We read the “Treat-to-target recommendations in giant cell arteritis and polymyalgia rheumatica” with great interest [1], as it provides a much-needed and updated approach to the management of polymyalgia rheumatica (PMR), a relatively common condition with significant disease burden. As indicated by the Research Agenda listed in the paper, there remains much to be learned about the clinical management of PMR. Specifically, we would like to emphasize the gaps in research regarding the physiological and clinical nuances in optimizing corticosteroid (CS) tapering.
By adapting a T2T approach, clinicians can strive towards the ideal goal of minimizing both symptom flare-ups and cumulative steroid exposure, with significant risk due to steroid usage. As this provides a qualitative guideline, the challenge is to determine an optimal tapering rate. Steroid tapering for PMR has often been recognized as an “art” that can be unpredictable and rarely has a smooth trajectory. A meta-analysis showed that the pooled relapse rate at 1 year from treatment initiation was 43% [2].
Our interest in these unanswered questions came from the personal case study of W.D. (a retired physician) who documented his tapering process. He was treated for a total of almost three years with four flares of PMR, with multiple flares in the third and fourth episodes, and the addition of methotrexate, ultimately resulting in a cumulative total of 9,130 mg of prednisone. This prompted our explorat...
We read the “Treat-to-target recommendations in giant cell arteritis and polymyalgia rheumatica” with great interest [1], as it provides a much-needed and updated approach to the management of polymyalgia rheumatica (PMR), a relatively common condition with significant disease burden. As indicated by the Research Agenda listed in the paper, there remains much to be learned about the clinical management of PMR. Specifically, we would like to emphasize the gaps in research regarding the physiological and clinical nuances in optimizing corticosteroid (CS) tapering.
By adapting a T2T approach, clinicians can strive towards the ideal goal of minimizing both symptom flare-ups and cumulative steroid exposure, with significant risk due to steroid usage. As this provides a qualitative guideline, the challenge is to determine an optimal tapering rate. Steroid tapering for PMR has often been recognized as an “art” that can be unpredictable and rarely has a smooth trajectory. A meta-analysis showed that the pooled relapse rate at 1 year from treatment initiation was 43% [2].
Our interest in these unanswered questions came from the personal case study of W.D. (a retired physician) who documented his tapering process. He was treated for a total of almost three years with four flares of PMR, with multiple flares in the third and fourth episodes, and the addition of methotrexate, ultimately resulting in a cumulative total of 9,130 mg of prednisone. This prompted our exploration of the CS tapering process in PMR.
One way to examine the CS regimen and rate of taper is the use of tapering slopes, as described in Kremers’ retrospective longitudinal study from 2005 that studied the relationship between cumulative prednisone and the probability of relapse in PMR patients [3]. Mathematical models of tapering rates (or “slopes”) were developed to characterize each patient’s cumulative dose and regimen, characterized as “slow”, “medium”, or “fast”. Almost 70% of the fast taper group experienced a relapse by the end of the first year, versus 10% of the slow taper group. The 2015 EULAR Guidelines recommended appropriate tapering doses to achieve an oral dose of 10 mg/day of prednisone within 4-8 weeks [4]; however, tapering within 4 weeks would represent a regimen akin to Kremers’ rapid tapering slopes. However, as only around 50% of patients have complete resolution of symptoms after 4 weeks [5], could defaulting to this conventional regimen to initiate therapy put patients at higher risk of flares?
Another challenge is tapering at lower doses, for which each absolute dosage decrement represents a large percentage change (ie. reduction from 5 to 4mg represents a 20% change). A practical solution is the use of liquid prednisone, which allows for decrements of 0.5 mg, 0.1 mg, and 0.05 mg. This allows for a smaller dose decrease every 2-3 days rather than a large decrease every week. With additional evidence, there is possible room for use of liquid prednisone in PMR tapering protocols. Kate Gilbert’s book on PMR [6] describes one rheumatologist’s gradual tapering approach from 8 to 7 mg as follows: 8 mg x 6 days and 7 mg x 1 day, followed by 8 mg x 5 days and 7 mg x 2 days, etc. This approach implicates a 7-day moving average of prednisone dosing that is more gradual. However, this may result in a longer duration for weaning and, thus, a higher cumulative dose. There has also yet to be robust evidence on these types of alternate-day regimens.
We hope that further quantitative guidance for clinical care can be provided, accompanied by further understanding of the physiology and clinical outcomes of CS tapering regimens.
References:
1. Dejaco C, Kerschbaumer A, Aletaha D, Bond M, Hysa E, Camellino D, et al. Treat-to-target recommendations in giant cell arteritis and polymyalgia rheumatica. Ann Rheum Dis. 2023;1–10.
2. Floris A, Piga M, Chessa E, Congia M, Erre GL, Angioni MM, et al. Long-term glucocorticoid treatment and high relapse rate remain unresolved issues in the real-life management of polymyalgia rheumatica: a systematic literature review and meta-analysis. Clin Rheumatol [Internet]. 2022;41(1):19–31. Available from: https://doi.org/10.1007/s10067-021-05819-z
3. Kremers HM, Reinalda MS, Crowson CS, Zinsmeister AR, Hunder GG, Gabriel SE. Relapse in a population based cohort of patients with polymyalgia rheumatica. J Rheumatol. 2005;32(1):65–73.
4. Dejaco C, Singh YP, Perel P, Hutchings A, Camellino D, Mackie S, et al. 2015 recommendations for the management of polymyalgia rheumatica: A European League Against Rheumatism/American College of Rheumatology collaborative initiative. Ann Rheum Dis. 2015;74(10):1799–807.
5. Matteson EL, Buttgereit F, Dejaco C, Dasgupta B. Glucocorticoids for Management of Polymyalgia Rheumatica and Giant Cell Arteritis. Rheum Dis Clin North Am. 2016;42(1):75–90.
6. Gilbert K. Polymyalgia Rheumatica and Giant Cell Arteritis: a survival guide. 2nd ed. Createspace Independent Publishing Platform; 2016.
I read the individual patient data metaanalysis by van Ouwerkerk et al [1] on the comparison of long term glucocorticoid use in initial glucocorticoid bridgers and non-bridgers with interest. Other than inevitable limitations such as the absence of randomised trials with low-dose glucocorticoid bridging, per protocol duration and tapering of the bridging glucocorticoid doses, and heterogeneity of disease severity and disease-modifying anti-rheumatic drug (DMARD) use in the comparator arms, which were discussed by the authors, I believe this study had an important and unmentioned limitation on its main conclusion: the similarity of late glucocorticoid use after bridging was completed in bridgers and non-bridgers.
The authors argued that after a planned ending of the bridging period, glucocorticoid use was higher in the initial bridgers compared to non-bridgers only 12 months after randomisation and no longer significantly higher at 18 and 24 months. The pooled frequency of glucocorticoid use in bridgers vs. non-bridgers were 21% vs. 6% corresponding to an OR of 3.27 (1.06-10.08) [1]. The frequencies were not reported but represented in a figure for the months 18 and 24. The reported ORs were 1.6 (0.46-5.6) and 1.7 (0.58-4.97) for the months 18 and 24. The risk ratios, which looked like at least 1.5 if not more particularly for the month 24 according to the figure, were not found to be significant. However, to be able to confidently (such as with 8...
I read the individual patient data metaanalysis by van Ouwerkerk et al [1] on the comparison of long term glucocorticoid use in initial glucocorticoid bridgers and non-bridgers with interest. Other than inevitable limitations such as the absence of randomised trials with low-dose glucocorticoid bridging, per protocol duration and tapering of the bridging glucocorticoid doses, and heterogeneity of disease severity and disease-modifying anti-rheumatic drug (DMARD) use in the comparator arms, which were discussed by the authors, I believe this study had an important and unmentioned limitation on its main conclusion: the similarity of late glucocorticoid use after bridging was completed in bridgers and non-bridgers.
