rheumatoid disease.
The evidence for a link between TNFi and RA-ILD is difficult to interpret. There are significant issues with confounding by indication when using real-life longitudinal data which call for caution when interpreting potential associations. Inadequate adjustment for RA disease severity and other potential confounders leaves studies open to potential channeling bias. Patients commencing TNFi therapy tend to have more advanced RA and have most likely been on a conventional DMARD previously. Despite no large studies identifying a significant risk, all five TNFi have been implicated in causing or worsening RA-ILD. The data would suggest caution when prescribing TNFi in patients with known RA-ILD and close monitoring to identify new cases of RA-ILD. As a result of the existing literature, the British Society of Rheumatology recommends caution when prescribing TNFi in RA-ILD.
Rituximab has emerged as the treatment of choice in RA-ILD and is also frequently used in ILD associated with connective tissue diseases. A 10-year single-center study from the United Kingdom examined 56 RA-ILD patients treated with rituximab. The main outcome measure was serial PFTs; 16% improved, 52% were stable, and 32% deteriorated. There were also nine deaths due to progressive ILD. A study utilizing the British Society for Rheumatology Biologics Register for RA included 352 patients with RA-ILD; mortality was reduced by half in the rituximab treated patients (compared to TNFi) but this did not reach statistical significance, HR 0.53, 95%CI 0.26–1.10. A study based on the Spanish NEREA registry included 68 patients with RA-ILD and examined a primary endpoint of a decline of ≥5% in the predicted forced vital capacity; rituximab exposure was associated with a lower risk, HR 0.51 (95% CI 0.31, 0.85).
While most of the data regarding rituximab use in RA-ILD is positive, there have been some notes of caution also. Rituximab has been associated with both infectious and noninfectious respiratory complications. A systematic review of published data to 2010 identified 121 cases of new-onset ILD attributed to rituximab treatment. Franzen et al. performed a prospective study of serial PFTs in 33 RA patients treated with rituximab. They reported an asymptomatic decline in the DLCO in 22% of their patient cohort over 26 weeks. Clearly, the relevance of this finding is limited by the absence of a control group or further investigation as to the etiology of the PFT decline.
Rituximab remains a first-line treatment for RA-ILD. The data on which this is based are quite limited however and further studies are needed to confirm the suggested beneficial effects.
Abatacept is a selective T-cell co-stimulation moderator. The initial trials for abatacept excluded patients with preexisting ILD. Pooled data from 4149 patients in these trials showed that 11 abatacept treated patients developed new-onset RA-ILD compared to none in the placebo group suggesting a possible association, incidence rate 0.11 (95% CI 0.06–0.20). Subsequent to this however there were case reports of abatacept's efficacy in treating refractory RA-ILD. Several trials have now suggested a role for abatacept in treating RA-ILD.,, A Spanish multicenter study of 263 patients with RA-ILD reported stabilization or improvement of PFTs in 87.7%–90.6% of patients and of HRCT appearances in 77% of patients. A retrospective Italian study reported similar results with stable or improved PFTs in 86.1%–91.7% and stable or improved HRCT in 81.4% of patients. A 49-patient single-center study in Japan reported a reduction of new onset or exacerbations of ILD in abatacept treated patients. A large US-based cohort study of 3295 patients with known RA-ILD showed a nonsignificant incidence rate ratio of 0.44 (95% CI 0.18–1.09) for abatacept (compared to TNFi) for ILD exacerbation. A systematic literature review and meta-analysis of nine studies of abatacept in RA-ILD has been performed and demonstrated improvement or stabilization of ILD imaging in 77%–93% and PFTs in >85%. Abatacept was associated with significantly lower ILD worsening rates than TNFi and a 90% reduction in ILD deterioration at 24 months. While these data are encouraging, all of these studies are limited by the observational nature of the data and the lack of a control group. Based on these data, abatacept is emerging as a promising treatment option in RA-ILD.
