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.
Bandak et al.[1] recently published a paper comparing the effect of an exercise and education program with an open-label placebo on a range of outcomes for people with knee osteoarthritis (OA). The exercise and education program consisted of two weeks of 1x1.5 hour education sessions/ week, then six weeks of 2x1 hour exercise sessions/ week. The open-label placebo involved four fortnightly knee intra-articular saline injections and arthrocentesis (if required).[1] The authors argued “open-label placebo provides an opportunity to compare exercise and education with an inert comparator and thereby mitigate some of the inbuilt challenges with blinded comparator groups in clinical trials of exercise and education.” However, the use of an open-label placebo does not attempt to facilitate any opportunity for blinding, and their ‘placebo’ intervention does not meet established placebo criteria.
Placebo interventions should have no therapeutic effect, and should be perceived to be identical to the intervention of interest,[2] to control for the placebo effect; neither of these criteria has been met by Bandak et al.’s[1] placebo. Although saline injections are pharmacologically inert, they may have a real therapeutic effect particularly when coupled with arthrocentesis, as they may exert specific physical and chemical effects that could improve symptoms.[3] As such, it has been recommended that saline intra-articular injections not be used as placebo interventions in studi...
Bandak et al.[1] recently published a paper comparing the effect of an exercise and education program with an open-label placebo on a range of outcomes for people with knee osteoarthritis (OA). The exercise and education program consisted of two weeks of 1x1.5 hour education sessions/ week, then six weeks of 2x1 hour exercise sessions/ week. The open-label placebo involved four fortnightly knee intra-articular saline injections and arthrocentesis (if required).[1] The authors argued “open-label placebo provides an opportunity to compare exercise and education with an inert comparator and thereby mitigate some of the inbuilt challenges with blinded comparator groups in clinical trials of exercise and education.” However, the use of an open-label placebo does not attempt to facilitate any opportunity for blinding, and their ‘placebo’ intervention does not meet established placebo criteria.
Placebo interventions should have no therapeutic effect, and should be perceived to be identical to the intervention of interest,[2] to control for the placebo effect; neither of these criteria has been met by Bandak et al.’s[1] placebo. Although saline injections are pharmacologically inert, they may have a real therapeutic effect particularly when coupled with arthrocentesis, as they may exert specific physical and chemical effects that could improve symptoms.[3] As such, it has been recommended that saline intra-articular injections not be used as placebo interventions in studies of knee OA.[3] Bandak et al.’s[1] use of saline intra-articular injections as a placebo intervention was inappropriate.
Although Bandak et al.[1] argued that by using an open-label placebo they controlled for the placebo effect, this is not the case. In addition to the abovementioned concerns regarding the real therapeutic effect of a saline intra-articular injection, by design the placebo intervention would have been perceived as different by participants who would be aware of the two treatments by the provision of their informed consent. Furthermore, researchers told participants that saline injections were “inert, yet with potential beneficial effects that may compare to those of exercise and education”, and that “investigators had no treatment preference”[1] in an attempt to make the placebo effect comparable. These statements may have negatively influenced the patient-reported outcomes for those in the education and exercise intervention group, as the researchers implied they anticipated no real effect. As a result, the open-label placebo has not controlled for the placebo effect, as implied by the authors.
The findings of Bandak et al.’s[1] study must be considered with caution, and we should not be swayed by the inappropriate use of the term ‘placebo’. Placebo-controlled trials are often considered the ‘gold standard’ when the aim is to compare an intervention with no intervention. However, if the chosen ‘placebo intervention’ does not meet the necessary criteria for a placebo, such studies provide misleading evidence that could lead to inappropriate management recommendations for knee OA, including negative perceptions about the value of education and exercise programs.
Bandak et al.[1] concluded that the pain and function results were equivalent between their treatment and placebo groups, stating that their “findings raise important questions about … the continued widespread recommendation of exercise and education in the management of knee OA.” We do not find their conclusion valid. Instead of aiming for (potentially invalid) placebo controls, we should be making meaningful comparisons that can guide therapy: for instance, studies that compare different education and exercise programs, compare such programs with treatment as usual or in addition to treatment as usual, would more directly inform positive case management.
