The MIRACLE study authors provide a very informative description that adds to the knowledgebase around the developing clinical value of assessing methotrexate polyglutamate (MTX-PG) RBC concentrations in patients with rheumatoid arthritis. While the authors estimate kidney function and report as eGFR in standardized units (mL/min/1.73 m2), they fail to clearly note or reference the specific formula employed. This is an unfortunate omission given the very recent changes and updates to these various estimation formula that removed race factors and re-fitted original data to derive new, less biased relationships.(1) It would be helpful for readers to know the specific formula employed in this MIRACLE study report given the multitude of available formula, ex MDRD eGFR, CKD-EPI 2009, CKD-EPI 2021 (creatinine), etc.

Finally, given that the authors report significant impact of kidney function on MTX-PG disposition, I recommend a more comprehensive assessment of the eGFR - MTX-PG relationship. The study participant demographics suggests that the mean body surface area (BSA) may be less than the standardized BSA (1.73m2) in the reported eGFR variable. If possible, the authors should calculate individual study participant BSA, using any of several BSA formula; Du Bois & Du Bois, or population specific methods such as Fujimoto et al or Takahira.(2) Each subject standardized eGFR can then be adjusted to reflect individual subject BSA. Standardized eGFR is multiplied by the ratio of subject BAS over Standard BSA. This adjustment will yield a subject-specific/individualized eGFR in units of mL/min. Recent human drug disposition research indicates that individualized BSA-adjusted eGFR is more predictive of renal drug clearance.(3,4) The MIRACLE authors may observe an even stronger relationship between eGFR and MTX-PG disposition.

1) L.A. Inker, N.D. Eneanya, J. Coresh, et al. New Creatinine- and Cystatin C–Based Equations to Estimate GFR without Race. N Engl J Med 2021;385:1737-49.
2) G. Redlarski, S. Koziel, M. Krawczuk, et al. An Improvement of Body Surface Area Formulas Using The 3D Scanning Technique. Int. J. Occup. Med. Environ. Health 2024;37(2):205-219.
3) MP Pai, S Sitaruno, M Abdelnabi. Removing race and body surface area indexation for estimated kidney function based drug dosing: Aminoglycosides as justification of these principles. Pharmacotherapy. 2023;43(1):35-42.
4) HG Yun, AJF Smith, KC DeBacker, et al. Estimated glomerular filtration rate with and without race for drug dosing: Cystatin C vs. serum creatinine. Br J Clin Pharmacol. 2023;89(3):1207-1210.

Dear Editor,
I thoroughly enjoyed reading the EULAR and PReS recommendations on the diagnosis and management of Still’s disease, authored by Fautrel et al., as a result of the joint efforts of these two communities (1). I congratulate the task force on their work on behalf of all physicians.
However, I would like to highlight some points that need further clarification and share my concerns.
1- As is well known, Still’s disease has various clinical courses: monocyclic, polycyclic, and chronic articular (2). The disease progression, outcomes, and treatment needs of these patients can differ. In addition to this classification, there are forms where systemic inflammation predominates, usually accompanied by macrophage activation syndrome, and forms characterized by chronic arthritis. Including these differences in the recommendations and shaping treatment suggestions accordingly would be more clinically beneficial.
2- In the proposed treatment algorithm and its explanation, it is recommended to initiate treatments targeting interleukin-1 or interleukin-6 regardless of the disease activity. The rationale given is that although there are small randomized controlled trials on therapies targeting interleukin-1 or interleukin-6, accumulated real-world data support the effectiveness of these agents. On the other hand, there is limited data regarding conventional DMARDs, and a randomized controlled trial in systemic JIA patients suggested that methotrexate was not superior to placebo. In this ranking, the long-standing use of conventional DMARDs, especially methotrexate, and the fact that clinicians who manage this patient group effectively and safely use these agents in clinical practice, have been overlooked, which may lead to various problems. One of the largest series on the use of conventional DMARDs in the treatment of Still’s disease was published by Kalyoncu et al., where 254 out of 306 patients (83%) achieved remission with corticosteroids and methotrexate ± other conventional DMARDs (3). Among 97 patients who received only corticosteroids and methotrexate, 85 (87.6%) achieved remission (3). In another recent study by Ruscitti et al., involving 171 Still’s disease patients registered in the AIDA Network Still Disease Registry, clinical remission was achieved in 38.6% of patients, regardless of whether they received a combination of any conventional or biological DMARDs (4). All these data show that conventional DMARDs, particularly methotrexate, cannot be easily excluded from the treatment process.
3- The authors mention that conventional DMARDs can be used in countries where treatments targeting interleukin-1 or interleukin-6 are not accessible. In countries where both options are available, this treatment hierarchy may lead to medicolegal problems. For instance, a patient diagnosed with Still’s disease who achieves remission with methotrexate might file a complaint with health authorities because interleukin-based therapies were not initiated.

