With great interest, we read the study by Proft et al. 1In this prospective multicenter study, the authors applied a dermatologist-centered screening tool followed by a structured rheumatologic examination, including MRI of the sacroiliac joints and spine, for the early identification of psoriatic arthritis with axial involvement (axPsA). We endorse the authors for completing an important clinical study, the results of which could have important implications for the early identification of axPsA in patients with psoriasis. However, there are some aspects that need to be focused on and discussed.
First, there is some controversy regarding the definition of axPsA. Some studies have emphasized the importance of imaging, and the presence of sacroiliac arthritis with grade 3 unilaterally or grade 2 and above bilaterally, or spinal syndesmophyte(s) according to CASPAR criteria is defined as axPsA.2 It has also been suggested that axPsA requires meeting the modified New York criteria of AS criteria or applying the Assessment of SpondyloArthritis International Society (ASAS) classification criteria for axial spondyloarthritis (axSpA), which require the presence of inflammatory back pain (IBP) in the patient. However, back pain is not always present in patients with axPsA. The use of chronic back pain as the primary screening condition is debatable. One study showed that up to 44% to 55% of patients with axPsA had only imaging involvement (including sacroiliac joints or spine...
With great interest, we read the study by Proft et al. 1In this prospective multicenter study, the authors applied a dermatologist-centered screening tool followed by a structured rheumatologic examination, including MRI of the sacroiliac joints and spine, for the early identification of psoriatic arthritis with axial involvement (axPsA). We endorse the authors for completing an important clinical study, the results of which could have important implications for the early identification of axPsA in patients with psoriasis. However, there are some aspects that need to be focused on and discussed.
First, there is some controversy regarding the definition of axPsA. Some studies have emphasized the importance of imaging, and the presence of sacroiliac arthritis with grade 3 unilaterally or grade 2 and above bilaterally, or spinal syndesmophyte(s) according to CASPAR criteria is defined as axPsA.2 It has also been suggested that axPsA requires meeting the modified New York criteria of AS criteria or applying the Assessment of SpondyloArthritis International Society (ASAS) classification criteria for axial spondyloarthritis (axSpA), which require the presence of inflammatory back pain (IBP) in the patient. However, back pain is not always present in patients with axPsA. The use of chronic back pain as the primary screening condition is debatable. One study showed that up to 44% to 55% of patients with axPsA had only imaging involvement (including sacroiliac joints or spine) with no symptoms of axial involvement such as back pain. 3In addition, in this study, the authors included the onset of back pain before the age of 45 as one of the screening conditions. This may have missed some patients, as one study showed that the mean (SD) age of axPsA patients with past or current back pain was 44.29 (11.3) years. 4In conclusion, we suggest that the inclusion of back pain as the primary screening condition may reduce inclusion of patients with axPsA.
Second, the authors included spinal MRI in the evaluation of axPsA, which is important for the recognition of axPsA. However, they found only 5 patients out of the 100 enrolled subjects who showed only spine involvement on MRI. This is close to the results of the previous study,in which axial involvement can be seen in approximately 7-20% of psoriasis. 5 Clearly, this number is relatively small, and the high cost of spinal MRI makes its use significantly more financially burdensome to screen psoriasis populations. The need for spine MRI to detect this population is controversial.
Third, the patient's psoriasis type may require attention during the initial screening or even a categorical screening based on the different psoriasis types. The likelihood of axial involvement may differ for different types of psoriasis. As a type of psoriasis with pustules, Palmoplantar pustulosis (PPP) has always been a concern. One of our previous cohort studies found that the percentage of axial involvement caused by PPP was about 40.9%（137/335）, while that caused by psoriasis of the common type was only 7.46%(25/335).6 This suggests that there may be a difference in the axial involvement of different psoriasis subtypes and that classification at the screening stage could reveal additional features that could be helpful for further studies.
Finally, the authors found elevated CRP and increased HLA-B27 positivity in axPsA, which are important for our detection of axPsA. In summary, our recommended referral strategy is for patients with axial features, including symptoms in the neck, low back, or sacroiliac region. This group of patients with elevated CRP, positive HLA-B27, and pustular psoriasis may need more attention.
REFERENCES
1. Proft F, Lüders S, Hunter T, et al. Early identification of axial psoriatic arthritis among patients with psoriasis: a prospective multicentre study. Annals of the rheumatic diseases 2022;81(11):1534-40.
2. Jadon DR, Sengupta R, Nightingale A, et al. Axial Disease in Psoriatic Arthritis study: defining the clinical and radiographic phenotype of psoriatic spondyloarthritis. Annals of the rheumatic diseases 2017;76(4):701-07.
3. Chandran V, Barrett J, Schentag CT, et al. Axial psoriatic arthritis: update on a longterm prospective study. The Journal of rheumatology 2009;36(12):2744-50.
4. Yap KS, Ye JY, Li S, et al. Back pain in psoriatic arthritis: defining prevalence, characteristics and performance of inflammatory back pain criteria in psoriatic arthritis. Annals of the rheumatic diseases 2018;77(11):1573-77.
5. Poddubnyy D, Jadon DR, Van den Bosch F, et al. Axial involvement in psoriatic arthritis: An update for rheumatologists. Seminars in arthritis and rheumatism 2021;51(4):880-87.
6. Cao Y, Li C, Xu W, et al. Spinal and sacroiliac involvement in SAPHO syndrome: A single center study of a cohort of 354 patients. Seminars in arthritis and rheumatism 2019;48(6):990-96.
Correspondence to Dr.Chen Li, Department of Rheumatology, Fangshan Hospital, Beijing University of Chinese Medicine, Beijing, China, casio1981@163.com
Contributors All other authors (XJS, QT, XJH,SFW, and CL) provided their input by contributing to the conceptualisation. SXJ and CL contributed to the editing of the manuscript. XJS, QT, SJH and SFW contributed equally.
Funding This research was funded by the National Natural Science Foundation of China (grant numbers 82074246).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved inthe design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Cheng et al. recently reported the changes in fecal microbiota and peripheral blood metabolites in patients with rheumatoid arthritis (RA) across four stages of the disease. In addition, they performed 16S rRNA sequencing and identified bacteria in synovial fluid of RA. and successfully isolated and identified many microbes in synovial fluid samples of RA patients at the stage 4 (RAS4). Moreover, substances shaped like bacteria in rod-like or spherical forms were also observed under scanning electron microscopy.1 This is the first time that bacteria were successfully isolated from the synovial fluid of RA and this finding deserves attention.
First, it is always an interesting question whether bacteria are actually present in the synovial fluid of RA. Up to date, several studies have reported the presence of microbial DNA in joint effusion of RA by 16S rRNA gene sequencing technology (Table 1). However, there is no direct evidence on isolation of bacteria from RA synovial fluid. The synovial fluid is usually sterile, and RA is a kind of chronic non-infectious arthritis induced by autoimmune disorder.2 It was indeed reported that bacteria were found in the synovial fluid of RA, however, this was mainly because of multiple arthroscopic washouts and joint injections. Unfortunately, the history information of repeated arthroscopy or arthrocentesis was missing in RAS4 of which bacteria were isolated from synovial fluid in this article. Thus, it is uncertain if these isolat...
