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]
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.
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
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.
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
We read with interest the study by Dr. Tedeschi and colleagues [1] which reported that patients with at least one episode of acute Calcium pyrophosphate (CPP) crystal arthritis had increased the risk of short (0-2 year) and long-term (2-10 year) non-fatal CV events compared with those without evidence of this acute crystalline arthritis. However, acute CPP crystal arthritis did not confer increased risk for all-cause mortality. This study focuses on an episode of acute calcium pyrophosphate (CPP) crystal arthritis as a significant clinical variable and is a valuable addition to the literature. However, some issues have not been addressed by the authors.
First, epidemiologists agree that several clinical risk factors are associated with cardiovascular outcome, including acute cerebrovascular insufficiency, hyperparathyroidism, and phenotypes of CPP disease [2,3]. However, the authors did not exclude people with these risk factors, and an evaluation of these risk factors was not presented. The confounding effect of these variables may have contributed to the significant effect in causing cardiovascular disease.
Second, it reported that longer disease duration of CPP crystal arthritis have also been considered to carry an elevated risk for cardiovascular disease [4]. Previous studies have clearly demonstrated that chronic CPP crystal arthritis did confer increased risk for myocardial infarction, acute coronary syndrome, and stroke[5]. However, the duration of CPP...
We read with interest the study by Dr. Tedeschi and colleagues [1] which reported that patients with at least one episode of acute Calcium pyrophosphate (CPP) crystal arthritis had increased the risk of short (0-2 year) and long-term (2-10 year) non-fatal CV events compared with those without evidence of this acute crystalline arthritis. However, acute CPP crystal arthritis did not confer increased risk for all-cause mortality. This study focuses on an episode of acute calcium pyrophosphate (CPP) crystal arthritis as a significant clinical variable and is a valuable addition to the literature. However, some issues have not been addressed by the authors.
First, epidemiologists agree that several clinical risk factors are associated with cardiovascular outcome, including acute cerebrovascular insufficiency, hyperparathyroidism, and phenotypes of CPP disease [2,3]. However, the authors did not exclude people with these risk factors, and an evaluation of these risk factors was not presented. The confounding effect of these variables may have contributed to the significant effect in causing cardiovascular disease.
Second, it reported that longer disease duration of CPP crystal arthritis have also been considered to carry an elevated risk for cardiovascular disease [4]. Previous studies have clearly demonstrated that chronic CPP crystal arthritis did confer increased risk for myocardial infarction, acute coronary syndrome, and stroke[5]. However, the duration of CPP crystal arthritis was not captured in this study, which may have impacted the risk for non-fatal CV events in patients with acute CPP crystal arthritis.
In conclusion, although we have some concerns about the study by Tedeschi et al.[1], we applaud the authors for their commendable work and hope that this study will benefit readers. We look forward to further work on the important topic of early prevention for cardiovascular diseases in patients with acute CPP crystal arthritis and hope that early preventive application for CV events will benefit high-risk people.
Contributors All authors reviewed the draft and approved the submission of the manuscript.
Competing interests None declared.
References:
1. Tedeschi SK, Huang W, Yoshida K, et al. Risk of cardiovascular events in patients having had acute calcium pyrophosphate crystal arthritis. Ann Rheum Dis 2022;81:1323-9.
2. Cheremushkina E, Eliseev M, Sheliabina O, et al. Effect of colchicine therapy on atherosclerosis-related cardiovascular outcome in patients with calcium pyrophosphate crystal deposition disease. Ann Rheum Dis 2022;8(Suppl 1):382.
3. Toussirot E, Marotte H, Mulleman D, et al.Increased high molecular weight adiponectin and lean mass during tocilizumab treatment in patients with rheumatoid arthritis: a 12-month multicentre study. Arthritis Res Ther 2020;22:224.
4. Bashir M, Sherman KA, Solomon DH, et al. Cardiovascular disease risk in calcium pyrophosphate deposition disease: a nationwide study of Veterans. Arthritis Care Res 2021;73:24783.