The authors argued that after a planned ending of the bridging period, glucocorticoid use was higher in the initial bridgers compared to non-bridgers only 12 months after randomisation and no longer significantly higher at 18 and 24 months. The pooled frequency of glucocorticoid use in bridgers vs. non-bridgers were 21% vs. 6% corresponding to an OR of 3.27 (1.06-10.08) [1]. The frequencies were not reported but represented in a figure for the months 18 and 24. The reported ORs were 1.6 (0.46-5.6) and 1.7 (0.58-4.97) for the months 18 and 24. The risk ratios, which looked like at least 1.5 if not more particularly for the month 24 according to the figure, were not found to be significant. However, to be able to confidently (such as with 80% power) say that there were no significant difference (such as no more than 1.5 times) in terms the frequency of glucocorticoid use in the bridgers compared to non-bridgers (assumed to be 6-8% according to the figure), one would need several thousands of patients. Therefore the main conclusion of this study may probably be prone to type II error. The reported rates of glucocorticoid use in bridgers vs. non-bridgers at month 24 were 10% vs. 0%, 12% vs. 2%, and 21% vs 5-15% in individual studies, reflecting a consistent though small increased risk of glucocorticoid use in initial bridgers. An inability rate of 23% to stop glucocorticoids and a reimplementation rate of 77% after the end of planned bridging period may further support a tendency towards an increased risk of continued/late glucocorticoid use in the initial bridgers, hence the conditional advice of the American College of Rheumatology guidelines [2] against glucocorticoid bridging.
References:
1. van Ouwerkerk L, Verschueren P, Boers M, et al. Initial glucocorticoid bridging in rheumatoid arthritis: does it affect glucocorticoid use over time? Ann Rheum Dis 2023. doi: 10.1136/ard-2023-224270.
2. Fraenkel L, Bathon JM, England BR, et al. American college of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 2021;73:1108–23.
Correspondence on “EULAR recommendations for the management of systemic lupus erythematosus: 2023 update” by “Fanouriakis A, et al”
I read the recently updated EULAR recommendations for the management of systemic lupus erythematosus (SLE) with great interest.[1] In recommendation 8, voclosporine was categorized alongside belimumab and tacrolimus. However, I am concerned about recommending voclosporine as an initial induction therapy for active lupus nephritis (LN).
The effectiveness of voclosporine, when added to a rapid-reduction glucocorticoid regimen and mycophenolate (MMF, typically administered at 2 g/day), has been demonstrated to be superior to placebo.[2] However, it is important to note that this study significantly deviated from the trials involving belimumab or tacrolimus[3, 4] as it included a large number of patients who were refractory to MMF. This indicates that 55% of the participants while taking MMF, met one of the inclusion criteria: a current urine protein creatinine ratio (UPCR) of ≥1·5. These individuals were then randomised to either the placebo or voclosporine group. Patients with these specific characteristics, if placed in the placebo group, would have been reintroduced to MMF, despite its previous ineffectiveness in addressing their lupus nephritis. Therefore, the treatment effect in the placebo group was assumed to be considerably lower. As expected, the efficacy of incorporating voclosporine was observed solely in the patient group...
Correspondence on “EULAR recommendations for the management of systemic lupus erythematosus: 2023 update” by “Fanouriakis A, et al”
I read the recently updated EULAR recommendations for the management of systemic lupus erythematosus (SLE) with great interest.[1] In recommendation 8, voclosporine was categorized alongside belimumab and tacrolimus. However, I am concerned about recommending voclosporine as an initial induction therapy for active lupus nephritis (LN).
The effectiveness of voclosporine, when added to a rapid-reduction glucocorticoid regimen and mycophenolate (MMF, typically administered at 2 g/day), has been demonstrated to be superior to placebo.[2] However, it is important to note that this study significantly deviated from the trials involving belimumab or tacrolimus[3, 4] as it included a large number of patients who were refractory to MMF. This indicates that 55% of the participants while taking MMF, met one of the inclusion criteria: a current urine protein creatinine ratio (UPCR) of ≥1·5. These individuals were then randomised to either the placebo or voclosporine group. Patients with these specific characteristics, if placed in the placebo group, would have been reintroduced to MMF, despite its previous ineffectiveness in addressing their lupus nephritis. Therefore, the treatment effect in the placebo group was assumed to be considerably lower. As expected, the efficacy of incorporating voclosporine was observed solely in the patient group that had undergone MMF treatment at the time of screening. In contrast, there was no significant improvement in the group of patients who had not received MMF previously (i.e. those who were treatment-naïve cases or cases treated with agents other than MMF). Furthermore, the add-on effect of voclosporine was significant in the subgroup that received an MMF dose of ≤2g/day during the trial, but not in the subgroup receiving a dose of >2g/day. [2] These results suggest that the add-on effect of voclosporine, when compared with the current standard of care (SOC) comprising MMF (target dose: 2 to 3 g/day) and glucocorticoids, remains to be fully elucidated.[5]
Conversely, the efficacy of belimumab when added to the current SOC was investigated, regardless of whether it included MMF or intravenous cyclophosphamide.[3] Regarding the inclusion criteria, individuals with prior MMF or cyclophosphamide use could be considered eligible, but the investigators retained the authority to select the immunosuppressive agents for induction therapy. The primary efficacy renal response (PERR) at both 1 and 2 years was significantly higher in the belimumab group than in the placebo group. In subgroup analyses, the efficacy of belimumab was particularly evident in relapsing cases (odds ratio of PERR at 2 years, 2.31 [95% confidence interval, 1.07 – 5.01]).[6] However, for newly diagnosed cases, the efficacy exhibited only a non-significant trend (odds ratio of 1.36 [0.85 – 2.20]). Nevertheless, belimumab lowered the hazard ratio (HR) for kidney-related events or death not only in the relapsing cases but also in the newly diagnosed cases [0.47 (95% CI 0.23 – 0.95) and 0.55 (0.33–0.93), respectively]. These results suggest that compared to the current SOC, the incorporation of belimumab in the SOC presents specific advantages in both the relapsing and newly diagnosed cases.
Taken together, we believe that combination therapy with belimumab (in conjunction with either cyclophosphamide or MMF) could be a viable option for initial induction therapy in cases of active proliferative lupus nephritis. However, combination therapy with voclosporine and MMF should be reserved exclusively for patients who remain refractory or resistant to the SOC.
Reference
1 Fanouriakis A, Kostopoulou M, Andersen J, et al. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann Rheum Dis 2023. doi: 10.1136/ard-2023-224762.
2 Rovin BH, Teng YKO, Ginzler EM, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2021;397:2070–80.
3 Furie R, Rovin BH, Houssiau F, et al. Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis. N Engl J Med 2020;383:1117–28.
4 Liu Z, Zhang H, Liu Z, et al. Multitarget therapy for induction treatment of lupus nephritis: a randomized trial. Ann Intern Med 2015;162:18–26.
5 Fanouriakis A, Kostopoulou M, Cheema K, et al. 2019 Update of the Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA) recommendations for the management of lupus nephritis. Ann Rheum Dis 2020 Jun;79:713–23.
6 Anders HJ, Furie R, Malvar A, et al. Effect of belimumab on kidney-related outcomes in patients with lupus nephritis: post hoc subgroup analyses of the phase 3 BLISS-LN trial. Nephrol Dial Transplant 2023. doi: 10.1093/ndt/gfad167.
The 2023 update of the EULAR recommendations for the management of systemic lupus erythematosus (SLE) recommend hydroxychloroquine (HCQ) for all patients with SLE at a target dose of 5 mg/kg real body weight (RBW)/day but also suggest individualizing the regimen in accordance with the risk of flares or retinal toxicity. The updated recommendations also emphasize the importance of non-pharmacological interventions, including the cessation of smoking, which may interfere with the efficacy of antimalarial agents, as seen in patients with cutaneous lupus erythematosus (CLE). 1 However, the evidence on the efficacy of the target dose of 5 mg/kg(RBW)/day and the effect of smoking on SLE is scarce.