References
1. Bandak E, Christensen R, Overgaard A, et al. Exercise and education versus saline injections for knee osteoarthritis: a randomised controlled equivalence trial. Ann Rheum Dis 2022;81(4):537-43. doi: 10.1136/annrheumdis-2021-221129
2. Fitzgerald GK, Hinman RS, Zeni Jr J, et al. OARSI Clinical Trials Recommendations: Design and conduct of clinical trials of rehabilitation interventions for osteoarthritis. Osteoarthritis Cartilage 2015;23(5):803-14. doi: 10.1016/j.joca.2015.03.013
3. Fazeli MS, McIntyre L, Huang Y, et al. Intra-articular placebo effect in the treatment of knee osteoarthritis: a survey of the current clinical evidence. Ther Adv Musculoskelet Dis 2022;14: 1759720X211066689. doi: 10.1177/1759720X211066689
The Impact of Clinical Setting on ANA Responses in SLE: Comment on the article by Choi et al.
David S. Pisetsky1 2 and Peter E. Lipsky3 4
1 Medical Research Service, Durham VA Medical Center, Durham, North Carolina, USA
2 Departments of Medicine and Immunology, Duke University Medical Center, Durham, North Carolina, USA
3 RILITE Foundation, Charlottesville, Virginia, USA
4 AMPEL BioSolutions LLC, Charlottesville, Virginia, USA
In a recent paper in the Annals of the Rheumatic Diseases, Choi et al report data on the expression of antinuclear antibodies (ANA) in the sera of patients with systemic lupus erythematosus (SLE).(1) Using a large cohort of well characterized patients from the SLICC (Systemic Lupus International Cooperating Clinics) consortium, the authors show that ANA expression is almost invariable in SLE using three ANA assays (two immunofluorescence or IFA and one ELISA); over time, some changes can occur, with the ELISA showing a greater reduction in the frequency of positive responses than the IFA assays. In this study, patients were early in disease, with the first sample obtained on average 0.58 years after diagnosis.
Choi et al are to be congratulated for this detailed and comprehensive study that includes longitudinal data. Most other studies on ANA expression in SLE have been cross-sectional in design or involved longitudinal data of relatively few patients.(2) Nevertheless, while consistent with data und...
The Impact of Clinical Setting on ANA Responses in SLE: Comment on the article by Choi et al.
David S. Pisetsky1 2 and Peter E. Lipsky3 4
1 Medical Research Service, Durham VA Medical Center, Durham, North Carolina, USA
2 Departments of Medicine and Immunology, Duke University Medical Center, Durham, North Carolina, USA
3 RILITE Foundation, Charlottesville, Virginia, USA
4 AMPEL BioSolutions LLC, Charlottesville, Virginia, USA
In a recent paper in the Annals of the Rheumatic Diseases, Choi et al report data on the expression of antinuclear antibodies (ANA) in the sera of patients with systemic lupus erythematosus (SLE).(1) Using a large cohort of well characterized patients from the SLICC (Systemic Lupus International Cooperating Clinics) consortium, the authors show that ANA expression is almost invariable in SLE using three ANA assays (two immunofluorescence or IFA and one ELISA); over time, some changes can occur, with the ELISA showing a greater reduction in the frequency of positive responses than the IFA assays. In this study, patients were early in disease, with the first sample obtained on average 0.58 years after diagnosis.
Choi et al are to be congratulated for this detailed and comprehensive study that includes longitudinal data. Most other studies on ANA expression in SLE have been cross-sectional in design or involved longitudinal data of relatively few patients.(2) Nevertheless, while consistent with data underpinning the designation of a positive ANA in the EULAR-ACR classification system, the conclusions of the study pertain only to the three assays used.
The performance characteristics of ANA testing are relevant, indeed, crucial, in two disparate settings: patient classification and assessment of eligibility of patients for clinical trials. The frequencies of ANA positivity in these two settings may be very different because of the features of the patient populations studied. Classification (or diagnosis) usually involves early disease; the clinical trial setting usually involves patients later in disease course and therefore extended periods of treatment.