5. Wang H, Bai J, He B, et al. Osteoarthritis and the risk of cardiovascular disease: a meta-analysis of observational studies. Sci Rep 2016;6:39672.
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
To the Editor
We recently have read the article written by Dr. Daien et al. entitled published in Annals of the Rheumatic Diseases in 31th of May, 2022 (1). The study assessed the effect of different doses of ABX464 on clinical and laboratory features of patients with active rheumatoid arthritis (RA) and the rate of development of treatment-emergent adverse events in these patients. In this study, it was showed that each day 50 mg use of ABX464 could exert beneficial effects in the patients with acceptable safety and tolerability profile. This study provides fascinating evidence regarding the use of this first-in-class drug candidate for patients not responding to more frequently used treatment regimens; however, there are some points that we would like to address.
The authors mentioned that patients with moderate to severe RA who had rheumatoid factor, anticitrullinated peptide antibody or bone erosions were recruited in the study. The study aimed at comparison of rate of response to the treatment and development of adverse events in each arm of the study. Although, it is generally considered that the randomized design of the clinical studies would produce comparable groups and result in unbiased assessment of the outcomes, different factors which were previously identified in the literature that could be in association with severity of rheumatoid arthritis or poor response to the treatment should had been considered in the quantitative analysis of this study....
To the Editor
We recently have read the article written by Dr. Daien et al. entitled published in Annals of the Rheumatic Diseases in 31th of May, 2022 (1). The study assessed the effect of different doses of ABX464 on clinical and laboratory features of patients with active rheumatoid arthritis (RA) and the rate of development of treatment-emergent adverse events in these patients. In this study, it was showed that each day 50 mg use of ABX464 could exert beneficial effects in the patients with acceptable safety and tolerability profile. This study provides fascinating evidence regarding the use of this first-in-class drug candidate for patients not responding to more frequently used treatment regimens; however, there are some points that we would like to address.
The authors mentioned that patients with moderate to severe RA who had rheumatoid factor, anticitrullinated peptide antibody or bone erosions were recruited in the study. The study aimed at comparison of rate of response to the treatment and development of adverse events in each arm of the study. Although, it is generally considered that the randomized design of the clinical studies would produce comparable groups and result in unbiased assessment of the outcomes, different factors which were previously identified in the literature that could be in association with severity of rheumatoid arthritis or poor response to the treatment should had been considered in the quantitative analysis of this study. The presence of comorbidities, smoking and ethnicity are among these factors that are associated with the response to treatment (2, 3). The participants enrolled in this study were from 21 centers from 4 countries which raises concern toward the potential for bias as ethnicity was not considered in the study. Besides, patient-reported symptoms, outcomes and true disease state have also been shown to be associated with social status of the patient, educational level, health literacy and presence of comorbidities and ethnicity (4, 5). Therefore, considering these potential confounding factors and performing appropriate techniques for adjusting of them lower the source of bias and increase the credibility of the findings in the study.
Second, the significance level considered in this study was 10 percent. This error rate is typically considered to 5 percent, especially when the efficacy of a new drug class is being assessed in clinical studies (6). Although this high cut off for type Ⅰ error could be justified by the authors based on the intrinsic issues of the study, they should have mentioned and addressed it in the article. Third, in the protocol of this study (NCT03813199), it was mentioned that 24 centers were chosen for participants enrollment; however, in the main text of the article, the authors stated that the study was conducted in 21 centers. The detail of this issue that 2 centers in Czechia and one center in Belgium were not considered in the study should be discussed in the article to avoid any concern regarding the potential bias of selective reporting.
Notwithstanding the foregoing, this study has provided first evidence on the efficacy and safety of this first-in-class drug in patients with moderate to severe RA nonresponding to methotrexate or anti-tumor necrosis factor-α agents. However, whether to administrate this drug or not requires further studies with larger sample size and longer duration of follow-up. Also, there is needs for conducting studies to compare efficacy and safety of this drug class with more frequently used therapeutic options in patients with RA who are not responding to first line treatments as there are other available treatment strategies in these patients.