In Japan, HCQ was approved in 2015 after a double-blind randomized clinical trial demonstrated a favorable effect on CLE. The approved dosage was based on 6.5 mg/kg of ideal body weight (IBW), namely, 200 mg/day for IBW ˂46 kg; 200 mg and 400 mg on alternating days for IBW ≥ 46 kg and ˂ 62 kg; and 400 mg/day for IBW ≥62 kg. The steady-state maximum whole blood HCQ level (ng/ml) at these dosages were simulated with 630.3±220.4, 942.7±191.2 and 850.3±174.5, respectively.23 Thereafter, a multicentric, prospective study evaluating the effect of HCQ on SLE and CLE in the real world setting was conducted for post-marketing surveillance in accordance with the Good Post-Marketing Study ordinance of the Ministry of Health, Labour and Welfare of Japan. 4
The 2023 update of the EULAR recommendations for the management of systemic lupus erythematosus (SLE) recommend hydroxychloroquine (HCQ) for all patients with SLE at a target dose of 5 mg/kg real body weight (RBW)/day but also suggest individualizing the regimen in accordance with the risk of flares or retinal toxicity. The updated recommendations also emphasize the importance of non-pharmacological interventions, including the cessation of smoking, which may interfere with the efficacy of antimalarial agents, as seen in patients with cutaneous lupus erythematosus (CLE). 1 However, the evidence on the efficacy of the target dose of 5 mg/kg(RBW)/day and the effect of smoking on SLE is scarce.
In Japan, HCQ was approved in 2015 after a double-blind randomized clinical trial demonstrated a favorable effect on CLE. The approved dosage was based on 6.5 mg/kg of ideal body weight (IBW), namely, 200 mg/day for IBW ˂46 kg; 200 mg and 400 mg on alternating days for IBW ≥ 46 kg and ˂ 62 kg; and 400 mg/day for IBW ≥62 kg. The steady-state maximum whole blood HCQ level (ng/ml) at these dosages were simulated with 630.3±220.4, 942.7±191.2 and 850.3±174.5, respectively.23 Thereafter, a multicentric, prospective study evaluating the effect of HCQ on SLE and CLE in the real world setting was conducted for post-marketing surveillance in accordance with the Good Post-Marketing Study ordinance of the Ministry of Health, Labour and Welfare of Japan. 4
The observation period for effectiveness was one year. The physician and patient used a seven-point scale consisting of the eight categories, “remarkably improved,” “improved,” “slightly improved,” “not changed,” “slightly aggravated,” “aggravated,” “remarkably aggravated,” and “unable to be evaluated” to assess skin manifestations while the physician assessed the other clinical symptoms. The responses, “remarkably improved” and “improved” indicated good treatment efficacy. Patients with SLE with non-dermatological, clinical symptoms then used the visual analog scale (VAS: 0-10) to evaluate fatigue and musculoskeletal pain.
In total, 1142 patients comprising the safety analysis population received a mean HCQ dosage of 4.9±1.2 mg/kg (RBW)/day. Throughout the period, the physician found drug adherence to be “as prescribed（75％ or higher）” in 94.3％ of the patients.
In a cohort consisting of 75 CLE patients and 385 SLE patients with skin manifestations at baseline, physicians judged the treatment to be effective in 49.3% (remarkably improved: 13.9%, improved: 35.4%, slightly improved: 21.3%, unchanged: 27.4%, slightly aggravated: 0.9%, aggravated: 1.1%, remarkably aggravated: 0%). Multivariate analysis produced an odds ratio (OR) (95% confidence interval) of 0.315 (0.139-0.716) and 0.547 (0.295-1.017) for current smoking habit and lower-than-approved dosage, respectively, and 48.7% of the patients judged the treatment to be effective (remarkably improved: 13.0%, improved: 35.7%, slightly improved: 18.9%, unchanged: 29.8%, slightly aggravated: 1.5%, aggravated: 0.9%, remarkably aggravated: 0.2%). Multivariate analysis produced an OR of 0.369 (0.167-0.819) and 0.533 (0.287-0.991) for current smoking habit and lower-than-approved dosage, respectively.
In the cohort of 872 SLE patients with clinical symptoms other than skin manifestations at baseline, physicians judged the treatment to be effective in 37.8% (remarkably improved: 4.8%, improved: 33.0%, slightly improved: 20.2%, unchanged: 38.5%, slightly aggravated: 1.5%, aggravated: 1.6%, remarkably aggravated: 0.3%). On multivariate analysis, the OR for current smoking habit and lower-than-approved dosage was 0.413 (0.215-0.793) and 0.587 (0.379-0.909), respectively. The patients’ VAS for fatigue and musculoskeletal pain decreased from 3.13±2.75 to 1.85±2.25 (p<0.0001) and from 2.76±2.70 to 1.56±2.09 (p<0.0001), respectively.
These results support the 2023 update of the EULAR recommendations regarding the use of HCQ at the target dosage of 5 mg/kg (RBW)/day and the importance of the non-pharmacological intervention of smoking cessation in the management of SLE.
References:
1. Fanouriakis A, Kostopoulou M, Andersen J, et al. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Annals of the rheumatic diseases 2023:ard-2023-224762. doi: 10.1136/ard-2023-224762
2. Yokogawa N, Eto H, Tanikawa A, et al. Effects of Hydroxychloroquine in Patients With Cutaneous Lupus Erythematosus: A Multicenter, Double-Blind, Randomized, Parallel-Group Trial. Arthritis & rheumatology (Hoboken, NJ) 2017;69(4):791-99. doi: 10.1002/art.40018 [published Online First: 2016/12/20]
3. Morita S, Takahashi T, Yoshida Y, et al. Population Pharmacokinetics of Hydroxychloroquine in Japanese Patients With Cutaneous or Systemic Lupus Erythematosus. Therapeutic drug monitoring 2016;38(2):259-67. doi: 10.1097/ftd.0000000000000261
4. Tomura A, et al. Safety and effectiveness of hydroxychloroquine in Japanese people with cutaneous lupus erythematosus and systemic lupus erythematosus:results of a drug use–results survey. Therapeutic Research 2022;43(10):817-42.
We are thrilled and grateful to see an update of the systemic lupus erythematosus (SLE) treatment recommendations after 4 years’ time since 2019. Because of the efforts of a Task Force of world-leading SLE experts, we are now able to follow these useful recommendations in daily clinical practice. In this version, several new ideas to treat SLE come into view. We are now entering the era of biologics, with more on the way, which might significantly change the way we treat SLE. Apart from rituximab, belimumab, and anifrolumab, there is another B cell related biologic, telitacicept, a BLyS/APRIL dual inhibitor, with a successful phase II trial1; larger confirmatory trials are currently underway. As recommended in the version, early diagnosis and treatment are emphasized. The biologics are used earlier than before, not requiring conventional immunosuppresants first; this change is a bit step forward, indicating that early intervention is important.
The treatment of SLE is like walking on a blade. Balancing the benefits and harms is an art, for which the use of glucocorticoids (GC) is a typical example. I totally agree that the use of GC is only for ‘bridging therapy’ in SLE. But we can expect that, different from the treatment of rheumatoid arthritis (RA), the taper of GC in SLE is not as easy as in RA and the duration will be longer. In this recommendation, it is clearly stated that GC should be taped gradually. However, in terms of the cessation of GC, it is not clear...
We are thrilled and grateful to see an update of the systemic lupus erythematosus (SLE) treatment recommendations after 4 years’ time since 2019. Because of the efforts of a Task Force of world-leading SLE experts, we are now able to follow these useful recommendations in daily clinical practice. In this version, several new ideas to treat SLE come into view. We are now entering the era of biologics, with more on the way, which might significantly change the way we treat SLE. Apart from rituximab, belimumab, and anifrolumab, there is another B cell related biologic, telitacicept, a BLyS/APRIL dual inhibitor, with a successful phase II trial1; larger confirmatory trials are currently underway. As recommended in the version, early diagnosis and treatment are emphasized. The biologics are used earlier than before, not requiring conventional immunosuppresants first; this change is a bit step forward, indicating that early intervention is important.
The treatment of SLE is like walking on a blade. Balancing the benefits and harms is an art, for which the use of glucocorticoids (GC) is a typical example. I totally agree that the use of GC is only for ‘bridging therapy’ in SLE. But we can expect that, different from the treatment of rheumatoid arthritis (RA), the taper of GC in SLE is not as easy as in RA and the duration will be longer. In this recommendation, it is clearly stated that GC should be taped gradually. However, in terms of the cessation of GC, it is not clear when, during clinical remission, GC can be stopped completely. Moreover, the GC dose is recommended to be lower than 5mg, but evidence is still scarce. In the 2019 recommendation, GC dose is recommended as lower than 7.5mg. In the future, is it possible that the dose of GC will fall to even less? As new drugs continue to appear, complete remission without GC might not be a dream.