Cheng et al. recently reported the changes in fecal microbiota and peripheral blood metabolites in patients with rheumatoid arthritis (RA) across four stages of the disease. In addition, they performed 16S rRNA sequencing and identified bacteria in synovial fluid of RA. and successfully isolated and identified many microbes in synovial fluid samples of RA patients at the stage 4 (RAS4). Moreover, substances shaped like bacteria in rod-like or spherical forms were also observed under scanning electron microscopy.1 This is the first time that bacteria were successfully isolated from the synovial fluid of RA and this finding deserves attention.
First, it is always an interesting question whether bacteria are actually present in the synovial fluid of RA. Up to date, several studies have reported the presence of microbial DNA in joint effusion of RA by 16S rRNA gene sequencing technology (Table 1). However, there is no direct evidence on isolation of bacteria from RA synovial fluid. The synovial fluid is usually sterile, and RA is a kind of chronic non-infectious arthritis induced by autoimmune disorder.2 It was indeed reported that bacteria were found in the synovial fluid of RA, however, this was mainly because of multiple arthroscopic washouts and joint injections. Unfortunately, the history information of repeated arthroscopy or arthrocentesis was missing in RAS4 of which bacteria were isolated from synovial fluid in this article. Thus, it is uncertain if these isolated bacteria are result of endogenous gut-derived microbiome or exogenous infection.
Second, if the isolated bacteria were indeed present in synovial fluid from RA without exogenous infection, the role of bacteria in joints is still worthy to inquire. In addition to initiating infection, according to the results of Cheng et al., it is unclear whether low-virulent bacteria in the synovial fluid are possessed of antigen activity to induce autoantibodies formation and participate in the pathological process of RA. Then whether these bacteria are through the way to transfer, which Cheng et al.'s elaboration, "microbes and microbial metabolites would then be transferred to the joints via blood ". In the current researches on gut-joint axis, the mainstream view is that gut microbiota contributed to the development of RA joints through microbial-derived metabolites and secreted compounds.3 Cheng et al.'s view is different from this. If gut microbiome is transferred through the blood circulation, gut microbiota is more likely to be enriched in visceral organs with rich blood supply, such as liver and kidney,4 5 causing bloodstream infections. It was also unclear if the RA patients involved in the study had related symptoms of accumulation of bacteria in organs or if the gut microbiota was affected by specific chemokines and directed to the joints.
Third, it is worthy to discuss how the presence of bacteria in the synovial fluid of RA affects our therapeutic choices. At present, biological agents such as TNF-α, IL-6 inhibitors have achieved excellent efficacy in the treatment of RA in clinical practice.6 But long-term usage can increase the risk of infection in RA.7 According to the findings of Cheng et al., bacteria are present in the synovial fluid of RAS4, and long-term use of biological agents may lead to increased bacteria and joint infection. In the future, doctors should be more cautious when using related biological agents in RAS4. For patients with advanced RA, topical or systemic antibiotic therapy could be considered to control microbial invasion into joint.
In conclusion, isolation of bacteria from RA synovial fluid is a novel finding. Further investigation of the effect of bacteria in synovial fluid on RA synovial fluid, which will definitely expand our understanding of the gut-joint axis, RA pathogenesis and clinical management.
References
1. Cheng M, Zhao Y, Cui Y, et al. Stage-specific roles of microbial dysbiosis and metabolic disorders in rheumatoid arthritis. Annals of the rheumatic diseases 2022 doi: 10.1136/ard-2022-222871 [published Online First: 2022/08/20]
2. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet (London, England) 2016;388(10055):2023-38. doi: 10.1016/s0140-6736(16)30173-8 [published Online First: 2016/10/30]
3. Zaiss MM, Joyce Wu HJ, Mauro D, et al. The gut-joint axis in rheumatoid arthritis. Nature reviews Rheumatology 2021;17(4):224-37. doi: 10.1038/s41584-021-00585-3 [published Online First: 2021/03/07]
4. Chung DR. Hypervirulent Klebsiella pneumoniae: Liver Abscess Isolates versus Intestinal Flora. Journal of Korean medical science 2020;35(2):e28. doi: 10.3346/jkms.2020.35.e28 [published Online First: 2020/01/11]
5. Shah NB, Nigwekar SU, Kalim S, et al. The Gut and Blood Microbiome in IgA Nephropathy and Healthy Controls. Kidney360 2021;2(8):1261-74. doi: 10.34067/kid.0000132021 [published Online First: 2022/04/05]
6. Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis & rheumatology (Hoboken, NJ) 2021;73(7):1108-23. doi: 10.1002/art.41752 [published Online First: 2021/06/09]
7. Chiu YM, Chen DY. Infection risk in patients undergoing treatment for inflammatory arthritis: non-biologics versus biologics. Expert review of clinical immunology 2020;16(2):207-28. doi: 10.1080/1744666x.2019.1705785 [published Online First: 2019/12/20]
With great interest, we have read the article by Timothy et al. exclusively examined the prevalence and differences associated with isolated axial PsA (axPsA) and isolated axial AS with psoriasis.1 To some extent, we agree with the authors that isolated axPsA and isolated axial AS with psoriasis may be two distinct clinical phenotypes. However, we would like to raise a few important issues that need to be addressed.
First, the definition of patients with axPsA needs to be discussed. Patients with PsA may have only isolated syndesmophytes without sacroiliitis, one study showed that up to a third of all patients with axPsA have spondylitis without sacroiliitis. 2 In this study, patients with axPsA were identified only by the presence of sacroiliitis on radiographs, which was defined as the presence of sacroiliitis ( grade 2 bilateral or grade 3 unilateral) on sacroiliac joint radiographs, according to the 1984 AS modified New York criteria. However, some patients with axPsA could present with spondylitis alone but without sacroiliitis, who were not included in the study. Therefore, the overall spectrum of axPsA in this study may be underestimated.
Second, AS patients with psoriasis must be defined with caution. In terms of clinical features, axPsA differs from AS in several ways, most notably in the radiographic patterns of the disease. axPsA shows radiographic features such as asymmetric sacroiliitis, nonmarginal (which includes “chunky” and “comma”), asymmet...
With great interest, we have read the article by Timothy et al. exclusively examined the prevalence and differences associated with isolated axial PsA (axPsA) and isolated axial AS with psoriasis.1 To some extent, we agree with the authors that isolated axPsA and isolated axial AS with psoriasis may be two distinct clinical phenotypes. However, we would like to raise a few important issues that need to be addressed.