REFERENCES
1. Fautrel B, Mitrovic S, De Matteis A, Bindoli S, Antón J, Belot A, et al. EULAR/PReS recommendations for the diagnosis and management of Still's disease, comprising systemic juvenile idiopathic arthritis and adult-onset Still's disease. Ann Rheum Dis. 2024.
2. Manger B, Rech J, Schett G. Use of methotrexate in adult-onset Still's disease. Clin Exp Rheumatol. 2010;28(5 Suppl 61):S168-71.
3. Kalyoncu U, Solmaz D, Emmungil H, Yazici A, Kasifoglu T, Kimyon G, et al. Response rate of initial conventional treatments, disease course, and related factors of patients with adult-onset Still's disease: Data from a large multicenter cohort. J Autoimmun. 2016;69:59-63.
4. Ruscitti P, Sota J, Vitale A, Lopalco G, Iannone F, Morrone M, et al. The administration of methotrexate in patients with Still's disease, "real-life" findings from AIDA Network Still Disease Registry. Semin Arthritis Rheum. 2023;62:152244.

The recently published paper by Yuan et al (1) convincingly show that NCF1 polymorphism is a major genetic cause of both diffuse cutaneous systemic sclerosis and lung fibrosis. The human association studies were confirmed in a single nucleotide polymorphism (SNP) knockin mouse. The description how the NCF1 polymorphism were discovered is however not correct. It is said that “We previously identified a hypofunctional variant (p.R90H) in neutrophil cytosolic factor 1 (NCF1), encoding a regulatory subunit of phagocyte NADPH oxidase 2 (NOX2), associated with robust risk of multiple autoimmune diseases including systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS) and rheumatoid arthritis (RA).” (2).
In fact the single nucleotide polymorphism (NCF1-339) leading to amino acid replacement of arginine to histidine at position 90 (R90H) was published by Olsson et al already 2012 (3). Importantly, this paper was built on positional cloning of NCF1 as the major underlying gene controlling autoimmune arthritis in rats (4). Based on this discovery, studies on copy number variation and sequencing of all functional exons of human NCF1 lead to identification of several SNPs leading to amino acid replacements(3). One of them was R90H, which lowered reactive oxygen species response in transfected COS cells. Based on this discovery both Olsson et al and Zhang et al independently found that the R90H variant was strongly associated with systemic lupus erythematosus (2, 5). Importantly the R90H variant is located in the same domain as the original T153M variant in rats and have similar effect on the NOX2 complex function and ROS response. In addition, the importance of R90H was later reproduced in humanised mice independently by several groups (6-9).
The discovery history is important as the NCF1 R90H variant is one of the few positionally cloned and functionally defined underlying genetic effects controlling complex disease. Importantly, the discovery was not based on genome wide association studies but on positional cloning using experimental animals and subsequently translated to humans.

1. Yuan X, Qin X, Takemoto K, Zhao J, Sanderson M, Xu X, et al. Human hypofunctional NCF1 variants promote pulmonary fibrosis in the bleomycin-induced mouse model and patients with systemic sclerosis via expansion of SPP1(+) monocytes-derived macrophages. Ann Rheum Dis. 2024.
2. Zhao J, Ma J, Deng Y, Kelly JA, Kim K, Bang SY, et al. A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases. Nat Genet. 2017;49(3):433-7.
3. Olsson LM, Nerstedt A, Lindqvist AK, Johansson AC, Medstrand P, Olofsson P, et al. Copy number variation of the gene NCF1 is associated with Rheumatoid Arthritis. Antioxid Redox Signal. 2012;16(1):71-8.
4. Olofsson P, Holmberg J, Tordsson J, Lu S, Akerstrom B, Holmdahl R. Positional identification of Ncf1 as a gene that regulates arthritis severity in rats. Nat Genet. 2003;33(1):25-32.
5. Olsson LM, Johansson AC, Gullstrand B, Jonsen A, Saevarsdottir S, Ronnblom L, et al. A single nucleotide polymorphism in the NCF1 gene leading to reduced oxidative burst is associated with systemic lupus erythematosus. Ann Rheum Dis. 2017;76(9):1607-13.
6. Geng L, Zhao J, Deng Y, Molano I, Xu X, Xu L, et al. Human SLE variant NCF1-R90H promotes kidney damage and murine lupus through enhanced Tfh2 responses induced by defective efferocytosis of macrophages. Ann Rheum Dis. 2022;81(2):255-67.
7. Meng Y, Ma J, Yao C, Ye Z, Ding H, Liu C, et al. The NCF1 variant aggravates autoimmunity by facilitating the activation of plasmacytoid dendritic cells. J Clin Invest. 2022.
8. Li Y, Li Z, Nandakumar KS, Holmdahl R. Human NCF1(90H) Variant Promotes IL-23/IL-17-Dependent Mannan-Induced Psoriasis and Psoriatic Arthritis. Antioxidants (Basel). 2023;12(7).
9. Luo H, Urbonaviciute V, Saei AA, Lyu H, Gaetani M, Vegvari A, et al. NCF1-dependent production of ROS protects against lupus by regulating plasmacytoid dendritic cell development and functions. JCI Insight. 2023;8(7).