In the treatment of thrombocytopenia, tacrolimus (TAC) and sirolimus were also reported 2,3. Moreover, recombinant human thrombopoietin can also be used as adjunct treatment4. Regarding the treatment of lupus nephritis (LN), the initial dose of GC in China, 1mg/kg/day of GC, is widely used and 250-1000mg/day as a pulse dose is not commonly used. Is 1mg/kg/day also an acceptable dose in new-onset LN? In figure 1, it is a question whether a calcineurin inhibitor such as TAC can be used as a second line treatment of mild disease, similar to mycophenolate mofetil, azathioprine, methotrexate. In clinical practice, it is also a commonly used regime, not only used in LN.
In this version, fatigue, non-inflammatory pain, mood disturbance and cognitive dysfunction, which are widely reported by the patients, were considered. More studies are needed to help patients obtain relief from these symptoms.
References:
1.Sohita Dhillon.Telitacicept: First Approval.Drugs.2021 Sep;81(14):1671-1675.
2.Y Li, X Feng.Efficacy and safety of tacrolimus in systemic lupus erythematosus patients with refractory thrombocytopenia: a retrospective study.Lupus. 2018 Jan;27(1):60-65.
3.Chanyuan Wu, Qian Wang, Dong Xu,et al. Sirolimus for patients with connective tissue disease-related refractory thrombocytopenia: a single-arm, open-label clinical trial.Rheumatology (Oxford). 2021 Jun 18;60(6):2629-2634.
4.Yafei Yu, Yu Hou, Yajing Zhao,et al.Platelet autoantibody specificity and response to rhTPO treatment in patients with primary immune thrombocytopenia.Br J Haematol. 2021 Jul;194(1):191-194.
With great interest, we have read the recent article by Konzett et al1 on determination of the most powerful American College of Rheumatology (ACR) response definition (ACR20, 50 or 70) between active treatment and placebo in RA trials. In this well-designed study, the authors systematically analyzed the time courses of ACR20, 50 and 70 responses from randomized, double-blind, placebo-controlled, phase II and phase III RA drug approval trials. The conclusion was ACR20 remains the most sensitive discriminator at early time points in the novel therapeutics (bDMARDs and tsDMARDs) placebo-controlled RA trials.
However, the placebo response seems ignored in the comparison of response trajectories of ACR20, 50 and 70. First, we noticed that the authors showed longitudinal dynamics of different ACR response rates and concluded ACR20 response provided highly sensitive to early treatment effect (Figure 2)1. The “treatment effect” in this case should be the relative effect of treatment compared with placebo ( treatment response - placebo response)2, however, it appears that the mean normalized ACR response rates in Figure 2 relies solely on data from the treatment group, without factoring in the placebo group. The placebo response rate in RA clinical trials has significantly increased in the era of bDMARDs/tsDMARDs3, which has also been confirmed in the supplementary material section 8.21. A substantial placebo response can hinder the ability to discern treatment effects4. Th...
With great interest, we have read the recent article by Konzett et al1 on determination of the most powerful American College of Rheumatology (ACR) response definition (ACR20, 50 or 70) between active treatment and placebo in RA trials. In this well-designed study, the authors systematically analyzed the time courses of ACR20, 50 and 70 responses from randomized, double-blind, placebo-controlled, phase II and phase III RA drug approval trials. The conclusion was ACR20 remains the most sensitive discriminator at early time points in the novel therapeutics (bDMARDs and tsDMARDs) placebo-controlled RA trials.
However, the placebo response seems ignored in the comparison of response trajectories of ACR20, 50 and 70. First, we noticed that the authors showed longitudinal dynamics of different ACR response rates and concluded ACR20 response provided highly sensitive to early treatment effect (Figure 2)1. The “treatment effect” in this case should be the relative effect of treatment compared with placebo ( treatment response - placebo response)2, however, it appears that the mean normalized ACR response rates in Figure 2 relies solely on data from the treatment group, without factoring in the placebo group. The placebo response rate in RA clinical trials has significantly increased in the era of bDMARDs/tsDMARDs3, which has also been confirmed in the supplementary material section 8.21. A substantial placebo response can hinder the ability to discern treatment effects4. Therefore, considering the placebo response may be more appropriate. Second, the control arms in the study not only included placebo only arms, but also placebo plus csDMARDs arms1. Evidence showed that patients receiving placebo in combination with csDMARDs had a higher placebo response compared to those receiving placebo only5. Hence, firstly, the placebo response should be taken into account. Secondly, the three ACR criteria should be discussed in terms of how well they can discriminate between active treatment and placebo in different control groups.
Additionally, the authors collected the ACR20, 50 and 70 scores at multiple time points over the course of phase II and phase III RCTs. There is a disconnect between phase II and phase III trials, where phase II trials could overestimate treatment effects6. Combining both for evaluation may introduce bias to the results. Therefore, it would be better if readers were able to view the results by separating the discussion of Phase II and Phase III studies.
Taken together, these aspects indicate the need to further consider the aforementioned methodological issues. We respect the significant contributions of the authors and look forward to more communications.
References
1. Konzett, V., Kerschbaumer, A., Smolen, J. S. & Aletaha, D. Determination of the most appropriate ACR response definition for contemporary drug approval trials in rheumatoid arthritis. Ann. Rheum. Dis. ard-2023-224477 (2023) doi:10.1136/ard-2023-224477.
2. Nikolakopoulou, A. et al. When does the placebo effect have an impact on network meta-analysis results? BMJ Evid.-Based Med. bmjebm-2022-112197 (2023) doi:10.1136/bmjebm-2022-112197.
3. Bechman, K., Yates, M., Norton, S., Cope, A. P. & Galloway, J. B. Placebo Response in Rheumatoid Arthritis Clinical Trials. J. Rheumatol. 47, 28–34 (2020).
4. Neogi, T. & Colloca, L. Placebo effects in osteoarthritis: implications for treatment and drug development. Nat. Rev. Rheumatol. 19, 613–626 (2023).
5. Kerschbaumer, A., Rivai, Z. I., Smolen, J. S. & Aletaha, D. Impact of pre-existing background therapy on placebo responses in randomised controlled clinical trials of rheumatoid arthritis. Ann. Rheum. Dis. 81, 1374–1378 (2022).
6. Kerschbaumer, A. et al. Efficacy outcomes in phase 2 and phase 3 randomized controlled trials in rheumatology. Nat. Med. 26, 974–980 (2020).
The EULAR 2023 recommendations for the management of systemic lupus erythematosus (SLE) outline a number of principles and approaches, most of which are based on high-level evidence [1]. Indeed, numerous studies, meta-analyses and double-blind randomized controlled trials have been conducted in recent years, leading to the approval or consolidation of the use of new molecules in SLE. The expansion of the therapeutic armamentarium represents an important development for patients, with the constant aim of limiting the morbidity and mortality of SLE. This is particularly true for lupus nephritis, for which clinical trials and therapeutic innovations over the last 20 years have led to a marked improvement in prognosis.
However, this progress needs to be tempered in certain populations where the risk of developing more severe kidney disease with poorer prognosis has long been known but still persists, and it is time to focus on these high-risk profiles. The most vulnerable population are individuals of African descent, who have the highest risk profile and the poorest long-term prognosis [2]. While socioeconomic factors and access to treatment are key determinants, other elements need to be explored to explain this risk profile. In a cohort of African-Europeans with similar access to care, long-term renal survival was significantly lower than in Caucasian patients [3]. One of the factors associated with this poor renal prognosis was the higher frequency of relapses in th...
The EULAR 2023 recommendations for the management of systemic lupus erythematosus (SLE) outline a number of principles and approaches, most of which are based on high-level evidence [1]. Indeed, numerous studies, meta-analyses and double-blind randomized controlled trials have been conducted in recent years, leading to the approval or consolidation of the use of new molecules in SLE. The expansion of the therapeutic armamentarium represents an important development for patients, with the constant aim of limiting the morbidity and mortality of SLE. This is particularly true for lupus nephritis, for which clinical trials and therapeutic innovations over the last 20 years have led to a marked improvement in prognosis.