First, the definition of patients with axPsA needs to be discussed. Patients with PsA may have only isolated syndesmophytes without sacroiliitis, one study showed that up to a third of all patients with axPsA have spondylitis without sacroiliitis. 2 In this study, patients with axPsA were identified only by the presence of sacroiliitis on radiographs, which was defined as the presence of sacroiliitis ( grade 2 bilateral or grade 3 unilateral) on sacroiliac joint radiographs, according to the 1984 AS modified New York criteria. However, some patients with axPsA could present with spondylitis alone but without sacroiliitis, who were not included in the study. Therefore, the overall spectrum of axPsA in this study may be underestimated.
Second, AS patients with psoriasis must be defined with caution. In terms of clinical features, axPsA differs from AS in several ways, most notably in the radiographic patterns of the disease. axPsA shows radiographic features such as asymmetric sacroiliitis, nonmarginal (which includes “chunky” and “comma”), asymmetric and irregular syndesmophytes, and paravertebral ossification. Discovertebral lesions such as Romanus lesion and vertebral squaring are less common in axPsA than in AS. The radiographic presentation of syndesmophytes in AS is symmetrical, regular and from margin to margin. These unique features can be helpful in differentiating axPsA from axial AS. 3 In this article, for the patients with AS and psoriasis, “the presence of psoriasis was defined as at least one documented occurrence of psoriasis from initial consultation to most recent follow-up, or any previous history of psoriasis as diagnosed by a rheumatologist or dermatologist”. Actually, in a number of patients with PsA, musculoskeletal manifestations may present prior to the onset of psoriasis or associated skin or nail lesions. Previous studies reported that approximately 10–15% of patients develop arthritis prior to psoriasis.4 AS patients with psoriasis should therefore be defined by specific manifestations rather than delayed onset of psoriasis. According to the authors described, those PsA patients who developed the skin disease after the onset of spondylitis could be mis-defined as AS patients with psoriasis. Additionally, AS patients were enrolled in this study from July 2003 to November 2019, however, the CASPAR criteria were developed in 2006 and then widely used for PsA classification. Based on the CASPAR criteria, the AS patients with a previous history of physician-diagnosed psoriasis should be re-classified as axPsA patients. Taken together, we reasonably speculate that some true axPsA patients in Timothy’s study might be mis-classified as “AS patients with psoriasis”.
REFERENCES
1. Kwok TSH, Sutton M, Pereira D, et al. Isolated axial disease in psoriatic arthritis and ankylosing spondylitis with psoriasis. Ann Rheum Dis. 2022; annrheumdis-2022-222537
2. Jadon DR, Sengupta R, Nightingale A, et al. Axial Disease in Psoriatic Arthritis study: defining the clinical and radiographic phenotype of psoriatic spondyloarthritis. Ann Rheum Dis. 2017;76(4):701-707
3. Feld J, Chandran V, Haroon N, Inman R, Gladman D. Axial disease in psoriatic arthritis and ankylosing spondylitis: a critical comparison. Nat Rev Rheumatol. 2018;14(6):363-371
4. Coates LC, Helliwell PS. Psoriatic arthritis: state of the art review. Clin Med (Lond). 2017;17(1):65-70
Correspondence to Dr Sheng-Ming Dai, Department of Rheumatology & Immunology, Shanghai Sixth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China, shengmingdai@163.com
Contributors All other authors (QT, HZ and SMD) provided their input by contributing to the conceptualisation. QT and SMD contributed to the editing of the manuscript. QT and HZ contributed equally.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in
the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
The question of whether the use of biologic disease-modifying antirheumatic drugs (bDMARDs) can prevent psoriatic arthritis (PsA) in psoriasis (PsO) patients may be confusing. Some observational studies reported that biologic therapies were associated with a decreased risk of PsA1-2, but other studies did not3-5.
We read with great interest the recent article published in Annals of the Rheumatic Diseases by Gisondiet and colleagues regarding the impact of biologic therapy on development of PsA1. This study is very interesting and important; however, we would like to share with the authors our perplexities about the conclusions drawn from this report.
First and foremost, Gisondiet et al identified that treatment with bDMARDs was significantly associated with a lower risk of incident PsA in moderate-to-severe PsO (aHR 0.27, 95%CI 0.11 to 0.66) compared with nb-UVB phototherapy. However, we noted that this association was reversed if HRs were calculated using propensity score matching (PSM) data (aHR 2.07, 95%CI 0.87 to 4.93, Supplementary Table 2), and the explanation provided by the authors may be related to the limited sample size after PSM. In fact, these well-known risk factors, including age, scalp psoriasis, nail psoriasis, psoriasis duration, and family history of PsA, showed larger effect values after PSM even with smaller sample sizes. Thus, we reckon that, rather than a smaller sample size, this discrepancy is more likely the consequence of the pre-matc...
The question of whether the use of biologic disease-modifying antirheumatic drugs (bDMARDs) can prevent psoriatic arthritis (PsA) in psoriasis (PsO) patients may be confusing. Some observational studies reported that biologic therapies were associated with a decreased risk of PsA1-2, but other studies did not3-5.
We read with great interest the recent article published in Annals of the Rheumatic Diseases by Gisondiet and colleagues regarding the impact of biologic therapy on development of PsA1. This study is very interesting and important; however, we would like to share with the authors our perplexities about the conclusions drawn from this report.
First and foremost, Gisondiet et al identified that treatment with bDMARDs was significantly associated with a lower risk of incident PsA in moderate-to-severe PsO (aHR 0.27, 95%CI 0.11 to 0.66) compared with nb-UVB phototherapy. However, we noted that this association was reversed if HRs were calculated using propensity score matching (PSM) data (aHR 2.07, 95%CI 0.87 to 4.93, Supplementary Table 2), and the explanation provided by the authors may be related to the limited sample size after PSM. In fact, these well-known risk factors, including age, scalp psoriasis, nail psoriasis, psoriasis duration, and family history of PsA, showed larger effect values after PSM even with smaller sample sizes. Thus, we reckon that, rather than a smaller sample size, this discrepancy is more likely the consequence of the pre-matched data not being fully adjusted for key confounder of the baseline Psoriasis Area and Severity Index (PASI). As shown in Table 1, baseline PASI was adjusted as a confounder in the form of dichotomous variables (cut-off of 10) in multivariate model 1 and model 2. However, based on baseline characteristics (Supplementary Table 1), the majority of baseline PASIs in the bDMARDS group were higher than 10 (Mean±SD, 15.24±0.37). Thus, it is more logical and reasonable to adjust baseline PASI as a continuous variable.
Second, even though the authors tried to adjust for several baseline variables, some significant risk factors, such as BMI and socioeconomic status, should be considered as potential confounders. Studies have identified obesity as a known risk factor for developing PsA6-8. Besides, obesity is linked to a high disease activity and a poor response to biological treatments7-8. Similarly, in addition to its association with PsA incidence and psoriasis severity9-10, socioeconomic status factors including economic income and education directly influenced the treatment choice in this study.