Authors’ contributions: Both authors contributed in all processes of the preparation of this paper.
Acknowledgement: None.
Conflict of Interest statement: Authors declare no conflict of interests.
Funding: None.
Patient and Public Involvement: Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research
References
1. Daien C, Krogulec M, Gineste P, Steens J-M, Desroys du Roure L, Biguenet S, et al. Safety and efficacy of the miR-124 upregulator ABX464 (obefazimod, 50 and 100 mg per day) in patients with active rheumatoid arthritis and inadequate response to methotrexate and/or anti-TNFα therapy: a placebo-controlled phase II study. 2022;81(8):1076-84.
2. de Hair MJH, Jacobs JWG, Schoneveld JLM, van Laar JM. Difficult-to-treat rheumatoid arthritis: an area of unmet clinical need. Rheumatology. 2017;57(7):1135-44.
3. Albrecht K, Zink A. Poor prognostic factors guiding treatment decisions in rheumatoid arthritis patients: a review of data from randomized clinical trials and cohort studies. Arthritis Research & Therapy. 2017;19(1):68.
4. Katz PP, Barton J, Trupin L, Schmajuk G, Yazdany J, Ruiz PJ, et al. Poverty, Depression, or Lost in Translation? Ethnic and Language Variation in Patient-Reported Outcomes in Rheumatoid Arthritis. Arthritis care & research. 2016;68(5):621-8.
5. Tan Y, Buch MH. 'Difficult to treat' rheumatoid arthritis: current position and considerations for next steps. 2022;8(2):e002387.
6. Confirmatory clinical trials : Analysis of categorical efficacy data.
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
Glucocorticoid (GC) therapy is still the mainstay in managing rheumatoid arthritis (RA). The benefits of low-dose GC therapy are well established after decades of clinical experience in RA. Yet, it is essential to appoint the danger of exposure to chronic GC therapy.
For many patients with RA and other inflammatory rheumatic musculoskeletal diseases (RMD), starting prednisolone means taking glucocorticoids for several years or decades, often indefinitely.1 The long-term complications of GC therapy are rarely emphasised by most clinical trials that usually run for only 1 or 2 years. In this regard, the GLORIA trial2 has illuminated both the harms and benefits of 2-year low-dose (5 mg daily) prednisolone in 451 elderly patients (≥65 years) with moderately active established RA. Indeed, there was an 11% increase in patients with at least one adverse event (AE) of special interest (mainly mild to moderate infections) in the prednisolone arm, accounting for a 1.24 (95% CL 0.4) fold higher risk compared to placebo, just within two years of treatment.2
The likelihood of major osteoporotic fractures in GC users increases with the dosage, but more importantly, with the cumulative dose and duration of GC therapy.3 Moreover, low-dose GC therapy (≤5 mg/day) did not seem to be associated with a reduction of bone mineral density (BMD) in patients with inflammatory RMD and current or prior exposure to GC.4 However, while GC therapy effectively alleviates inflammation, it has...
Glucocorticoid (GC) therapy is still the mainstay in managing rheumatoid arthritis (RA). The benefits of low-dose GC therapy are well established after decades of clinical experience in RA. Yet, it is essential to appoint the danger of exposure to chronic GC therapy.