However, this progress needs to be tempered in certain populations where the risk of developing more severe kidney disease with poorer prognosis has long been known but still persists, and it is time to focus on these high-risk profiles. The most vulnerable population are individuals of African descent, who have the highest risk profile and the poorest long-term prognosis [2]. While socioeconomic factors and access to treatment are key determinants, other elements need to be explored to explain this risk profile. In a cohort of African-Europeans with similar access to care, long-term renal survival was significantly lower than in Caucasian patients [3]. One of the factors associated with this poor renal prognosis was the higher frequency of relapses in this population, raising the question of their sustained response to immunosuppressive therapy [3].
In fact, there is no data in the literature to support superiority between drugs in individuals of African descent. The EUROLUPUS study included a very small number of patients of African descent, and the ALMS study, although including the largest number of patients of this ethnicity (46/370; 12.4%), does not allow to draw any conclusions about the superiority of mycophenolate over cyclophosphamide [4]. Although numerically superior, the difference in response rates was not statistically significant in the post hoc analysis (OR 1.8 95%CI [0.5 to 5.7], p=0.39) [5]. Here, one could argue that lack of power explains the lack of statistical significance, but is actually consistent with the need of special focus and increased inclusion in randomized clinical trials (RCTs) of these high-risk profile patients.
Furthermore, lessons can be learned from RCTs with the recent example of belimumab, which failed to reach statistical significance on its primary endpoint in a trial specifically designed to assess its efficacy in African-Americans patients with SLE [6]. Some preliminary data have suggested ethnic differences in B Lymphocyte Stimulator levels, which may require adaptation of the treatment regimen in people of African descent [7]. Similarly, other preclinical data suggest ethnic differences in SLE pathways that may explain differences in treatment response and potentially highlight future therapeutic targets [7–9]. The prevalence and impact of high-risk apolipoprotein 1 (ApoL1) gene variants in this population, while important, should not be seen as a dead end [10], as renal inflammation can respond to immunosuppressive therapies, even among patients with these specific genetic background.
Taken together, it is unlikely that increased enrollment of individuals of African descent in RCTs will be sufficient on its own until the potential molecular mechanisms behind the differences and excess risk in these populations are thoroughly investigated and elucidated. Given the worst outcomes of SLE and lupus nephritis among African descents, it's a safe bet that efforts to elucidate the pathophysiology of high-risk profiles will not be in vain and that the resulting therapeutic innovations will benefit to all patients, regardless of their ancestry.
References
1 Fanouriakis A, Kostopoulou M, Andersen J, et al. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann Rheum Dis. 2023;ard-2023-224762.
2 Farinha F, Pepper RJ, Oliveira DG, et al. Outcomes of membranous and proliferative lupus nephritis – analysis of a single-centre cohort with more than 30 years of follow-up. Rheumatology. 2020;59:3314–23.
3 Enfrein A, Pirson V, Le Guern V, et al. Worse long-term renal outcome of lupus nephritis patients of African descent living in Europe. RMD Open. 2022;8:e002386.
4 Appel GB, Contreras G, Dooley MA, et al. Mycophenolate versus Cyclophosphamide for Induction Treatment of Lupus Nephritis. J Am Soc Nephrol. 2009;20:1103–12.
5 Isenberg D, Appel GB, Contreras G, et al. Influence of race/ethnicity on response to lupus nephritis treatment: the ALMS study. Rheumatology. 2010;49:128–40.
6 Ginzler E, Guedes Barbosa LS, D’Cruz D, et al. Phase III/IV, Randomized, Fifty-Two-Week Study of the Efficacy and Safety of Belimumab in Patients of Black African Ancestry With Systemic Lupus Erythematosus. Arthritis Rheumatol. 2022;74:112–23.
7 Ritterhouse LL, Crowe SR, Niewold TB, et al. B lymphocyte stimulator levels in systemic lupus erythematosus: Higher circulating levels in African American patients and increased production after influenza vaccination in patients with low baseline levels. Arthritis Rheum. 2011;63:3931–41.
8 Allen PC, Roberts K, Rubio JE, et al. Genome-wide DNA methylation analysis implicates enrichment of interferon pathway in African American patients with Systemic Lupus Erythematosus and European Americans with lupus nephritis. J Autoimmun. 2023;139:103089.
9 Slight-Webb S, Thomas K, Smith M, et al. Ancestry-based differences in the immune phenotype are associated with lupus activity. JCI Insight. 2023;8:e169584.
10 Freedman BI, Langefeld CD, Andringa KK, et al. End-Stage Renal Disease in African Americans With Lupus Nephritis Is Associated With APOL1: APOL1 in Lupus Nephritis ESRD. Arthritis Rheumatol. 2014;66:390–6.
We read with interest Dr Pisetsky’s review of the role of autoantibodies in rheumatic diseases in which he states ‘neither the amount nor specificity of ACPAs appears to demarcate a transition from arthralgia to arthritis. Similarly, ACPA responses appear stable with remission and persist despite decreases in synovitis’ [1]. While we appreciate Dr. Pisetsky’s review is restricted to papers published in ARD, we do believe there is evidence to suggest the contrary view.
It is well established that the presence of circulating ACPA confers a greater risk of RA development and furthermore, that ACPA seropositive RA subjects have a more aggressive disease course with an increased risk of joint damage as detected by radiographic erosions [2]. The duration in which ACPA and rheumatoid factor (RF) are detectable before clinically apparent or classifiable RA develops varies greatly, and there is some evidence that this relates to age, with younger individuals having a shorter duration of seropositivity before development of RA when compared to older individuals [3]. It has been suggested that less than 50% of seropositive individuals will develop RA in a median follow-up time of 28 months, but this duration of follow up appears too short to accurately define the risk conferred by seropositivity [4].
ACPA titres may rise over time and higher titres are associated with development of clinically suspect arthralgia (CSA) before frank RA [5]. ACPA-positive individuals wi...
We read with interest Dr Pisetsky’s review of the role of autoantibodies in rheumatic diseases in which he states ‘neither the amount nor specificity of ACPAs appears to demarcate a transition from arthralgia to arthritis. Similarly, ACPA responses appear stable with remission and persist despite decreases in synovitis’ [1]. While we appreciate Dr. Pisetsky’s review is restricted to papers published in ARD, we do believe there is evidence to suggest the contrary view.
It is well established that the presence of circulating ACPA confers a greater risk of RA development and furthermore, that ACPA seropositive RA subjects have a more aggressive disease course with an increased risk of joint damage as detected by radiographic erosions [2]. The duration in which ACPA and rheumatoid factor (RF) are detectable before clinically apparent or classifiable RA develops varies greatly, and there is some evidence that this relates to age, with younger individuals having a shorter duration of seropositivity before development of RA when compared to older individuals [3]. It has been suggested that less than 50% of seropositive individuals will develop RA in a median follow-up time of 28 months, but this duration of follow up appears too short to accurately define the risk conferred by seropositivity [4].
ACPA titres may rise over time and higher titres are associated with development of clinically suspect arthralgia (CSA) before frank RA [5]. ACPA-positive individuals with CSA have a tendency to higher ACPA and rheumatoid factor (RF) titres compared to lower risk arthralgia patients [6]. Higher titres imply recognition of more citrullinated epitopes recognised by several immunoglobulin subtypes including IgG, IgM, IgA and IgE. The increase in ACPA subtypes have been shown to correlate with an increase in cytokine levels such as TNF-, IL-6, IL-12 and interferon- [7,8]. It appears that maturation of this response occurs prior to the conversion of CSA to RA. Several studies have observed that higher ACPA titres in CSA are associated with development of RA [4,9]. Our group has shown that seropositive arthralgia patients at risk for developing RA had greater than 50% macroscopic synovitis or vascularity scores at knee arthroscopy and that an ACPA titre of >340IU (the upper limit of sensitivity at our laboratory), was associated with progression to RA [10].