Third, several numerical discrepancies appear in Supplementary Table 1. The duration of psoriasis after PSM was 54.06±0.02 and 54.06±0.02 in the two groups, respectively? How can the duration of psoriasis be older than age?
Finally, there is an inaccurate description in the results of univariate Cox regression analysis. Here, the description of baseline PASI≥10 was significantly associated with a higher risk of incident PsA. can the effect value HR 0.47 (95%CI 0.27 to 0.82) be related to the higher risk of PsA (Table 1)?
In summary, the limited evidence available does not fully address the issue of biologic treatment of PsO to prevent PsA. Retrospective observational studies involve significant methodological limitations and biases that may skew the relationship between treatment and arthritis development3,7. Randomized controlled trials (RCTs) seem to be the gold standard for establishing causality. However, it is hardly feasible because it would recruit two groups of patients with moderate to severe psoriasis and long-term comparison of treatment outcomes against no treatment. Therefore, the question of "treating the skin to intercept PsA" will remain a fascinating challenge for years.
References
1.Gisondi P, Bellinato F, Targher G, Idolazzi L, Girolomoni G. Biological disease-modifying antirheumatic drugs may mitigate the risk of psoriatic arthritis in patients with chronic plaque psoriasis. Ann Rheum Dis 2022;81(1):68-73.
2.Acosta Felquer ML, LoGiudice L, Galimberti ML, et al. Treating the skin with biologics in patients with psoriasis decreases the incidence of psoriatic arthritis. Ann Rheum Dis 2022;81(1):74-79.
3.Meer E, Merola JF, Fitzsimmons R, et al. Does biologic therapy impact the development of PsA among patients with psoriasis? Ann Rheum Dis 2022;81(1):80-86.
4.Napolitano M, Balato N, Caso F, et al. Paradoxical onset of psoriatic arthritis during treatment with biologic agents for plaque psoriasis: a combined dermatology and rheumatology clinical study. Clin Exp Rheumatol 2017;35:137–40
5.Cuchacovich R, Espinoza CG, Virk Z, et al. Biologic therapy (TNF- alpha antagonists)-induced psoriasis: a cytokine imbalance between TNF- alpha and IFN- alpha? J ClinRheumatol 2008;14:353–6.
6.Armstrong AW, Harskamp CT, Armstrong EJ. The association between psoriasis and obesity: a systematic review and meta-analysis of observational studies. Nutr Diabetes 2012; 2:e54.
7.Scher JU, Ogdie A, Merola JF, Ritchlin C. Preventing psoriatic arthritis: focusing on patients with psoriasis at increased risk of transition. Nat Rev Rheumatol 2019;15:153–66.
8.Green A, Shaddick G, Charlton R, et al. Modifiable risk factors and the development of psoriatic arthritis in people with psoriasis. Br J Dermatol 2020;182(3):714-720.
9.Hawro T, Zalewska A, Hawro M, et al. Impact of psoriasis severity on family income and quality of life. J Eur Acad Dermatol Venereol 2015;29(3):438-443.
10.De Vlam K, Steinfeld S, Toukap AN, et al. The burden of psoriatic arthritis in the biologics era: data from the Belgian Epidemiological Psoriatic Arthritis Study. Rheumatology 2021;60(12):5677-5685.
Dear Editor,
We read with great interest the recent paper published in ARD by Fu et al.
Based on their prospective open-label randomised control trial in 270 patients with active Class III/IV/V lupus nephritis, the authors conclude that the efficacy and safety profile of leflunomide is non-inferior to azathioprine for maintenance therapy of LN.
Importantly, this study was designed as a non-inferiority trial with the non-inferiority margin set at 12% for the primary outcome (flare at 36 months of maintenance-phase follow-up), meaning that the lower bound of the two-sided 95% CI for the difference in flare rates between LEF and AZA (as reference) should exceed −12%. Unexpectedly for a non-inferiority trial, the difference between groups for all data was considered significant at p<0.05.
Time to kidney flare was reported as not statistically different between the LEF group (17/108 patients, 15.7%; median time: 16 months) compared with that in the AZA group (19/107 patients, 17.8%; median time 14 months) during the 36 months of follow-up, yielding a Hazard Ratio (HR) of 0.89 (95%CI: 0.57-1.21), with the lower bound of the 95%CI below the non-inferiority margin (-12%) which should be interpreted as an inclusive non-inferiority trial.
We therefore believe that the main conclusion of the authors is not supported by the data presented, and as leflunomide is currently not shown as non-inferior to azathioprine for the maintenance of LN.
Leflunomide for lupus nephritis
Mycophenolate mofetil and azathioprine are drugs with proven efficacy for lupus nephritis (LN) treatment. In excellent prospective, randomised, open-label trial, Fu et al.1 emphasize the competitive clinical response between azathioprine and leflunomide in 215 adult patients with biopsy-confirmed active LN after cyclophosphamide and glucocorticoids, as maintenance therapy during 36 months.
Both kidney flares and their onset time were similar, as well as their proteinuria, serum creatinine and complement levels response, with similar adverse events. AEs leading to permanent treatment discontinuation were 2/108 patients treated with leflunomide (20 mg/d) and 5/107 in the azathioprine group (100mg/d). Authors, also mentioned that leflunomide is associated with some other advantages, such as easy accessibility, long-term safety profile and cost effectiveness, particularly in developing countries.
In Mexico, most of rheumatologist have vast experience with leflunomide as monotherapy for rheumatoid arthritis or combined with other csDMARD’s, most of them with good pregnancy outcomes, as has been reported recently, with no significant difference in malformations rates between leflunomide exposed and unexposed pregnancies.2 The cost of leflunomide is lower than azathioprine, equivalent to $10 USD every 4 to 6 weeks.
Additionally, the potential benefit of leflunomide as LN remission induction treatment has been reported. Wang...
Leflunomide for lupus nephritis
Mycophenolate mofetil and azathioprine are drugs with proven efficacy for lupus nephritis (LN) treatment. In excellent prospective, randomised, open-label trial, Fu et al.1 emphasize the competitive clinical response between azathioprine and leflunomide in 215 adult patients with biopsy-confirmed active LN after cyclophosphamide and glucocorticoids, as maintenance therapy during 36 months.
Both kidney flares and their onset time were similar, as well as their proteinuria, serum creatinine and complement levels response, with similar adverse events. AEs leading to permanent treatment discontinuation were 2/108 patients treated with leflunomide (20 mg/d) and 5/107 in the azathioprine group (100mg/d). Authors, also mentioned that leflunomide is associated with some other advantages, such as easy accessibility, long-term safety profile and cost effectiveness, particularly in developing countries.
In Mexico, most of rheumatologist have vast experience with leflunomide as monotherapy for rheumatoid arthritis or combined with other csDMARD’s, most of them with good pregnancy outcomes, as has been reported recently, with no significant difference in malformations rates between leflunomide exposed and unexposed pregnancies.2 The cost of leflunomide is lower than azathioprine, equivalent to $10 USD every 4 to 6 weeks.
