Neutropenia and Felty Syndrome in the Twenty-First Century: Redefining Ancient Concepts in Rheumatoid Arthritis Patients

Citation: Rodas Flores, J.L.; Hernández-Cruz, B.; Sánchez-Margalet, V.; Fernández-Reboul Fernández, A.; Fernández Panadero, E.; Moral García, G.; Pérez Venegas, J.J. Neutropenia and Felty Syndrome in the Twenty-First Century: Redefining Ancient Concepts in Rheumatoid Arthritis Patients. J. Clin. Med. 2024, 13, 7677. https://doi.org/10.3390/ jcm13247677 Academic Editor: Mitsuhiro Takeno Received: 22 October 2024 Revised: 17 November 2024 Accepted: 10 December 2024 Published: 17 December 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Article Neutropenia and Felty Syndrome in the Twenty-First Century: Redefining Ancient Concepts in Rheumatoid Arthritis Patients Jorge Luis Rodas Flores 1, Blanca Hernández-Cruz 1,* , Víctor Sánchez-Margalet 2, Ana Fernández-Reboul Fernández 1, Esther Fernández Panadero 1, Gracia Moral García1 and JoséJavier Pérez Venegas 1 1Rheumatology Department, Virgen Macarena University Hospital, Health Service of Andalucian, 41009 Seville, Spain; jorgel.r[email protected] (J.L.R.F.); [email protected] (A.F.-R.F.); [email protected] (E.F.P.); [email protected] (G.M.G.); jjavier[email protected] (J.J.P.V.) 2Department of Medical Biochemistry and Molecular Biology and Immunology, School of Medicine, Virgen Macarena University Hospital, 41009 Seville, Spain; [email protected] *Correspondence: [email protected] Abstract: Objectives: To describe the frequency of neutropenia and Felty syndrome in patients with rheumatoid arthritis (RA) attended in routine clinical practice. Methods: We selected by randomization a sample of 270 RA patients attended from January 2014 to November 2022. Demographic, clinical, and neutropenia-related variables were collected from the electronic medical records. Neutropenia was defined as having an absolute neutrophil count (ANC) of less than 1500/mm 3 once, and acute if it persisted for <3 months. Felty syndrome was defined as RA-related neutropenia, rheumatoid factor (RF) and/or anti citrullinated protein antibody (ACPA) positivity. Results: We found 50 patients who had at least one neutropenia episode, with an incidence of 18.5% (14.0–25.6%). Most were women, with age (mean, p25–p75) at the time of neutropenia of 61.5 (57.4–69.3) years, 85% RF+ and 76% ACPA+. The demographic and RA characteristics of patients with and without neutropenia were very similar, except for sex: most patients with neutropenia were women. The 50 patients had 99 episodes of neutropenia; 59% were acute. The lower ANC was 1240 (1000–1395) mm 3 , and most of the episodes were mild (74%). In 32% of cases, there was other cytopenia. The RA activity measured by DAS28 in patients with neutropenia was low, at 2.18 (1.75–2.97). A total of 82 of 99 neutropenia episodes were related to DMARDs, 60% to Anti-IL6 drugs in monotherapy, 13% to RA activity, 3% to infectious diseases and 1% to hematologic malignancy. There were five (1.8%) cases with Felty syndrome, but only one woman with the classic combination of RA, positivity of autoantibodies (RF and ACPA), neutropenia and splenomegaly. Conclusions: In the 21st century, neutropenia in RA patients is most commonly related to biologics, mostly IL6 inhibitors and methotrexate. Episodes are mild, acute, with low RA activity, and associated with severe infections in few cases. Felty syndrome is rare. Keywords: rheumatoid arthritis; neutropenia; DMARDs; Felty