As shown most pertinently in studies with belimumab, many patients at the time of screening for trial eligibility have a high frequency of ANA negativity.(3) These studies also showed that treatment responses can vary depending on serological status, with patients who are ANA positive more likely to respond than those who are serologically negative. These findings led to the current approach for serological testing in the trial setting, with eligibility dependent on serological positivity in terms of tests for ANAs by IFA, anti-DNA and/or anti-Sm.(4, 5)
The lower frequency of ANA positivity in patients considered for clinical trials has a number of possible explanations including the performance characteristics of the assays used. Our previous study showed that different assays can lead to widely varying frequencies of ANA positivity in cross-sectional studies of patients followed in a university setting as well as patients enrolled in a clinical trial.(6, 7) Pending more data on the results of different ANA kits in both the classification and clinical trial settings, it seems reasonable that studies involving ANA testing specify the kit used and relevant data about the frequency of responses in patients with SLE and control populations.
Another factor that may influence the frequency of ANA positivity in any lupus population is disease duration. The study of Choi et al demonstrated a decline in the frequency of ANA positivity over time. The time-frame for this study was only 5 years, however, meaning that most patients had shorter disease duration than in the clinical trial setting. In the trial of anifrolumab, for example, the placebo population had a median time from diagnosis of 78.0 months (range 6-494) whereas the treatment group had a median time of 94.5 months (range 6-555).(8)
The study of Choi et al indicates the persistence of ANA responses within a few years of diagnosis; this observation, however, should not obscure the equally important point that ANA levels can change significantly in response to therapy. The time course of anti-DNA expression clearly illustrates the mutability of ANA responses with treatment. The effects of belimumab are another example of the impact of treatment on ANA levels since this agent can lower autoantibody levels by up to approximately 50%.(4, 9) Other agents used to treat SLE also have effects on B cell number and function that could decrease ANA expression. These agents include cyclophosphamide, rituximab and mycophenolate among commonly used agents, although the effects of these agents can differ with respect to B cell subpopulations, plasmablasts and plasma cells.(10-13)
In studies on the effects of various immunomodulatory therapies, it is important to note that some autoantibodies (e.g., anti-DNA) can show decreases out of proportion to the effects of total Ig levels. While other ANAs such as anti-Sm or anti-RNP can show decreases perhaps not as profound as anti-DNA, anti-Ro antibody may not be affected by belimumab, for example.(9) The maintenance of a consistent level of antibody production could suggest production by long-lived plasma cells. An intriguing study by Lindop et al showed that the anti-Ro response, while showing little change in levels over time, resulted from the emergence of new clones as indicated by variable region sequences.(14) In this case, the stability in levels of the ANA gave a false impression of an origin from long-lived plasma cells, whereas the clonal diversification implicates ongoing tick-over from memory B cells.
Given the range of new therapies under investigation for SLE, it is important to recognize the unique immunological features of the clinical trial population (i.e., longer disease duration, history of previous immunosuppressive agents, active disease) and develop a serological profile of this patient population with quantitative assays and optimally a range of different testing kits. The study by Choi is an important step in exploring the immune landscape of SLE in the first years after disease onset. In view of advances in serological testing and future clinical trials, further exploration of this landscape in subsequent years will be both fascinating and essential.
1. Choi MY, Clarke AE, Urowitz M, et al. Longitudinal analysis of ANA in the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort. Ann Rheum Dis 2022.
2. Frodlund M, Wetterö J, Dahle C, et al. Longitudinal anti-nuclear antibody (ANA) seroconversion in systemic lupus erythematosus: a prospective study of Swedish cases with recent-onset disease. Clin Exp Immunol 2020;199(3):245-54.
3. Wallace DJ, Stohl W, Furie RA, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum 2009;61(9):1168-78.
4. Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 2011;63(12):3918-30.
5. Pisetsky DS, Rovin BH, Lipsky PE, et al. New Perspectives in Rheumatology: biomarkers as entry criteria for clinical trials of new therapies for systemic lupus erythematosus: the example of antinuclear antibodies and anti-DNA. Arthritis Rheumatol 2017;69:487-93.
6. Pisetsky DS, Spencer DM, Lipsky PE, et al. Assay variation in the detection of antinuclear antibodies in the sera of patients with established SLE. Ann Rheum Dis 2018;77(6):911-3.
7. Pisetsky DS, Thompson DK, Wajdula J, et al. Variability in Antinuclear Antibody Testing to Assess Patient Eligibility for Clinical Trials of Novel Treatments for Systemic Lupus Erythematosus. Arthritis Rheumatol 2019;71(9):1534-8.