Additionally, the potential benefit of leflunomide as LN remission induction treatment has been reported. Wang et al.3 showed complete and partial remission, as well as adverse events similar to cyclophosphamide. The group treated with leflunomide (30 mg/d) had significant reduction of active lesions in kidney re-biopsies after 6 months.
Therefore, we must keep in mind leflunomide within our therapeutic weaponry for patients with lupus nephritis, both for remission induction as well as for maintenance treatment, with evidence of efficacy and adequate safety profile, even in pregnancy.
Fu Q, Wu C, Dai M et al. Leflunomide versus azathioprine for maintenance therapy of lupus nephritis: a prospective, multicentre, randomised trial and long-term follow-up. Ann Rheum Dis 2022. doi:10.1136/annrheumdis-2022-222486
Pfaller B, Pupco A, Leibson T et al. A critical review of the reproductive safety of Leflunomide. Clin Rheumatol 2020; 39:607-12. doi.org/10.1007/s10067-019-04819-4
Wang H, Cui T, Hou, F et al. Induction treatment of proliferative lupus nephritis with leflunomide combined with prednisone: a prospective multi-centre observational study. Lupus 2008; 17: 638-44. doi:10.1177/0961203308089408
We have read with great interest the results of the cross-over randomized controlled trial (RCT) by Hasni et al. assessing the effect of pioglitazone on arterial stiffness indices and cardio-metabolic risk parameters in subjects with systemic lupus erythematosus (SLE).1 Renal involvement is of utmost importance for the prognosis of SLE, with a significant proportion of affected patients developing lupus nephritis within the first years after diagnosis.2
As demonstrated in the supplementary material of the article by Hasni et al.,1 treatment with pioglitazone resulted in a significant increase in blood urea nitrogen (BUN) (p = 0.005) and serum creatinine levels (p = 0.03), although the result seems to be of no clinical significance. It would be really interesting to know if the researchers also assessed the effect of pioglitazone on albuminuria levels in the enrolled participants. Among patients with diabetes mellitus thiazolidinediones have been shown to produce a significant reduction in urinary albumin to creatinine ratio (UACR), even among those with normo-albuminuria at baseline.3 Albuminuria should be taken into account, since it represents an additional prognostic marker for cardiovascular disease development, besides the established, traditional, cardiovascular risk factors.4 In addition, albuminuria is significantly associated with arterial stiffness indices, even in the general population setting, posing a potential causal link.5
We have read with great interest the results of the cross-over randomized controlled trial (RCT) by Hasni et al. assessing the effect of pioglitazone on arterial stiffness indices and cardio-metabolic risk parameters in subjects with systemic lupus erythematosus (SLE).1 Renal involvement is of utmost importance for the prognosis of SLE, with a significant proportion of affected patients developing lupus nephritis within the first years after diagnosis.2
As demonstrated in the supplementary material of the article by Hasni et al.,1 treatment with pioglitazone resulted in a significant increase in blood urea nitrogen (BUN) (p = 0.005) and serum creatinine levels (p = 0.03), although the result seems to be of no clinical significance. It would be really interesting to know if the researchers also assessed the effect of pioglitazone on albuminuria levels in the enrolled participants. Among patients with diabetes mellitus thiazolidinediones have been shown to produce a significant reduction in urinary albumin to creatinine ratio (UACR), even among those with normo-albuminuria at baseline.3 Albuminuria should be taken into account, since it represents an additional prognostic marker for cardiovascular disease development, besides the established, traditional, cardiovascular risk factors.4 In addition, albuminuria is significantly associated with arterial stiffness indices, even in the general population setting, posing a potential causal link.5
Therefore, if available, such data would be really interesting and of additional value, since pioglitazone appears to be a drug with beneficial effect on cardio-metabolic profile of patients with SLE.
References
1. Hasni S, Temesgen-Oyelakin Y, Davis M, et al. Peroxisome proliferator activated receptor-γ agonist pioglitazone improves vascular and metabolic dysfunction in systemic lupus erythematosus [published online ahead of print, 2022 Aug 1]. Ann Rheum Dis. 2022;annrheumdis-2022-222658. doi:10.1136/ard-2022-222658
2. Mahajan A, Amelio J, Gairy K, et al. Systemic lupus erythematosus, lupus nephritis and end-stage renal disease: a pragmatic review mapping disease severity and progression. Lupus. 2020;29(9):1011-1020. doi:10.1177/0961203320932219
3. Sarafidis PA, Stafylas PC, Georgianos PI, Saratzis AN, Lasaridis AN. Effect of thiazolidinediones on albuminuria and proteinuria in diabetes: a meta-analysis. Am J Kidney Dis. 2010;55(5):835-847. doi:10.1053/j.ajkd.2009.11.013
4. Matsushita K, Coresh J, Sang Y, et al. Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: a collaborative meta-analysis of individual participant data. Lancet Diabetes Endocrinol. 2015;3(7):514-525. doi:10.1016/S2213-8587(15)00040-6
5. Wang T, Fan F, Gong Y, et al. Comparison of brachial-ankle pulse wave velocity and carotid-femoral pulse wave velocity in association with albuminuria in a community of Beijing: a cross-sectional study [published online ahead of print, 2022 Apr 26]. J Hum Hypertens. 2022;10.1038/s41371-022-00697-7. doi:10.1038/s41371-022-00697-7
I read with interest the post hoc analysis of pooled data from two phase III trials by Vital et al. [1]. 73.0% (267/366) and 67.5% (243/360) of patients treated with placebo and anifrolumab, respectively, were taking antimalarials at the time of randomisation of the trial [2, 3]. I would like to know if there was a difference in achievement of the outcomes with or without the drug at baseline, as antimalarials have an inhibitory role against type 1 interferon [4], which may have attenuated the effect of anifrolumab.
Reference
1. Vital EM, Merrill JT, Morand EF, et al. Ann Rheum Dis 2022;81:951-61.
2. Furie RA, Morand EF, Bruce IN, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol 2019;1:e208-19
3. Morand EF, Furie R, Tanaka Y,et al. Trial of Anifrolumab in Active Systemic Lupus Erythematosus. N Engl J Med 2020;382:211-21.
4. Sacre K, Criswell LA, McCune JM. Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Res Ther 2012; 14:R155
Dear Editor,
We read with great interest the article by Boers and colleagues [1]. The GLORIA trial is one-of-a-kind study and certainly represents a milestone for rheumatoid arthritis (RA) treatment in seniors. The overall message conveyed by the investigators is that glucocorticoids (GCs) at a dose of 5 mg/day is somehow safe and effective (at least for 2-years) in older patients with RA. However, we have some concerns regarding the latter claim and several questions for the authors.