syndrome 1. Introduction Neutropenia in patients with rheumatoid arthritis (RA) occurs in 0.5 to 37% of cases depending on several variables, mainly involving treatment with disease-modifying antirheumatic drugs (DMARDs) [ 1 – 4 ]. In patients with early untreated RA, the frequency of neutropenia is as low as 0.65–1.4% [ 3 , 4 ]. For RA patients treated with synthetic conventional DMARDs (scDMARDs), this rate is about 8% (2–12%) [ 1 ]. In those treated with biologics (bDMARDs), it is 14–19%, with higher values for IL6-inhibitors (IL6i) like tocilizumab (1–10%) and anti-CD20 drugs like rituximab (3–27%) and lower ones for tumoral necrosis factor inhibitors (TNFi) (2–3%) [ 1 , 2 ]. In those treated with Janus Kinase inhibitors (JAKi), the rate is about 5% [ 1 , 2 ]. A recent study estimated the frequency of neutropenia in early J. Clin. Med. 2024,13, 7677. https://doi.org/10.3390/jcm13247677 https://www.mdpi.com/journal/jcm J. Clin. Med. 2024,13, 7677 2 of 13 AR, finding a value of 7.5% [ 1 ]. Neutropenia increases with the combination of scDMARDs and bDMARDs, and significantly increases comorbidity and complicates the management of the disease with DMARDs within the treat-to-target strategy [ 3 , 4 ]. The most common complication of neutropenia, whatever the cause, is infection, which can be serious [ 1 – 3 ]. The risk of severe infection is greater if neutropenia is severe, if it appears quickly and with a longer duration, if it is associated with chronic foci of infections, previous infections, anemia or other cytopenia and if it occurs in the presence of certain comorbidities (chronic kidney disease, lung pathology, heart failure or chronic infections). And the risk is mainly for bacterial infections [1–3]. The etiology of neutropenia in RA patients is complex. Neutropenia can be congenital, a very rare condition that occurs with the same frequency as in individuals without RA, or acquired, which is the most common. The causes of acquired neutropenia are i. peripheral destruction by an autoimmune reaction or toxics (drugs as DMARDs or others); ii. sequestration, either splenic (hypersplenism), in reticuloendothelial tissue or excess of vascular marginalization of neutrophils; and iii. inadequate neutrophil production in hematopoietic organs due to vitamin deficiency (i.e., folic acid deficiency in patients treated with methotrexate), tumor invasion or toxicity (drugs as DMARDS or others) [1–4]. A special form of RA was described in 1924 as a combination of RA, leucopenia and splenomegaly by Augustus Felty [ 5 ]. Currently, Felty syndrome is defined as the presence of neutropenia (absolute neutrophil counts of less than 1500 × mm 3 ), splenomegaly and typical antibodies (RF and/or ACPA) in RA patients. Although it has been described in association with other autoimmune conditions as systemic lupus erythematosus; in these cases, the term autoimmune neutropenia is preferred. Its prevalence is low and decreasing: 1% in 1985 to 0.5% in the 21st century [ 6 ]. Other common signs are extra-articular RA manifestations, fever, anemia, mucosal and skin ulcers, respiratory tract infections, thrombocytopenia and lymphadenopathy. These patients have poor prognostics [5,6]. The treatment of neutropenia depends on its etiology. If related to toxics, withdrawal of the drug or toxic substance or material is recommended. In some cases, the addition of folic acid supplementation is pursued. Optimizing the treatment of RA is useful, as in Felty syndrome. Neoplasia should be looked for and treated, for example, by the screening and treatment of large granular lymphocyte leukemia. In addition, the correct prevention of infections with vaccination or antibiotic prophylaxis must be pursued in specific cases, as well as the early treatment of associated infections [1–3]. The objectives of our study were to determine the frequency of neutropenia and Felty syndrome, and to determine its clinical characteristics. 