Interleukin 6 (IL-6) inhibition with tocilizumab has been theorized to be protective of RA-ILD due to the profibrotic effects of IL-6. However, observational data and published studies suggest an unclear picture. The majority of RCTs with tocilizumab did not report the occurrence of cases of ILD.,, There was one death from ILD in a tocilizumab and MTX treated the patient in the SURPRISE study. Retrospective case series demonstrate worsening of RA-ILD. One study found an increased risk of worsening of RA-ILD in patients on tocilizumab monotherapy. A retrospective Japanese study of 395 consecutive RA patients who received tocilizumab identified six patients with worsening of their RA-ILD post tocilizumab monotherapy. These studies have suggested preexisting RA-ILD and high disease activity as potential risk factors for exacerbations., Case-series have also demonstrated potential protective effects of tocilizumab in RA-ILD and the stabilization of respiratory function with its use. In a study of 11,219 patients based on the MarketScan databases, no significant difference between the risk of RA-ILD or its exacerbation was seen between other biologic DMARDs and tocilizumab.
As the literature is unclear, despite the assumed anti-fibrotic effects of tocilizumab, we are unable to clearly comment on its potential role in RA-ILD.
| Targeted Synthetic Disease-Modifying Antirheumatic Drugs|| |
JAK inhibitors (JAKi) are the newest option available for the treatment of RA. To date baricitinib, tofacitinib, filgotinib, and upadacitinib have been licensed. As these medications are relatively new there is a limited amount of observational data and our understanding of the off-target effects of the inhibition of the JAK pathway in ILD is somewhat limited. There is a mechanistic rationale for the blockade of the JAK/STAT pathway in ILD given the demonstration of the potential importance of this pathway in the pathogenesis of ILD. The literature to data has not demonstrated any significant concerns regarding the respiratory safety of JAKi, however, given the limited data remains inconclusive. The initial RCTs showing the efficacy and safety of the JAK inhibitors had a lack of patients with preexisting lung disease, including RA-ILD. There were small numbers of cases of ILD reported in the RCTs, however, these were not more than would be expected due to the natural history of RA itself. A long-term extension of a Japanese study which followed 187 patients receiving upadacitinib for 84 weeks reported no cases of ILD. A descriptive report of 3,770 patients from eight RCTs and one long-term extension study of baricitinib found 21 cases of ILD with an exposure-adjusted incidence rate of 0.17 per 100 patient-years. A retrospective study of 47 patients in Scotland compared the use of baricitinib and tofacitinib to rituximab in the treatment of RA patients with known ILD or bronchiectasis. They found that JAKi use (compared to rituximab) was not associated with an increase in the rate of hospitalization or mortality due to respiratory causes. A meta-analysis of pulmonary adverse events in 79 studies with 159,652 patients treated with JAKi did not show any increase in ILD with JAKi.
The preliminary data for the safety of JAK inhibitors in RA-ILD is encouraging, however, longer-term trials are needed to further elucidate this.
| Conclusion|| |
This article has summarised the current evidence on the use of DMARDs in the context of RA-ILD. There are important and significant limitations in the existing literature which we need to be cognizant of when interpreting the data; these include confounding by indication, channeling bias, a lack of suitable comparator groups, and the use of retrospective observational data. For nearly every treatment option available there is a group of case studies suggesting exacerbation or new-onset RA-ILD, [Table 1]. Larger studies have to date failed to corroborate such a relationship. New evidence for MTX suggests it is much safer than previously supposed. Some experts have recommended against TNFi in the treatment of RA with RA-ILD, but the evidence is inconclusive. Rituximab and abatacept have the most supportive data in the treatment of RA-ILD, however, it remains limited. The newest group of medications, the JAK inhibitors, so far show promising safety data in RA-ILD but do not as yet have a commensurate amount of real-world evidence as other bDMARDs. Treatment in RA-ILD should be decided on a case-by-case basis with tailored therapy for each patient, [Figure 2].
Financial support and sponsorship
Conflicts of interest
Luke Corcoran: None declared, Richard Conway: Speakers bureau - Janssen, Roche, Sanofi, Abbvie, Elena Nikiphorou: Speakers bureau - AbbVie, Eli-Lilly, Gilead, Celltrion, Pfizer, Sanofi.
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