First, mean time on study drug was 19 months and only 60% completed the study. The authors stated that “the high rates of events in both groups over the observation period make it unlikely that the risk estimate would be substantially different in a more complete data set”. We somehow disagree. Fracture risk in glucocorticoid induced osteoporosis (GIOP) strictly depends on the treatment duration [2]. In addition, fracture risk remains elevated even after 1 year from GCs withdrawal [3], with possible long-term effects that were not captured by the GLORIA trial.
Second, “over 2 years, spine bone density decreased by about 1% in prednisolone, but increased by 3% in placebo patients”. We frankly think that this difference might be relevant to many patients. BMD increases (in similar magnitude of the placebo group of the GLORIA trial) have been associated with significantly lower incidence of fracture in both clinical trials and observational studies [4,5]. Remarkably, a 2% perce...
Dear Editor,
We read with great interest the article by Boers and colleagues [1]. The GLORIA trial is one-of-a-kind study and certainly represents a milestone for rheumatoid arthritis (RA) treatment in seniors. The overall message conveyed by the investigators is that glucocorticoids (GCs) at a dose of 5 mg/day is somehow safe and effective (at least for 2-years) in older patients with RA. However, we have some concerns regarding the latter claim and several questions for the authors.
First, mean time on study drug was 19 months and only 60% completed the study. The authors stated that “the high rates of events in both groups over the observation period make it unlikely that the risk estimate would be substantially different in a more complete data set”. We somehow disagree. Fracture risk in glucocorticoid induced osteoporosis (GIOP) strictly depends on the treatment duration [2]. In addition, fracture risk remains elevated even after 1 year from GCs withdrawal [3], with possible long-term effects that were not captured by the GLORIA trial.
Second, “over 2 years, spine bone density decreased by about 1% in prednisolone, but increased by 3% in placebo patients”. We frankly think that this difference might be relevant to many patients. BMD increases (in similar magnitude of the placebo group of the GLORIA trial) have been associated with significantly lower incidence of fracture in both clinical trials and observational studies [4,5]. Remarkably, a 2% percent difference in BMD change at lumbar spine has been associated with 28% lower risk of vertebral fractures [5] which is, by coincidence, the same increase in risk seen in the GLORIA trial (RR 1.28) for vertebral fractures. Though, the study sample was not powered to assess such outcome.
Third, we noted that the exclusion criteria mentioned: “Absolute contraindication to low-dose prednisolone, as determined by the treating physician, such as: […] osteoporosis. When these conditions are under control (e.g., with anti-osteoporosis drugs) these patients can enter”. We wonder if patients with osteoporosis at baseline (and not on anti-osteoporosis medications) were subsequently treated with an anti-osteoporosis drug. Such confounder might be relevant and, possibly, alter the results of the study. We also think that clarifications on baseline diagnosis of osteoporosis would be helpful. In other words, osteoporosis was reported in 25% of patients, baseline T-score <-2.5 in 11% and prevalent spine fracture in 32%, were these patients overlapping?
Four, as regards infections, the authors claimed that “low-dose GC are not of special concern but should be viewed through the same lens as those of other DMARDs”. However, George et al found that GCs were associated with incremental risk of infection when associated with DMARDs [6]. Therefore, since it is highly plausible that a patient with RA will receive at least one DMARD as part of her treatment, one might argue that the trade off from treating chronically with GCs is questionable.
Fifth, the authors claimed that confounding by indication is a peculiar feature of observational studies and should be attenuated by randomization. Nonetheless, they admit that “long-term treatment benefits were probably underestimated due to confounding”. We agree with the latter statement, but we ask ourselves if a similar consideration should be made also for the safety outcomes. Infection, as an example, are influenced by short-term course of steroids, which were permitted in the GLORIA trial. Would this confounding attenuate the differences in terms of infections?
Finally, we agree with the authors that, in selected patients, the benefit and harm balance might be favorable. However, clinicians should fully recognize some of the GLORIA study limitations during the shared decision-making process and treat patients accordingly.
References
1 Boers M, Hartman L, Opris-Belinski D, et al. Low dose, add-on prednisolone in patients with rheumatoid arthritis aged 65+: the pragmatic randomised, double-blind placebo-controlled GLORIA trial. Annals of the Rheumatic Diseases 2022;81:925–36. doi:10.1136/annrheumdis-2021-221957
2 Adami G, Saag KG. Glucocorticoid-induced osteoporosis: 2019 concise clinical review. Osteoporos Int 2019;30:1145–56. doi:10.1007/s00198-019-04906-x
3 De Vries F, Bracke M, Leufkens HGM, et al. Fracture risk with intermittent high-dose oral glucocorticoid therapy. Arthritis Rheum 2007;56:208–14. doi:10.1002/art.22294
4 Adami G, Gavioli I, Rossini M, et al. Real-life short-term effectiveness of anti-osteoporotic treatments: a longitudinal cohort study. Therapeutic Advances in Musculoskeletal 2022;14:1759720X221105009. doi:10.1177/1759720X221105009
5 Bouxsein ML, Eastell R, Lui L-Y, et al. Change in Bone Density and Reduction in Fracture Risk: A Meta-Regression of Published Trials. J Bone Miner Res 2019;34:632–42. doi:10.1002/jbmr.3641
6 George MD, Baker JF, Winthrop K, et al. Risk for Serious Infection With Low-Dose Glucocorticoids in Patients With Rheumatoid Arthritis : A Cohort Study. Ann Intern Med 2020;173:870–8. doi:10.7326/M20-1594
The article by Smeele et al.[1] investigated influence of biologics on infants and pregnancy outcomes. We would like to raise some concerns on this important study.
Regarding measurement of depression, we suggest the use of Beck Depression Inventory (BDI), Geriatric Depression Scale (GDS) or other clinically used indexes might have better information. Besides, life style and habbit were important information on pregnance outcomes.[2] We suggested that Baecke Questionnaire or Pregnancy Physical Activity Questionnaire (PPAQ) would provide a good insight for us in this field. Moreover, some residudal confounders should be considered, such as alcohol and nutritioan status.[3, 4]
In terms of comparator group selection, the authors compared participants with TNFi and without TNFi use during pregnancy. However, this could cause confounding-by-indication because that those who didn’t use TNFi might originally have mild symptom, which causes fewer comorbidities. Hence, we think that it would be more appropriate if the control group could be non-TNF biologics users. We believe that the active comparator design with same indication would be better to ensure baseline comparability.
References
1. Smeele, H.T.W., et al., Tumour necrosis factor inhibitor use during pregnancy is associated with increased birth weight of rheumatoid arthritis patients’ offspring. Annals of the Rheumatic Diseases, 2022: p. annrheumdis-2022-222679.
2. Vargas-Terrones, M., T....
The article by Smeele et al.[1] investigated influence of biologics on infants and pregnancy outcomes. We would like to raise some concerns on this important study.