2. Materials and Methods An observational, retrospective and analytical study was designed. From a database of 858 patients with adult RA diagnosed according to ACR/EULAR criteria [ 7 ] treated in usual clinical practice in the Rheumatology Department of the Virgen Macarena University Hospital (a tertiary level hospital belonging to the Public Health System of Andalusia, in Seville, Spain) from January 2014 to November 2022, we selected a sample. The sample size was calculated based on an estimated prevalence of neutropenia of 10%, and the patients were selected by randomization with a computer program. Patients without an accurate RA diagnosis, those under 18 years of age, those with overlapping syndromes and those with other immune mediated diseases were excluded. Demographic, clinical, laboratory and neutropenia-specific data were collected from electronic medical records, with emphasis on the identification of neutropenia. Neutropenia information was cross-checked with electronic laboratory records. Data on treatment were reviewed in the electronic prescription, and its relationship with neutropenia was defined by the treating rheumatologist. Definitions: Neutropenia was when the absolute neutrophil count (ANC) was ≤ 1500/mm 3 in a determination. Mild neutropenia (grade II) was diagnosed in patients with an ANC of 1500 to 1000/mm 3 ; moderate (grade III) of 1000 to 500/mm 3 ; and severe (grade IV) < 500/mm3 . Neutropenia was considered acute if it persisted <3 months and chronic if it persisted J. Clin. Med. 2024,13, 7677 3 of 13 ≥ 3 months. Anemia was defined as having a hemoglobin level <13 g/dL (men) and <12 g/dL (women). Lymphopenia was defined as having an absolute lymphocyte count of <1000/mm 3 . Thrombocytopenia was defined as having an absolute platelet count of <140,000/mm 3 (men) and <130,000/mm 3 (women) [ 8 , 9 ]. Infection associated with the neutropenia process was that present within 3 months of the detected neutropenia episode. Felty syndrome was diagnosed if patients had rheumatoid factor positivity (RF+) and/or anti-citrullinated protein antibody positivity (ACPA+) and/or neutropenia attributed to RA activity; and classic Felty syndrome was if splenomegaly plus typical signs and symptoms were present. Statistical analysis was performed by descriptive statistics with calculation of median and percentiles 25 and 75, percentages, and 95% confidence intervals. Nonparametric tests were used to calculate p values (Xi 2 and Mann–Whitney U tests), assuming non-normal distribution of variables and unequal sample sizes. A logistic regression was performed to determinate the variables related to neutropenia. In them, the dependent variable was neutropenia, and the independent variables were those with clinical relevance and those that, in the univariate analysis, showed a pvalue ≤ 0.2. Analyses were performed using Stata version 13.1 (StataCorp LP, College Station, TX, USA). The study was approved by the regional Ethics and Clinical Research Committee of the Andalusian Health Service. 