Another clinical area where ACPA and RF titres are relevant in RA is when selecting a therapeutic agent. Seropositive patients are more likely to respond to abatacept and rituximab [7,11–14]. Those with higher ACPA titres had a better clinical response to abatacept compared to adalimumab in the AMPLE trial [7]. Significant reductions in both ACPA and RF titres have been observed in RA patients after 3 months on abatacept and the reduction in ACPA has been shown to be an independent predictor of abatacept persistence at 12 months, possibly attributable to sustained therapeutic response [11]. B-cell depletion with rituximab has also been shown to reduce ACPA levels and improve disease activity in RA [15]. However, not all seropositive patients respond to these agents, constituting a significant unmet need
Despite the work to date, it is clear that further large prospective studies are needed to improve risk prediction models in the pre-clinical RA phase to allow for better identification of these individuals “at risk” and to develop new preventative strategies, as well as more and improved treatment options.
References
1 Pisetsky DS. Annals of the Rheumatic Diseases collection on autoantibodies in the rheumatic diseases: new insights into pathogenesis and the development of novel biomarkers. Ann Rheum Dis. 2023;82:1243–7.
2 Van Der Woude D, Syversen SW, Van Der Voort EIH, et al. The ACPA isotype profile reflects long-term radiographic progression in rheumatoid arthritis. Ann Rheum Dis. 2010;69:1110–6.
3 Majka DS, Deane KD, Parrish LA, et al. Duration of preclinical rheumatoid arthritis-related autoantibody positivity increases in subjects with older age at time of disease diagnosis. Annals of the Rheumatic Diseases. 2008;67:801–7.
4 Bos WH, Wolbink GJ, Boers M, et al. Arthritis development in patients with arthralgia is strongly associated with anti-citrullinated protein antibody status: a prospective cohort study. Ann Rheum Dis. 2010;69:490–4.
5 Nielen MMJ, Van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: A study of serial measurements in blood donors. Arthritis & Rheumatism. 2004;50:380–6.
6 Westra J, Brouwer E, Raveling-Eelsing E, et al. Arthritis autoantibodies in individuals without rheumatoid arthritis: follow-up data from a Dutch population-based cohort (Lifelines). Rheumatology. 2021;60:658–66.
7 Sokolove J, Schiff M, Fleischmann R, et al. Impact of baseline anti-cyclic citrullinated peptide-2 antibody concentration on efficacy outcomes following treatment with subcutaneous abatacept or adalimumab: 2-year results from the AMPLE trial. Ann Rheum Dis. 2016;75:709–14.
8 Suwannalai P, Van De Stadt LA, Radner H, et al. Avidity maturation of anti-citrullinated protein antibodies in rheumatoid arthritis. Arthritis & Rheumatism. 2012;64:1323–8.
9 Van De Stadt LA, Van Der Horst AR, De Koning MHMT, et al. The extent of the anti-citrullinated protein antibody repertoire is associated with arthritis development in patients with seropositive arthralgia. Annals of the Rheumatic Diseases. 2011;70:128–33.
10 Gorman A, Flynn K, Turk M, et al. Predicting Progression to RA in Patients with Seropositive Arthralgia. Arthritis Rheumatol. 2021;73.
11 Endo Y, Koga T, Kawashiri S-Y, et al. Anti-citrullinated protein antibody titre as a predictor of abatacept treatment persistence in patients with rheumatoid arthritis: a prospective cohort study in Japan. Scandinavian Journal of Rheumatology. 2020;49:13–7.
12 Sellam J, Hendel-Chavez H, Rouanet S, et al. B cell activation biomarkers as predictive factors for the response to rituximab in rheumatoid arthritis: A six-month, national, multicenter, open-label study. Arthritis & Rheumatism. 2011;63:933–8.
13 Chatzidionysiou K, Lie E, Nasonov E, et al. Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries. Annals of the Rheumatic Diseases. 2011;70:1575–80.
14 Isaacs JD, Cohen SB, Emery P, et al. Effect of baseline rheumatoid factor and anticitrullinated peptide antibody serotype on rituximab clinical response: a meta-analysis. Ann Rheum Dis. 2013;72:329–36.
15 Teng YO, Wheater G, Hogan VE, et al. Induction of long-term B-cell depletion in refractory rheumatoid arthritis patients preferentially affects autoreactive more than protective humoral immunity. Arthritis Res Ther. 2012;14:R57.
We have carefully reviewed the study by Mark D. Russell et al., titled "JAK Inhibitors and the Risk of Malignancy: A Meta-Analysis Across Disease Indications."[1].This meta-analysis, which compares JAK inhibitors with methotrexate, placebo, and TNF inhibitors (TNFi), suggests a heightened risk of tumors associated with JAK inhibitors. We commend the authors for their work and would like to offer several observations.
Firstly, the study indicates a higher tumor risk with JAK inhibitors compared to
TNFi. However, considering methotrexate's known anti-tumor properties[2], and the
lack of significant difference in tumor risk between methotrexate and JAK inhibitors
observed in this study, it raises a question: Is the tumor risk associated with JAK
inhibitors comparable to that of methotrexate? Additionally, the study does not
compare the tumor risk between methotrexate and TNFi, which could have provided a
clearer perspective on the relative risk associated with JAK inhibitors.
Secondly, the study's scope in terms of types of tumors and risk factors[3], such
as smoking, BMI, and alcohol consumption, appears limited. Including more
comprehensive baseline information could enhance the study's persuasiveness. Thirdly, as meta-analyses typically involve subgroup analyses based on factors
like age, gender, and disease type to address heterogeneity, the absence of such
analyses in this st...
We have carefully reviewed the study by Mark D. Russell et al., titled "JAK Inhibitors and the Risk of Malignancy: A Meta-Analysis Across Disease Indications."[1].This meta-analysis, which compares JAK inhibitors with methotrexate, placebo, and TNF inhibitors (TNFi), suggests a heightened risk of tumors associated with JAK inhibitors. We commend the authors for their work and would like to offer several observations.
Firstly, the study indicates a higher tumor risk with JAK inhibitors compared to
TNFi. However, considering methotrexate's known anti-tumor properties[2], and the
lack of significant difference in tumor risk between methotrexate and JAK inhibitors
observed in this study, it raises a question: Is the tumor risk associated with JAK
inhibitors comparable to that of methotrexate? Additionally, the study does not
compare the tumor risk between methotrexate and TNFi, which could have provided a
clearer perspective on the relative risk associated with JAK inhibitors.
Secondly, the study's scope in terms of types of tumors and risk factors[3], such
as smoking, BMI, and alcohol consumption, appears limited. Including more
comprehensive baseline information could enhance the study's persuasiveness. Thirdly, as meta-analyses typically involve subgroup analyses based on factors
like age, gender, and disease type to address heterogeneity, the absence of such
analyses in this study is notable. We suggest that further subgroup analysis could
strengthen the study's conclusions.
This article highlights the use of methotrexate, TNFi, and JAK inhibitors in
treating rheumatoid arthritis (RA) and discusses the evolving role of JAK inhibitors in
RA treatment[4]. Recent studies, including this one, suggest an increased tumor risk
associated with JAK inhibitors, warranting caution among rheumatologists[5].
In summary, while this meta-analysis underscores a potential increased tumor
risk with JAK inhibitors, the limited number and scope of studies due to the relatively
recent introduction of these drugs suggest that these findings are preliminary. We
appreciate the authors' efforts in highlighting these risks, which serve as an important
caution for clinicians.
References:
[1] Russell MD, Stovin C, Alveyn E, et al. JAK inhibitors and the risk of malignancy: a
meta-analysis across disease indications. Ann Rheum Dis. 2023;82(8):1059-1067. [2] Mishra P, Ali Ahmad MF, Al-Keridis LA, et al. Methotrexate-conjugated zinc oxide
nanoparticles exert a substantially improved cytotoxic effect on lung cancer cells by inducing
apoptosis. Front Pharmacol. 2023;14:1194578. [3] Crepeau PK, Sutton W, Sahli Z, et al. Prevalence and risk factors for dysphagia in older adults
after thyroid and parathyroid surgery. Surgery. 2023. [4] Harrington R, Al Nokhatha SA, Conway R. JAK inhibitors in rheumatoid arthritis: an
evidence-based review on the emerging clinical data. J Inflamm Res. 2020;14(13):519-531. [5] Yoshida S, Miyata M, Suzuki E, et al. Safety of JAK and IL-6 inhibitors in patients with
rheumatoid arthritis: a multicenter cohort study. Front Immunol. 2023;14:1267749.