For many patients with RA and other inflammatory rheumatic musculoskeletal diseases (RMD), starting prednisolone means taking glucocorticoids for several years or decades, often indefinitely.1 The long-term complications of GC therapy are rarely emphasised by most clinical trials that usually run for only 1 or 2 years. In this regard, the GLORIA trial2 has illuminated both the harms and benefits of 2-year low-dose (5 mg daily) prednisolone in 451 elderly patients (≥65 years) with moderately active established RA. Indeed, there was an 11% increase in patients with at least one adverse event (AE) of special interest (mainly mild to moderate infections) in the prednisolone arm, accounting for a 1.24 (95% CL 0.4) fold higher risk compared to placebo, just within two years of treatment.2
The likelihood of major osteoporotic fractures in GC users increases with the dosage, but more importantly, with the cumulative dose and duration of GC therapy.3 Moreover, low-dose GC therapy (≤5 mg/day) did not seem to be associated with a reduction of bone mineral density (BMD) in patients with inflammatory RMD and current or prior exposure to GC.4 However, while GC therapy effectively alleviates inflammation, it has a devastating effect on bone.5 Indeed, it is hard to estimate the risk of major osteoporotic fractures from glucocorticoid-induced osteoporosis (GIOP) using dual X-ray absorptiometry (DXA), as frailty fractures occur with normal or osteopenic BMD in many patients with GIOP. It is also worrisome that GIOP is often overlooked since only 13% of elderly patients with a diagnosis of osteoporosis received antiresorptive drugs despite initiating GC therapy.2 Moreover, minor complaints of ecchymosis, haematoma and skin atrophy are more common amongst long-dose GC users2 but highly relevant to their quality of life.
In our cohort of 1366 RA patients actively treated with biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), those older than 65 years represent almost 50% of the treated population. However, the risks of low-dose GC therapy in older RA patients taking b/tsDMARDs have received only a little attention. No randomised controlled trial has investigated the safety of low-dose GC in RA patients taking b/tsDMARDs. In the GLORIA trial, one of the few randomised controlled trials of low-dose GC therapy in RA, only 16% and 13% of patients took biologics at baseline in the prednisolone and placebo groups, respectively, and just ≃6% of participants per group initiated or switched to biological DMARDs during follow-up.2 Patients with RA included in the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis were at higher risk for nonserious infections if treated concomitantly with GC therapy (hazard ratio 1.25, 95% CI 1.19–1.32).6 One more extensive cohort study from the United States found similar higher risks for severe infection in patients receiving low-dose GC (≤5 mg daily) in addition to a b/tsDMARD (adjusted HR 1.26, 95% CI 1.20–1.33) or methotrexate without a b/tsDMARD (adjusted HR 1.32, 95% CI 1.26–1.37), compared to not using glucocorticoids.7
In conclusion, there is a need for more data to determine the long-term (>2 years) balance between efficacy and harms of low-dose GC therapy for patients with RA.
References
1. Giollo A, Rossini M, Bettili F, et al. Permanent Discontinuation of Glucocorticoids in Polymyalgia Rheumatica Is Uncommon but May Be Enhanced by Amino Bisphosphonates. J Rheumatol 2019;46:318-322.
2. Boers M, Hartman L, Opris-Belinski D for the GLORIA Trial consortium et al. Low dose, add-on prednisolone in patients with rheumatoid arthritis aged 65+: the pragmatic randomised, double-blind placebo-controlled GLORIA trial. Ann Rheum Dis 2022;81:925-936.
3. Abtahi S, Driessen JHM, Burden AM, et al. Low-dose oral glucocorticoid therapy and risk of osteoporotic fractures in patients with rheumatoid arthritis: a cohort study using the Clinical Practice Research Datalink. Rheumatology (Oxford) 2022;61:1448-1458.
4. Wiebe E, Huscher D, Schaumburg D, et al. Optimising both disease control and glucocorticoid dosing is essential for bone protection in patients with rheumatic disease. Ann Rheum Dis 2022 Jun 9:annrheumdis-2022-222339.
5. Takahata M, Shimizu T, Yamada S, et al. Bone biopsy findings in patients receiving long-term bisphosphonate therapy for glucocorticoid-induced osteoporosis. J Bone Miner Metab 2022;40:613-622.
6. Bechman K, Halai K, Yates M, et al. Nonserious Infections in Patients With Rheumatoid Arthritis: Results From the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Arthritis Rheumatol 2021;73:1800-1809.