3. Results Out of a base of 858 patients with RA who attended usual clinical practice, 270 (30%) were randomly selected. The sample included 213 (79%) women. The median age (percentile 25–percentile 75) at the time of the study was 61.5 (53.0–69.3) years. They had an RA of 10.5 (6.6–18.2) years; 84% had RF+, 78% ACPA+ and 72% both FR+ and ACPA+. Of the 270 patients included, 50 (18.5% CI95% 14.0–25.6%) had at least one episode of neutropenia. The demographic and RA characteristics of both groups, with and without neutropenia, were very similar, except for sex, since most patients with neutropenia were women. Patients with neutropenia had other cytopenias, mainly thrombocytopenia. They used bDMARDs most frequently, without statistical differences, as shown in Table 1. Table 1. Clinical characteristics of patients with neutropenia. Variable Neutropenia Without Neutropenia pValue n % n % 50 19 220 81 Female sex 45 90 168 76 0.03 RF+ 43 86 184 84 0.6 ACPA+ 36 73 175 80 0.3 ACPA+ and RF+ 32 65 163 74 0.06 Other cytopenia 21 48 57 27 0.006 Anemia 19 38 47 21 0.01 Thrombocytopenia 11 22 12 5 0.0001 Lymphopenia 2 5 3 1 0.1 Splenomegaly 1 2 0 0 Felty syndrome 1 2 0 0 Deaths 2 4 2 1 0.1 DMARD 48 96 205 94 0.5 scDMARD 27 54 140 64 0.1 One 26 52 136 62 0.4 Two 1 2 4 2 0.1 J. Clin. Med. 2024,13, 7677 4 of 13 Table 1. Cont. Variable Neutropenia Without Neutropenia pValue n % n % MTX 19 68 102 73 0.1 bDMARD 35 71 128 58 0.08 Monotherapy 1 2 20 7 0.09 Combo with scDMARD 16 32 73 33 0.09 sdDMARD 1 2 20 9 0.09 Combo with scDMARD 0 0 6 3 0.2 Median p25–p75 Median p25–p75 Age at diagnosis, years 45.7 38.2–53.7 48.5 39.1–57.9 0.1 Age (at time of neutropenia or cut off), years 61.6 49.8–69.2 61.4 53.0–69.5 0.2 Disease duration, (at time of neutropenia or cut off) years 11.6 6.4–21.3 10.4 6.6–17.7 0.5 RF title, U/mL 274 96.2–591.2 236 119.2– 367.7 0.2 ACPA title, U/mL 299 87–343.5 340 113.7–359 0.2 RF: rheumatoid factor, ACPA: anti-citrullinated protein antibody positivity, DMARD: disease-modifying antirheumatic drugs, scDMARD: synthetic conventional disease-modifying anti rheumatic drugs, MTX: methotrexate, Combo: in combination with, sdDMARD: synthetic directed disease-modifying anti-rheumatic drugs. Data are presented as median and percentiles 25 and 75 (p25 and p75). 3.1. Multivariate Analysis In the best logistic regression model, the variables that were associated with neutropenia were treatment with IL6i, the presence of other cytopenias, and female sex. Neither activity according DAS28, age or the duration of the RA showed association. The data are shown in Table 2. Table 2. Logistic regression model. Variable Odds Ratio 95% Confidence Interval n = 256 p= 0.0001 LR Chi242.5 pValue IL6 inhibitors 10.73 3.56–32.2 0.0001 Other cytopenia * 3.83 1.93–7.60 0.0001 Gender, female 5.10 1.36–19.18 0.01 TNF inhibitors 2.50 1.0–6.29 0.05 Rituximab 4.18 0.32–62.8 0.2 DAS28 1.35 0.95–1.90 0.08 Age 0.99 0.95–1.02 0.6 Disease duration 1.01 0.97–1.05 0.5 * includes anemia, thrombocytopenia or lymphopenia. LR Likelihood ratio. DAS28 Disease activity score with 28 joint count. 