Regarding measurement of depression, we suggest the use of Beck Depression Inventory (BDI), Geriatric Depression Scale (GDS) or other clinically used indexes might have better information. Besides, life style and habbit were important information on pregnance outcomes.[2] We suggested that Baecke Questionnaire or Pregnancy Physical Activity Questionnaire (PPAQ) would provide a good insight for us in this field. Moreover, some residudal confounders should be considered, such as alcohol and nutritioan status.[3, 4]
In terms of comparator group selection, the authors compared participants with TNFi and without TNFi use during pregnancy. However, this could cause confounding-by-indication because that those who didn’t use TNFi might originally have mild symptom, which causes fewer comorbidities. Hence, we think that it would be more appropriate if the control group could be non-TNF biologics users. We believe that the active comparator design with same indication would be better to ensure baseline comparability.
References
1. Smeele, H.T.W., et al., Tumour necrosis factor inhibitor use during pregnancy is associated with increased birth weight of rheumatoid arthritis patients’ offspring. Annals of the Rheumatic Diseases, 2022: p. annrheumdis-2022-222679.
2. Vargas-Terrones, M., T.S. Nagpal, and R. Barakat, Impact of exercise during pregnancy on gestational weight gain and birth weight: an overview. Braz J Phys Ther, 2019. 23(2): p. 164-169.
3. Hamułka, J., M.A. Zielińska, and K. Chądzyńska, The combined effects of alcohol and tobacco use during pregnancy on birth outcomes. Rocz Panstw Zakl Hig, 2018. 69(1): p. 45-54.
4. Avnon, T., et al., The impact of a vegan diet on pregnancy outcomes. Journal of Perinatology, 2021. 41(5): p. 1129-1133.
With great interest, we read the study by Proft et al. 1In this prospective multicenter study, the authors applied a dermatologist-centered screening tool followed by a structured rheumatologic examination, including MRI of the sacroiliac joints and spine, for the early identification of psoriatic arthritis with axial involvement (axPsA). We endorse the authors for completing an important clinical study, the results of which could have important implications for the early identification of axPsA in patients with psoriasis. However, there are some aspects that need to be focused on and discussed.
Show MoreFirst, there is some controversy regarding the definition of axPsA. Some studies have emphasized the importance of imaging, and the presence of sacroiliac arthritis with grade 3 unilaterally or grade 2 and above bilaterally, or spinal syndesmophyte(s) according to CASPAR criteria is defined as axPsA.2 It has also been suggested that axPsA requires meeting the modified New York criteria of AS criteria or applying the Assessment of SpondyloArthritis International Society (ASAS) classification criteria for axial spondyloarthritis (axSpA), which require the presence of inflammatory back pain (IBP) in the patient. However, back pain is not always present in patients with axPsA. The use of chronic back pain as the primary screening condition is debatable. One study showed that up to 44% to 55% of patients with axPsA had only imaging involvement (including sacroiliac joints or spine...
Cheng et al. recently reported the changes in fecal microbiota and peripheral blood metabolites in patients with rheumatoid arthritis (RA) across four stages of the disease. In addition, they performed 16S rRNA sequencing and identified bacteria in synovial fluid of RA. and successfully isolated and identified many microbes in synovial fluid samples of RA patients at the stage 4 (RAS4). Moreover, substances shaped like bacteria in rod-like or spherical forms were also observed under scanning electron microscopy.1 This is the first time that bacteria were successfully isolated from the synovial fluid of RA and this finding deserves attention.
Show MoreFirst, it is always an interesting question whether bacteria are actually present in the synovial fluid of RA. Up to date, several studies have reported the presence of microbial DNA in joint effusion of RA by 16S rRNA gene sequencing technology (Table 1). However, there is no direct evidence on isolation of bacteria from RA synovial fluid. The synovial fluid is usually sterile, and RA is a kind of chronic non-infectious arthritis induced by autoimmune disorder.2 It was indeed reported that bacteria were found in the synovial fluid of RA, however, this was mainly because of multiple arthroscopic washouts and joint injections. Unfortunately, the history information of repeated arthroscopy or arthrocentesis was missing in RAS4 of which bacteria were isolated from synovial fluid in this article. Thus, it is uncertain if these isolat...
With great interest, we have read the article by Timothy et al. exclusively examined the prevalence and differences associated with isolated axial PsA (axPsA) and isolated axial AS with psoriasis.1 To some extent, we agree with the authors that isolated axPsA and isolated axial AS with psoriasis may be two distinct clinical phenotypes. However, we would like to raise a few important issues that need to be addressed.
Show MoreFirst, the definition of patients with axPsA needs to be discussed. Patients with PsA may have only isolated syndesmophytes without sacroiliitis, one study showed that up to a third of all patients with axPsA have spondylitis without sacroiliitis. 2 In this study, patients with axPsA were identified only by the presence of sacroiliitis on radiographs, which was defined as the presence of sacroiliitis ( grade 2 bilateral or grade 3 unilateral) on sacroiliac joint radiographs, according to the 1984 AS modified New York criteria. However, some patients with axPsA could present with spondylitis alone but without sacroiliitis, who were not included in the study. Therefore, the overall spectrum of axPsA in this study may be underestimated.
Second, AS patients with psoriasis must be defined with caution. In terms of clinical features, axPsA differs from AS in several ways, most notably in the radiographic patterns of the disease. axPsA shows radiographic features such as asymmetric sacroiliitis, nonmarginal (which includes “chunky” and “comma”), asymmet...
The question of whether the use of biologic disease-modifying antirheumatic drugs (bDMARDs) can prevent psoriatic arthritis (PsA) in psoriasis (PsO) patients may be confusing. Some observational studies reported that biologic therapies were associated with a decreased risk of PsA1-2, but other studies did not3-5.
Show MoreWe read with great interest the recent article published in Annals of the Rheumatic Diseases by Gisondiet and colleagues regarding the impact of biologic therapy on development of PsA1. This study is very interesting and important; however, we would like to share with the authors our perplexities about the conclusions drawn from this report.
First and foremost, Gisondiet et al identified that treatment with bDMARDs was significantly associated with a lower risk of incident PsA in moderate-to-severe PsO (aHR 0.27, 95%CI 0.11 to 0.66) compared with nb-UVB phototherapy. However, we noted that this association was reversed if HRs were calculated using propensity score matching (PSM) data (aHR 2.07, 95%CI 0.87 to 4.93, Supplementary Table 2), and the explanation provided by the authors may be related to the limited sample size after PSM. In fact, these well-known risk factors, including age, scalp psoriasis, nail psoriasis, psoriasis duration, and family history of PsA, showed larger effect values after PSM even with smaller sample sizes. Thus, we reckon that, rather than a smaller sample size, this discrepancy is more likely the consequence of the pre-matc...
Dear Editor,
We read with great interest the recent paper published in ARD by Fu et al.
Based on their prospective open-label randomised control trial in 270 patients with active Class III/IV/V lupus nephritis, the authors conclude that the efficacy and safety profile of leflunomide is non-inferior to azathioprine for maintenance therapy of LN.