7. 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;173:870-878.
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...
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...
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
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....
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...
We read with interest the study by Dr. Tedeschi and colleagues [1] which reported that patients with at least one episode of acute Calcium pyrophosphate (CPP) crystal arthritis had increased the risk of short (0-2 year) and long-term (2-10 year) non-fatal CV events compared with those without evidence of this acute crystalline arthritis. However, acute CPP crystal arthritis did not confer increased risk for all-cause mortality. This study focuses on an episode of acute calcium pyrophosphate (CPP) crystal arthritis as a significant clinical variable and is a valuable addition to the literature. However, some issues have not been addressed by the authors.
Show MoreFirst, epidemiologists agree that several clinical risk factors are associated with cardiovascular outcome, including acute cerebrovascular insufficiency, hyperparathyroidism, and phenotypes of CPP disease [2,3]. However, the authors did not exclude people with these risk factors, and an evaluation of these risk factors was not presented. The confounding effect of these variables may have contributed to the significant effect in causing cardiovascular disease.
Second, it reported that longer disease duration of CPP crystal arthritis have also been considered to carry an elevated risk for cardiovascular disease [4]. Previous studies have clearly demonstrated that chronic CPP crystal arthritis did confer increased risk for myocardial infarction, acute coronary syndrome, and stroke[5]. However, the duration of CPP...
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 MoreTo the Editor
Show MoreWe recently have read the article written by Dr. Daien et al. entitled published in Annals of the Rheumatic Diseases in 31th of May, 2022 (1). The study assessed the effect of different doses of ABX464 on clinical and laboratory features of patients with active rheumatoid arthritis (RA) and the rate of development of treatment-emergent adverse events in these patients. In this study, it was showed that each day 50 mg use of ABX464 could exert beneficial effects in the patients with acceptable safety and tolerability profile. This study provides fascinating evidence regarding the use of this first-in-class drug candidate for patients not responding to more frequently used treatment regimens; however, there are some points that we would like to address.
The authors mentioned that patients with moderate to severe RA who had rheumatoid factor, anticitrullinated peptide antibody or bone erosions were recruited in the study. The study aimed at comparison of rate of response to the treatment and development of adverse events in each arm of the study. Although, it is generally considered that the randomized design of the clinical studies would produce comparable groups and result in unbiased assessment of the outcomes, different factors which were previously identified in the literature that could be in association with severity of rheumatoid arthritis or poor response to the treatment should had been considered in the quantitative analysis of this study....
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...
Glucocorticoid (GC) therapy is still the mainstay in managing rheumatoid arthritis (RA). The benefits of low-dose GC therapy are well established after decades of clinical experience in RA. Yet, it is essential to appoint the danger of exposure to chronic GC therapy.
Show MoreFor many patients with RA and other inflammatory rheumatic musculoskeletal diseases (RMD), starting prednisolone means taking glucocorticoids for several years or decades, often indefinitely.1 The long-term complications of GC therapy are rarely emphasised by most clinical trials that usually run for only 1 or 2 years. In this regard, the GLORIA trial2 has illuminated both the harms and benefits of 2-year low-dose (5 mg daily) prednisolone in 451 elderly patients (≥65 years) with moderately active established RA. Indeed, there was an 11% increase in patients with at least one adverse event (AE) of special interest (mainly mild to moderate infections) in the prednisolone arm, accounting for a 1.24 (95% CL 0.4) fold higher risk compared to placebo, just within two years of treatment.2
The likelihood of major osteoporotic fractures in GC users increases with the dosage, but more importantly, with the cumulative dose and duration of GC therapy.3 Moreover, low-dose GC therapy (≤5 mg/day) did not seem to be associated with a reduction of bone mineral density (BMD) in patients with inflammatory RMD and current or prior exposure to GC.4 However, while GC therapy effectively alleviates inflammation, it has...
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