3.2. Neutropenia Episodes Features A total of 50 patients had 99 episodes of neutropenia (Table 3); 59% episodes were acute and 41% chronic. The lower ANC was 1240 (1000–1395) mm 3 , and most of the episodes were mild (74%). In 32%, there was other cytopenia: anemia in 19%, thrombocytopenia in 14% and lymphopenia in 9%. J. Clin. Med. 2024,13, 7677 5 of 13 Table 3. Main characteristics of neutropenia episodes. Variable n % Patients 50 18.5 Number of episodes of neutropenia 1 26 53 2 7 14 3 9 18 4 5 10 5 1 2 7 1 2 Total 99 100 Duration of neutropenia Acute 58 59 Chronic 41 41 Severity of neutropenia Mild 73 74 Moderate 20 20 Severe 6 6 Cause of neutropenia Drugs 78 78 RA activity 13 13 Systemic viral infections 3 3 Hematologic cancer 1 1 Neutropenic episodes occurred in older patients with long-standing illnesses. Interestingly, the RA activity measured by DAS28 at each neutropenia episode was low, at 2.18 (1.75–2.97). The most common adverse event related to neutropenia was infection in 12 (12%) cases. Most infections were mild, auto-limited and resolved with symptomatic or oral antibiotic therapy; 6% of those were of the upper respiratory tract and 4% of the lower urinary tract. There were two (2%) severe infections: one case of herpes simplex keratitis and another of pneumonia by K. pneumoniae, which we describe below. Regarding etiology, neutropenia drugs (78%) and RA activity (13%) were the most common causes. Biologics were related to 79 episodes of neutropenia: IL6i in 54, with tocilizumab either in monotherapy (40%) or in combination with scDMARDs (19%) as the bDMARD. The second one was TNFi, in 24 episodes, etanercept either in monotherapy (11%) or combination (6%), followed by adalimumab and infliximab. The third was rituximab, with only one case. scDMARDs were, as a group, the second most common cause of neutropenia either in monotherapy or combination with biologics in 44 episodes. Methotrexate in monotherapy caused 20% of episodes, and methotrexate with bDMARDs caused 41% of episodes. The JAKi were related to neutropenia episodes only in 3% of cases. In addition, the treatment of oncologic conditions was related to two episodes (Table 4). In total, 86% of neutropenia episodes were resolved: 59% spontaneously, 31% with reduction in the dose of DMARD, 11% with stopping DMARD, and 4% changing DMARD. J. Clin. Med. 2024,13, 7677 6 of 13 Table 4. Drugs related to neutropenia episodes. Synthetic Conventional DMARDs Either in Monotherapy or in Combination with Biologic DMARDs Type Monotherapy Combo with Synthetic Conventional DMARDs Combo with Biologic DMARDs Total Total n (%) n (%) n (%) n (%) Methotrexate 9 (20) 1 (2) 18 (41) 28 (64) Leflunomide 3 (7) 1 (2) 6 (14) 10 (23) Hydroxychloroquine 0 1 (2) 5 (11) 6 (14) Total 12 (27) 3 (7) 29 (66) 44 (100) Biologic DMARDs related to neutropenia Tocilizumab 32 (40) 15 (19) 47 (59) Etanercept 9 (11) 5 (6) 14 (18) Adalimumab 3 (4) 4 (5) 7 (9) Sarilumab 5 (6) 2 (2) 7 (9) Infliximab 0 3 (4) 3 (4) Rituximab 1 (1) 0 1 (1) Total 49 (62) 29 (37) 79 (100) Targeted synthetic DMARDs related to neutropenia Baricitinib 2 (66) 0 2 (66) Upadicitinib 1 (33) 0 1 (33) Total 3 (-) 0 3 (100) Other treatments Rucaparib 1 (50) 0 1 (50 Carboplatin/ paclitaxel 1 (50) 0 1 (50) Total 2 (100) 0 2 (100) DMARDs: disease-modifying anti rheumatic drugs. 