Dear editorial team,
I recently had the opportunity to read the article titled "Disease activity drives transcriptomic heterogeneity in early untreated rheumatoid synovitis," and I wanted to express my appreciation for the insightful research you and your team have conducted in the field of rheumatoid arthritis (RA). Your study utilized RNASeq to analyze synovial tissue samples from patients with early, untreated RA, and I was particularly intrigued by your use of unbiased, data-driven approaches to identify clinically relevant subgroups. The application of principal components analysis (PCA) and unsupervised clustering to define patient clusters based on the expression of the most variable genes provided valuable insights into the disease's heterogeneity.
The identification of two patient clusters, PtC1 and PtC2, based on the expression of key genes associated with disease activity was a significant finding. The differentiation of these clusters in terms of disease activity and the probability of response to methotrexate therapy sheds light on the potential clinical implications of transcriptomic profiles. The observed upregulation of immune system genes in PtC1 and lipid metabolism genes in PtC2 provides important clues into the underlying pathophysiology of these subgroups. Additionally, I found your investigation of M2-like and M1-like macrophage ratios in relation to disease activity and synovial inflammation to be especially intriguing. The...
Dear editorial team,
I recently had the opportunity to read the article titled "Disease activity drives transcriptomic heterogeneity in early untreated rheumatoid synovitis," and I wanted to express my appreciation for the insightful research you and your team have conducted in the field of rheumatoid arthritis (RA). Your study utilized RNASeq to analyze synovial tissue samples from patients with early, untreated RA, and I was particularly intrigued by your use of unbiased, data-driven approaches to identify clinically relevant subgroups. The application of principal components analysis (PCA) and unsupervised clustering to define patient clusters based on the expression of the most variable genes provided valuable insights into the disease's heterogeneity.
The identification of two patient clusters, PtC1 and PtC2, based on the expression of key genes associated with disease activity was a significant finding. The differentiation of these clusters in terms of disease activity and the probability of response to methotrexate therapy sheds light on the potential clinical implications of transcriptomic profiles. The observed upregulation of immune system genes in PtC1 and lipid metabolism genes in PtC2 provides important clues into the underlying pathophysiology of these subgroups. Additionally, I found your investigation of M2-like and M1-like macrophage ratios in relation to disease activity and synovial inflammation to be especially intriguing. The inverse correlation between M2:M1 macrophage ratios and disease activity scores suggests a potential protective role for tissue-resident macrophages in RA. This could have profound implications for understanding disease progression and identifying novel therapeutic targets.
However, I acknowledge the limitations you discussed in your study. The observational nature of the cohort and the lack of controlled steroid treatment may introduce confounding factors that could be addressed in a controlled, prospective setting. Moreover, your suggestion of longer-term follow-up and repeat biopsies to validate the clinical relevance of your findings seems promising and may offer deeper insights into the disease's dynamics.
I appreciate your transparency in discussing the limitations, especially regarding intra-joint heterogeneity. I agree that spatial single-cell transcriptomic profiling could provide a powerful perspective in examining the subphenotypes of synovial tissue macrophages and their interactions with synoviocytes. However, there are some other issues with the methodologies of the study that I would like to mention. The number of patients included in this study was low and the authors did not justify why they conducted their study with lower than what actually needed for robust statistical analyses. The relatively low number of patients included and the absence of justification for the sample size might raise questions about the robustness of the statistical analyses.
Besides, the authors did not give any information regarding the recruitment of the patient; therefore, the timespan of patient selection, the setting of recruitment, and the method of sampling are not clear in this study. The lack of these details could limit the study's reproducibility and comparability.
Overall, your research contributes significantly to our understanding of early, untreated RA and highlights the importance of transcriptomic heterogeneity in disease activity and treatment response. The findings of your study hold great potential to impact the management and therapeutic approaches for RA patients.
Once again, thank you for your invaluable contribution to the field of rheumatoid arthritis research. I look forward to witnessing how your work progresses in the future and how it will potentially shape clinical practice and patient outcomes.
We read the “Treat-to-target recommendations in giant cell arteritis and polymyalgia rheumatica” with great interest [1], as it provides a much-needed and updated approach to the management of polymyalgia rheumatica (PMR), a relatively common condition with significant disease burden. As indicated by the Research Agenda listed in the paper, there remains much to be learned about the clinical management of PMR. Specifically, we would like to emphasize the gaps in research regarding the physiological and clinical nuances in optimizing corticosteroid (CS) tapering.
By adapting a T2T approach, clinicians can strive towards the ideal goal of minimizing both symptom flare-ups and cumulative steroid exposure, with significant risk due to steroid usage. As this provides a qualitative guideline, the challenge is to determine an optimal tapering rate. Steroid tapering for PMR has often been recognized as an “art” that can be unpredictable and rarely has a smooth trajectory. A meta-analysis showed that the pooled relapse rate at 1 year from treatment initiation was 43% [2].
Our interest in these unanswered questions came from the personal case study of W.D. (a retired physician) who documented his tapering process. He was treated for a total of almost three years with four flares of PMR, with multiple flares in the third and fourth episodes, and the addition of methotrexate, ultimately resulting in a cumulative total of 9,130 mg of prednisone. This prompted our explorat...
Show MoreDear Editor,
I read the individual patient data metaanalysis by van Ouwerkerk et al [1] on the comparison of long term glucocorticoid use in initial glucocorticoid bridgers and non-bridgers with interest. Other than inevitable limitations such as the absence of randomised trials with low-dose glucocorticoid bridging, per protocol duration and tapering of the bridging glucocorticoid doses, and heterogeneity of disease severity and disease-modifying anti-rheumatic drug (DMARD) use in the comparator arms, which were discussed by the authors, I believe this study had an important and unmentioned limitation on its main conclusion: the similarity of late glucocorticoid use after bridging was completed in bridgers and non-bridgers.
The authors argued that after a planned ending of the bridging period, glucocorticoid use was higher in the initial bridgers compared to non-bridgers only 12 months after randomisation and no longer significantly higher at 18 and 24 months. The pooled frequency of glucocorticoid use in bridgers vs. non-bridgers were 21% vs. 6% corresponding to an OR of 3.27 (1.06-10.08) [1]. The frequencies were not reported but represented in a figure for the months 18 and 24. The reported ORs were 1.6 (0.46-5.6) and 1.7 (0.58-4.97) for the months 18 and 24. The risk ratios, which looked like at least 1.5 if not more particularly for the month 24 according to the figure, were not found to be significant. However, to be able to confidently (such as with 8...
Show MoreCorrespondence on “EULAR recommendations for the management of systemic lupus erythematosus: 2023 update” by “Fanouriakis A, et al”
I read the recently updated EULAR recommendations for the management of systemic lupus erythematosus (SLE) with great interest.[1] In recommendation 8, voclosporine was categorized alongside belimumab and tacrolimus. However, I am concerned about recommending voclosporine as an initial induction therapy for active lupus nephritis (LN).
Show MoreThe effectiveness of voclosporine, when added to a rapid-reduction glucocorticoid regimen and mycophenolate (MMF, typically administered at 2 g/day), has been demonstrated to be superior to placebo.[2] However, it is important to note that this study significantly deviated from the trials involving belimumab or tacrolimus[3, 4] as it included a large number of patients who were refractory to MMF. This indicates that 55% of the participants while taking MMF, met one of the inclusion criteria: a current urine protein creatinine ratio (UPCR) of ≥1·5. These individuals were then randomised to either the placebo or voclosporine group. Patients with these specific characteristics, if placed in the placebo group, would have been reintroduced to MMF, despite its previous ineffectiveness in addressing their lupus nephritis. Therefore, the treatment effect in the placebo group was assumed to be considerably lower. As expected, the efficacy of incorporating voclosporine was observed solely in the patient group...
Dear Editor,
The 2023 update of the EULAR recommendations for the management of systemic lupus erythematosus (SLE) recommend hydroxychloroquine (HCQ) for all patients with SLE at a target dose of 5 mg/kg real body weight (RBW)/day but also suggest individualizing the regimen in accordance with the risk of flares or retinal toxicity. The updated recommendations also emphasize the importance of non-pharmacological interventions, including the cessation of smoking, which may interfere with the efficacy of antimalarial agents, as seen in patients with cutaneous lupus erythematosus (CLE). 1 However, the evidence on the efficacy of the target dose of 5 mg/kg(RBW)/day and the effect of smoking on SLE is scarce.