Importantly, this study was designed as a non-inferiority trial with the non-inferiority margin set at 12% for the primary outcome (flare at 36 months of maintenance-phase follow-up), meaning that the lower bound of the two-sided 95% CI for the difference in flare rates between LEF and AZA (as reference) should exceed −12%. Unexpectedly for a non-inferiority trial, the difference between groups for all data was considered significant at p<0.05.
Time to kidney flare was reported as not statistically different between the LEF group (17/108 patients, 15.7%; median time: 16 months) compared with that in the AZA group (19/107 patients, 17.8%; median time 14 months) during the 36 months of follow-up, yielding a Hazard Ratio (HR) of 0.89 (95%CI: 0.57-1.21), with the lower bound of the 95%CI below the non-inferiority margin (-12%) which should be interpreted as an inclusive non-inferiority trial.
We therefore believe that the main conclusion of the authors is not supported by the data presented, and as leflunomide is currently not shown as non-inferior to azathioprine for the maintenance of LN.
Leflunomide for lupus nephritis
Show MoreMycophenolate mofetil and azathioprine are drugs with proven efficacy for lupus nephritis (LN) treatment. In excellent prospective, randomised, open-label trial, Fu et al.1 emphasize the competitive clinical response between azathioprine and leflunomide in 215 adult patients with biopsy-confirmed active LN after cyclophosphamide and glucocorticoids, as maintenance therapy during 36 months.
Both kidney flares and their onset time were similar, as well as their proteinuria, serum creatinine and complement levels response, with similar adverse events. AEs leading to permanent treatment discontinuation were 2/108 patients treated with leflunomide (20 mg/d) and 5/107 in the azathioprine group (100mg/d). Authors, also mentioned that leflunomide is associated with some other advantages, such as easy accessibility, long-term safety profile and cost effectiveness, particularly in developing countries.
In Mexico, most of rheumatologist have vast experience with leflunomide as monotherapy for rheumatoid arthritis or combined with other csDMARD’s, most of them with good pregnancy outcomes, as has been reported recently, with no significant difference in malformations rates between leflunomide exposed and unexposed pregnancies.2 The cost of leflunomide is lower than azathioprine, equivalent to $10 USD every 4 to 6 weeks.
Additionally, the potential benefit of leflunomide as LN remission induction treatment has been reported. Wang...
We have read with great interest the results of the cross-over randomized controlled trial (RCT) by Hasni et al. assessing the effect of pioglitazone on arterial stiffness indices and cardio-metabolic risk parameters in subjects with systemic lupus erythematosus (SLE).1 Renal involvement is of utmost importance for the prognosis of SLE, with a significant proportion of affected patients developing lupus nephritis within the first years after diagnosis.2
As demonstrated in the supplementary material of the article by Hasni et al.,1 treatment with pioglitazone resulted in a significant increase in blood urea nitrogen (BUN) (p = 0.005) and serum creatinine levels (p = 0.03), although the result seems to be of no clinical significance. It would be really interesting to know if the researchers also assessed the effect of pioglitazone on albuminuria levels in the enrolled participants. Among patients with diabetes mellitus thiazolidinediones have been shown to produce a significant reduction in urinary albumin to creatinine ratio (UACR), even among those with normo-albuminuria at baseline.3 Albuminuria should be taken into account, since it represents an additional prognostic marker for cardiovascular disease development, besides the established, traditional, cardiovascular risk factors.4 In addition, albuminuria is significantly associated with arterial stiffness indices, even in the general population setting, posing a potential causal link.5
Therefore, if avai...
Show MoreI read with interest the post hoc analysis of pooled data from two phase III trials by Vital et al. [1]. 73.0% (267/366) and 67.5% (243/360) of patients treated with placebo and anifrolumab, respectively, were taking antimalarials at the time of randomisation of the trial [2, 3]. I would like to know if there was a difference in achievement of the outcomes with or without the drug at baseline, as antimalarials have an inhibitory role against type 1 interferon [4], which may have attenuated the effect of anifrolumab.
Reference
1. Vital EM, Merrill JT, Morand EF, et al. Ann Rheum Dis 2022;81:951-61.
2. Furie RA, Morand EF, Bruce IN, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol 2019;1:e208-19
3. Morand EF, Furie R, Tanaka Y,et al. Trial of Anifrolumab in Active Systemic Lupus Erythematosus. N Engl J Med 2020;382:211-21.
4. Sacre K, Criswell LA, McCune JM. Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Res Ther 2012; 14:R155
Dear Editor,
Show MoreWe read with great interest the article by Boers and colleagues [1]. The GLORIA trial is one-of-a-kind study and certainly represents a milestone for rheumatoid arthritis (RA) treatment in seniors. The overall message conveyed by the investigators is that glucocorticoids (GCs) at a dose of 5 mg/day is somehow safe and effective (at least for 2-years) in older patients with RA. However, we have some concerns regarding the latter claim and several questions for the authors.
First, mean time on study drug was 19 months and only 60% completed the study. The authors stated that “the high rates of events in both groups over the observation period make it unlikely that the risk estimate would be substantially different in a more complete data set”. We somehow disagree. Fracture risk in glucocorticoid induced osteoporosis (GIOP) strictly depends on the treatment duration [2]. In addition, fracture risk remains elevated even after 1 year from GCs withdrawal [3], with possible long-term effects that were not captured by the GLORIA trial.
Second, “over 2 years, spine bone density decreased by about 1% in prednisolone, but increased by 3% in placebo patients”. We frankly think that this difference might be relevant to many patients. BMD increases (in similar magnitude of the placebo group of the GLORIA trial) have been associated with significantly lower incidence of fracture in both clinical trials and observational studies [4,5]. Remarkably, a 2% perce...
The article by Smeele et al.[1] investigated influence of biologics on infants and pregnancy outcomes. We would like to raise some concerns on this important study.
Regarding measurement of depression, we suggest the use of Beck Depression Inventory (BDI), Geriatric Depression Scale (GDS) or other clinically used indexes might have better information. Besides, life style and habbit were important information on pregnance outcomes.[2] We suggested that Baecke Questionnaire or Pregnancy Physical Activity Questionnaire (PPAQ) would provide a good insight for us in this field. Moreover, some residudal confounders should be considered, such as alcohol and nutritioan status.[3, 4]
In terms of comparator group selection, the authors compared participants with TNFi and without TNFi use during pregnancy. However, this could cause confounding-by-indication because that those who didn’t use TNFi might originally have mild symptom, which causes fewer comorbidities. Hence, we think that it would be more appropriate if the control group could be non-TNF biologics users. We believe that the active comparator design with same indication would be better to ensure baseline comparability.
References
Show More1. Smeele, H.T.W., et al., Tumour necrosis factor inhibitor use during pregnancy is associated with increased birth weight of rheumatoid arthritis patients’ offspring. Annals of the Rheumatic Diseases, 2022: p. annrheumdis-2022-222679.
2. Vargas-Terrones, M., T....
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