3.2.1. Description of Cases with Severe Infections • Case 1. The patient is a 79-year-old woman with RA FR+, ACPA+, erosive and sicca symptoms with a duration of 23 years. She had received multiple scDMARDs and, since 2010, tocilizumab monotherapy, maintaining remission with DAS < 2.4. Her comorbidities include arterial hypertension and stable stage 3a chronic kidney disease. In October 2022, when she was receiving tocilizumab at a reduced dose ( 162 mg / 2 weeks ) during an episode of mild acute leucopenia and neutropenia for two months (total leukocytes 3990 × mm 3 , total neutrophils 1310 × mm 3 , total lymphocytes 1380 × mm 3 , platelets 190,000 × mm 3 , serum creatinine 1.02 mg/dL, glomerular filtration rate 53 mL/min , erythrocyte sedimentation rate (ESR) 7 mm/hour, C-Reactive protein (CRP) 0.3 mg/L), she was admitted to the emergency room with a red left eye, photophobia plus epiphora. The ophthalmologists established the diagnosis of herpetic keratitis, and she was treated on an outpatient basis with topical ganciclovir with resolution after 7 days, without recurrence. Tocilizumab was discontinued during the infection and restarted in reduced doses, according to the label [ 10 ]. She currently remains in remission with tocilizumab (162 mg/2 weeks/SC) and has not had infections, keratitis or neutropenia. J. Clin. Med. 2024,13, 7677 7 of 13 • Case 2. The patient is a 79-year-old woman with RA, FR+ ACPA+, erosive plus fibromyalgia and bronchial asthma of 25 years. After multiple scDMARDs, she started her first biologic, tocilizumab, in 2009, and maintained remission with reduced dose (4 mg/kg/IV each 28 days) . The reduction in dose was due to good clinical response but moderate neutropenia. She was admitted due to fever, chills, cough with hemoptoic sputum plus left pleural pain during 5 days. A pulmonary condensation image in the left base and a positive blood culture for Klebsiella pneumoniae were confirmed. At the time of pneumonia, RA was in remission (DAS28VSG 2.1) without leukopenia or neutropenia (total leucocytes 6900 × mm 3 , and total neutrophils 6430 × mm 3 ) but severe lymphopenia (130 × mm 3 ) and mild thrombocytopenia (total platelets 129,000×mm3 ), ESR 2 mm/hour, CRP 46.1 mg/L. After 10 days of IV antibiotic therapy, the condition resolved. Tocilizumab was restarted one month later and was discontinued after 10 months due to chronic moderate neutropenia, according to the label [ 10 ]. She was switched to etanercept, which is maintained to date at 50 mg/week SC. She is in remission, without infections and without neutropenia. 3.2.2. Classic Felty Syndrome Five of fifty (1.8%) patients with neutropenia had characteristics of Felty Syndrome, i.e., neutropenia plus RF+ and/or ACPA+, but just one of the three classic features (RA, FR+ and ACPA+, neutropenia and splenomegaly), for a prevalence of 0.3% of the total of patients. • Case 3. Felty Syndrome. The patient is a 46-year-old woman with RA according to EULAR/ACR criteria [ 7 ], with poor prognostic characteristics (high levels of activity, RF+, ACPA+, erosions and poor physical function) as evaluated in 2011, with poor compliance. From 2011 to 2015, she received irregular treatment with methotrexate, leflunomide, and low doses of oral prednisone and refused bDMARDs. In 2019, she returned to the clinic with six swollen joints, eight tender joints, 6 cm of visual analogue scale of pain (0 = no pain to 10 = maximum pain), and 6 cm of VAS of RA activity (0 = no activity to 10 = maximum activity), with DAS28PCR 5.07, HAQ 1.5 and poor perception of health. We found hand deformity with ulnar burst and swan neck fingers (Figure 1). J.Clin.Med.2024,13,xFORPEERREVIEW7of13   3.2.2.ClassicFeltySyndrome Fiveoffifty(1.8%)patientswithneutropeniahadcharacteristicsofFeltySyndrome, i.e.,neutropeniaplusRF+and/orACPA+,butjustoneofthethreeclassicfeatures(RA, FR+andACPA+,neutropeniaandsplenomegaly),foraprevalenceof0.3%ofthetotalof patients.  