In Japan, HCQ was approved in 2015 after a double-blind randomized clinical trial demonstrated a favorable effect on CLE. The approved dosage was based on 6.5 mg/kg of ideal body weight (IBW), namely, 200 mg/day for IBW ˂46 kg; 200 mg and 400 mg on alternating days for IBW ≥ 46 kg and ˂ 62 kg; and 400 mg/day for IBW ≥62 kg. The steady-state maximum whole blood HCQ level (ng/ml) at these dosages were simulated with 630.3±220.4, 942.7±191.2 and 850.3±174.5, respectively.23 Thereafter, a multicentric, prospective study evaluating the effect of HCQ on SLE and CLE in the real world setting was conducted for post-marketing surveillance in accordance with the Good Post-Marketing Study ordinance of the Ministry of Health, Labour and Welfare of Japan. 4
The ob...
Show MoreWe are thrilled and grateful to see an update of the systemic lupus erythematosus (SLE) treatment recommendations after 4 years’ time since 2019. Because of the efforts of a Task Force of world-leading SLE experts, we are now able to follow these useful recommendations in daily clinical practice. In this version, several new ideas to treat SLE come into view. We are now entering the era of biologics, with more on the way, which might significantly change the way we treat SLE. Apart from rituximab, belimumab, and anifrolumab, there is another B cell related biologic, telitacicept, a BLyS/APRIL dual inhibitor, with a successful phase II trial1; larger confirmatory trials are currently underway. As recommended in the version, early diagnosis and treatment are emphasized. The biologics are used earlier than before, not requiring conventional immunosuppresants first; this change is a bit step forward, indicating that early intervention is important.
The treatment of SLE is like walking on a blade. Balancing the benefits and harms is an art, for which the use of glucocorticoids (GC) is a typical example. I totally agree that the use of GC is only for ‘bridging therapy’ in SLE. But we can expect that, different from the treatment of rheumatoid arthritis (RA), the taper of GC in SLE is not as easy as in RA and the duration will be longer. In this recommendation, it is clearly stated that GC should be taped gradually. However, in terms of the cessation of GC, it is not clear...
Show MoreWith great interest, we have read the recent article by Konzett et al1 on determination of the most powerful American College of Rheumatology (ACR) response definition (ACR20, 50 or 70) between active treatment and placebo in RA trials. In this well-designed study, the authors systematically analyzed the time courses of ACR20, 50 and 70 responses from randomized, double-blind, placebo-controlled, phase II and phase III RA drug approval trials. The conclusion was ACR20 remains the most sensitive discriminator at early time points in the novel therapeutics (bDMARDs and tsDMARDs) placebo-controlled RA trials.
However, the placebo response seems ignored in the comparison of response trajectories of ACR20, 50 and 70. First, we noticed that the authors showed longitudinal dynamics of different ACR response rates and concluded ACR20 response provided highly sensitive to early treatment effect (Figure 2)1. The “treatment effect” in this case should be the relative effect of treatment compared with placebo ( treatment response - placebo response)2, however, it appears that the mean normalized ACR response rates in Figure 2 relies solely on data from the treatment group, without factoring in the placebo group. The placebo response rate in RA clinical trials has significantly increased in the era of bDMARDs/tsDMARDs3, which has also been confirmed in the supplementary material section 8.21. A substantial placebo response can hinder the ability to discern treatment effects4. Th...
Show MoreThe EULAR 2023 recommendations for the management of systemic lupus erythematosus (SLE) outline a number of principles and approaches, most of which are based on high-level evidence [1]. Indeed, numerous studies, meta-analyses and double-blind randomized controlled trials have been conducted in recent years, leading to the approval or consolidation of the use of new molecules in SLE. The expansion of the therapeutic armamentarium represents an important development for patients, with the constant aim of limiting the morbidity and mortality of SLE. This is particularly true for lupus nephritis, for which clinical trials and therapeutic innovations over the last 20 years have led to a marked improvement in prognosis.
However, this progress needs to be tempered in certain populations where the risk of developing more severe kidney disease with poorer prognosis has long been known but still persists, and it is time to focus on these high-risk profiles. The most vulnerable population are individuals of African descent, who have the highest risk profile and the poorest long-term prognosis [2]. While socioeconomic factors and access to treatment are key determinants, other elements need to be explored to explain this risk profile. In a cohort of African-Europeans with similar access to care, long-term renal survival was significantly lower than in Caucasian patients [3]. One of the factors associated with this poor renal prognosis was the higher frequency of relapses in th...
Show MoreWe read with interest Dr Pisetsky’s review of the role of autoantibodies in rheumatic diseases in which he states ‘neither the amount nor specificity of ACPAs appears to demarcate a transition from arthralgia to arthritis. Similarly, ACPA responses appear stable with remission and persist despite decreases in synovitis’ [1]. While we appreciate Dr. Pisetsky’s review is restricted to papers published in ARD, we do believe there is evidence to suggest the contrary view.
It is well established that the presence of circulating ACPA confers a greater risk of RA development and furthermore, that ACPA seropositive RA subjects have a more aggressive disease course with an increased risk of joint damage as detected by radiographic erosions [2]. The duration in which ACPA and rheumatoid factor (RF) are detectable before clinically apparent or classifiable RA develops varies greatly, and there is some evidence that this relates to age, with younger individuals having a shorter duration of seropositivity before development of RA when compared to older individuals [3]. It has been suggested that less than 50% of seropositive individuals will develop RA in a median follow-up time of 28 months, but this duration of follow up appears too short to accurately define the risk conferred by seropositivity [4].
ACPA titres may rise over time and higher titres are associated with development of clinically suspect arthralgia (CSA) before frank RA [5]. ACPA-positive individuals wi...
Show MoreWe have carefully reviewed the study by Mark D. Russell et al., titled "JAK Inhibitors and the Risk of Malignancy: A Meta-Analysis Across Disease Indications."[1].This meta-analysis, which compares JAK inhibitors with methotrexate, placebo, and TNF inhibitors (TNFi), suggests a heightened risk of tumors associated with JAK inhibitors. We commend the authors for their work and would like to offer several observations.
Show MoreFirstly, the study indicates a higher tumor risk with JAK inhibitors compared to
TNFi. However, considering methotrexate's known anti-tumor properties[2], and the
lack of significant difference in tumor risk between methotrexate and JAK inhibitors
observed in this study, it raises a question: Is the tumor risk associated with JAK
inhibitors comparable to that of methotrexate? Additionally, the study does not
compare the tumor risk between methotrexate and TNFi, which could have provided a
clearer perspective on the relative risk associated with JAK inhibitors.
Secondly, the study's scope in terms of types of tumors and risk factors[3], such
as smoking, BMI, and alcohol consumption, appears limited. Including more
comprehensive baseline information could enhance the study's persuasiveness. Thirdly, as meta-analyses typically involve subgroup analyses based on factors
like age, gender, and disease type to address heterogeneity, the absence of such
analyses in this st...
Dear editorial team,
Show MoreI recently had the opportunity to read the article titled "Disease activity drives transcriptomic heterogeneity in early untreated rheumatoid synovitis," and I wanted to express my appreciation for the insightful research you and your team have conducted in the field of rheumatoid arthritis (RA). Your study utilized RNASeq to analyze synovial tissue samples from patients with early, untreated RA, and I was particularly intrigued by your use of unbiased, data-driven approaches to identify clinically relevant subgroups. The application of principal components analysis (PCA) and unsupervised clustering to define patient clusters based on the expression of the most variable genes provided valuable insights into the disease's heterogeneity.
The identification of two patient clusters, PtC1 and PtC2, based on the expression of key genes associated with disease activity was a significant finding. The differentiation of these clusters in terms of disease activity and the probability of response to methotrexate therapy sheds light on the potential clinical implications of transcriptomic profiles. The observed upregulation of immune system genes in PtC1 and lipid metabolism genes in PtC2 provides important clues into the underlying pathophysiology of these subgroups. Additionally, I found your investigation of M2-like and M1-like macrophage ratios in relation to disease activity and synovial inflammation to be especially intriguing. The...
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