8. Morand EF, Furie R, Tanaka Y, et al. Trial of Anifrolumab in Active Systemic Lupus Erythematosus. N Engl J Med 2020;382(3):211-21.
9. Parodis I, Åkerström E, Sjöwall C, et al. Autoantibody and Cytokine Profiles during Treatment with Belimumab in Patients with Systemic Lupus Erythematosus. Int J Mol Sci 2020;21(10).
10. Eickenberg S, Mickholz E, Jung E, et al. Mycophenolic acid counteracts B cell proliferation and plasmablast formation in patients with systemic lupus erythematosus. Arthritis Res Ther 2012;14(3).
11. Heidt S, Roelen DL, Eijsink C, et al. Effects of immunosuppressive drugs on purified human B cells: evidence supporting the use of MMF and rapamycin. Transplantation 2008;86(9):1292-300.
12. Karnell JL, Karnell FG, 3rd, Stephens GL, et al. Mycophenolic acid differentially impacts B cell function depending on the stage of differentiation. J Immunol 2011;187(7):3603-12.
13. Fassbinder T, Saunders U, Mickholz E, et al. Differential effects of cyclophosphamide and mycophenolate mofetil on cellular and serological parameters in patients with systemic lupus erythematosus. Arthritis Res Ther 2015;17(1):92.
14. Lindop R, Arentz G, Bastian I, et al. Long-term Ro60 humoral autoimmunity in primary Sjögren's syndrome is maintained by rapid clonal turnover. Clin Immunol 2013;148(1):27-34.
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...
Bandak et al.[1] recently published a paper comparing the effect of an exercise and education program with an open-label placebo on a range of outcomes for people with knee osteoarthritis (OA). The exercise and education program consisted of two weeks of 1x1.5 hour education sessions/ week, then six weeks of 2x1 hour exercise sessions/ week. The open-label placebo involved four fortnightly knee intra-articular saline injections and arthrocentesis (if required).[1] The authors argued “open-label placebo provides an opportunity to compare exercise and education with an inert comparator and thereby mitigate some of the inbuilt challenges with blinded comparator groups in clinical trials of exercise and education.” However, the use of an open-label placebo does not attempt to facilitate any opportunity for blinding, and their ‘placebo’ intervention does not meet established placebo criteria.
Placebo interventions should have no therapeutic effect, and should be perceived to be identical to the intervention of interest,[2] to control for the placebo effect; neither of these criteria has been met by Bandak et al.’s[1] placebo. Although saline injections are pharmacologically inert, they may have a real therapeutic effect particularly when coupled with arthrocentesis, as they may exert specific physical and chemical effects that could improve symptoms.[3] As such, it has been recommended that saline intra-articular injections not be used as placebo interventions in studi...
Show MoreThe Impact of Clinical Setting on ANA Responses in SLE: Comment on the article by Choi et al.
David S. Pisetsky1 2 and Peter E. Lipsky3 4
1 Medical Research Service, Durham VA Medical Center, Durham, North Carolina, USA
2 Departments of Medicine and Immunology, Duke University Medical Center, Durham, North Carolina, USA
3 RILITE Foundation, Charlottesville, Virginia, USA
4 AMPEL BioSolutions LLC, Charlottesville, Virginia, USA
In a recent paper in the Annals of the Rheumatic Diseases, Choi et al report data on the expression of antinuclear antibodies (ANA) in the sera of patients with systemic lupus erythematosus (SLE).(1) Using a large cohort of well characterized patients from the SLICC (Systemic Lupus International Cooperating Clinics) consortium, the authors show that ANA expression is almost invariable in SLE using three ANA assays (two immunofluorescence or IFA and one ELISA); over time, some changes can occur, with the ELISA showing a greater reduction in the frequency of positive responses than the IFA assays. In this study, patients were early in disease, with the first sample obtained on average 0.58 years after diagnosis.
Show MoreChoi et al are to be congratulated for this detailed and comprehensive study that includes longitudinal data. Most other studies on ANA expression in SLE have been cross-sectional in design or involved longitudinal data of relatively few patients.(2) Nevertheless, while consistent with data und...
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