Case3.FeltySyndrome.Thepatientisa46-year-oldwomanwithRAaccordingto EULAR/ACRcriteria[7],withpoorprognosticcharacteristics(highlevelsofactivity, RF+,ACPA+,erosionsandpoorphysicalfunction)asevaluatedin2011,withpoor compliance.From2011to2015,shereceivedirregulartreatmentwithmethotrexate, leflunomide,andlowdosesoforalprednisoneandrefusedbDMARDs.In2019,she returnedtotheclinicwithsixswollenjoints,eighttenderjoints,6cmofvisualanaloguescaleofpain(0=nopainto10=maximumpain),and6cmofVASofRAactivity (0=noactivityto10=maximumactivity),withDAS28PCR5.07,HAQ1.5andpoor perceptionofhealth.Wefoundhanddeformitywithulnarburstandswanneckfingers(Figure1).  Figure1.HandsofpatientwithFeltysyndrome.Shehascharacteristicsswanneckdeformity,metacarpophalangealsubluxationandulnarblunt. Herlaboratorydatawereasfollows:hemoglobin10.7g/dL,totalleukocytes3850× mm3,totalneutrophils1000×mm3,serumIgA693mg/dL,serumIgG2706mg/dL,serum IgM868mg/dL,FR522UI/dL,ACPA>340U/mL,ESR35mm/hora,CRP15mg/dL.Her X-raysshowedulnarsubluxationofbilateralfirstfingerinterphalangeal,witherosionsin carpals,metacarpophalangealandproximalinterphalangeal(Figure2)aswellaserosions inmetatarsalheads. Figure 1. Hands of patient with Felty syndrome. She has characteristics swan neck deformity, metacarpophalangeal subluxation and ulnar blunt. J. Clin. Med. 2024,13, 7677 8 of 13 Her laboratory data were as follows: hemoglobin 10.7 g/dL, total leukocytes 3850×mm3 , total neutrophils 1000 × mm 3 , serum IgA 693 mg/dL, serum IgG 2706 mg/dL, serum IgM 868 mg/dL, FR 522 UI/dL, ACPA > 340 U/mL, ESR 35 mm/hora, CRP 15 mg/dL. Her X-rays showed ulnar subluxation of bilateral first finger interphalangeal, with erosions in carpals, metacarpophalangeal and proximal interphalangeal (Figure 2) as well as erosions in metatarsal heads. J.Clin.Med.2024,13,xFORPEERREVIEW8of13    Figure2.AnteroposteriorhandX-raywithsubluxationofthemetacarpophalangealandinterphalangealjointsoffirstfingers,anderosionsinmetacarpalheadsandproximalinterphalangealheads. Treatmentwasattemptedwithadalimumabandetanercept,whichshedidnottolerateandpreferredlowdosesofprednisone(1.25to5mg/day).Sheevolvedpoorlywith persistentRAactivity(DAS28-PCRindexbetween4.5to6.0)andpancytopenia(mildto moderateanemia,neutropenia,lymphopenia,andthrombocytopenia),withoutclinical manifestations.AbdominalultrasoundwasperformedforsuspectedFeltysyndrome,confirming14cmsplenomegaly(Figure3).  Figure3.Splenomegalywithspleenof14cm. Thepatientdidnotagreetocompletethehematologicalstudy(bonemarrowaspirationandlargegranularcellleukemiastudy).Aftermultipleattemptstoreachaconsensus ondiagnostictestandtreatmentwithoutsuccess,shewasadmittedduetofever,nosebleedsandanemicsyndromerelatedtoseverethrombopeniapluspancytopenia.Upon admission,shehadfeverwithoutinfection.Aftermultiplebloodurineculturesandspecificserology,herlaboratorytestsshowedHb7.9g/dL,hematocrit26.4%,totalleucocytes 3770×mm3,totalneutrophils1400×mm3,platelets28,000×mm3,serumIgA1004mg/dL, serumIgE107UI/mL,serumIgG6038mg/dL,serumIgM611mg/dL,ESR125mm/hora, CRP22.4mg/L,serumamyloid3.34mg/L,procalcitonin0.32ng/mL,RF5623U/Land Figure 2. Anteroposterior hand X-ray with subluxation of the metacarpophalangeal and interphalangeal joints of first fingers, and erosions in metacarpal heads and proximal interphalangeal heads. Treatment was attempted with adalimumab and etanercept, which she did not tolerate and preferred low doses of prednisone (1.25 to 5 mg/day). She evolved poorly with persistent RA activity (DAS28-PCR index between 4.5 to 6.0) and pancytopenia (mild to moderate anemia, neutropenia, lymphopenia, and thrombocytopenia), without clinical manifestations. Abdominal ultrasound was performed for suspected Felty syndrome, confirming 14 cm splenomegaly (Figure 3). J.Clin.Med.2024,13,xFORPEERREVIEW8of13    Figure2.AnteroposteriorhandX-raywithsubluxationofthemetacarpophalangealandinterphalangealjointsoffirstfingers,anderosionsinmetacarpalheadsandproximalinterphalangealheads. Treatmentwasattemptedwithadalimumabandetanercept,whichshedidnottolerateandpreferredlowdosesofprednisone(1.25to5mg/day).Sheevolvedpoorlywith persistentRAactivity(DAS28-PCRindexbetween4.5to6.0)andpancytopenia(mildto moderateanemia,neutropenia,lymphopenia,andthrombocytopenia),withoutclinical manifestations.AbdominalultrasoundwasperformedforsuspectedFeltysyndrome,confirming14cmsplenomegaly(Figure3).  Figure3.Splenomegalywithspleenof14cm. Thepatientdidnotagreetocompletethehematologicalstudy(bonemarrowaspirationandlargegranularcellleukemiastudy).Aftermultipleattemptstoreachaconsensus ondiagnostictestandtreatmentwithoutsuccess,shewasadmittedduetofever,nosebleedsandanemicsyndromerelatedtoseverethrombopeniapluspancytopenia.Upon admission,shehadfeverwithoutinfection.Aftermultiplebloodurineculturesandspecificserology,herlaboratorytestsshowedHb7.9g/dL,hematocrit26.4%,totalleucocytes 3770×mm3,totalneutrophils1400×mm3,platelets28,000×mm3,serumIgA1004mg/dL, serumIgE107UI/mL,serumIgG6038mg/dL,serumIgM611mg/dL,ESR125mm/hora, CRP22.4mg/L,serumamyloid3.34mg/L,procalcitonin0.32ng/mL,RF5623U/Land Figure 3. Splenomegaly with spleen of 14 cm. J. Clin. Med. 2024,13, 7677 9 of 13 The patient did not agree to complete the hematological study (bone marrow aspiration and large granular cell leukemia study). After multiple attempts to reach a consensus on diagnostic test and treatment without success, she was admitted due to fever, nosebleeds and anemic syndrome related to severe thrombopenia plus pancytopenia. Upon admission, she had fever without infection. After multiple blood urine cultures and specific serology, her laboratory tests showed Hb 7.9 g/dL, hematocrit 26.4%, total leucocytes 3770 × mm 3 , total neutrophils 1400 × mm 3 , platelets 28,000 × mm 3 , serum IgA 1004 mg/dL, serum IgE 107 UI/mL, serum IgG 6038 mg/dL, serum IgM 611 mg/dL, ESR 125 mm/hora, CRP 22.4 mg/L , serum amyloid 3.34 mg/L, procalcitonin 0.32 ng/mL, RF 5623 U/L and ACPA > 340 U/mL. Multiple myeloma (absence of serum monoclonal protein, heavy chain expression by immunofixation, urinary monoclonal protein) and large granular lymphocyte leukemia (absence of CD8+ cell proliferation by flux cytometry) were ruled out (Figure 4). J.Clin.Med.2024,13,xFORPEERREVIEW9of13   ACPA>340U/mL.Multiplemyeloma(absenceofserummonoclonalprotein,heavychain expressionbyimmunofixation,urinarymonoclonalprotein)andlargegranularlymphocyteleukemia(absenceofCD8+cellproliferationbyfluxcytometry)wereruledout(Figure4).  Figure4.FlowcytometrydotplotsthatshowabsenceofclonalexpansionofNKcellsexpressingor notCD8+. Sheacceptedtreatmentwithbiannualrituximab.Untilthelastreview,shehadreceivedtwocyclesof1000mgIV(day0andday15),withthelastoneinMarch2024,withoutcomplications.Therewasevidenceofimprovementininflammatoryactivity DAS28PCR,1.8,anemiaandthrombocytopenia,butsofar,notfortheremaininglaboratoryparameters.ShehadHb14.5g/dL,totalleukocytes2000×mm3,totalneutrophils 1060×mm3,platelets53,000×mm3,ESR121mm/h,CRP1.3mg/L,RF4935UI/mLand ACPA>340U/mL.Shehadhadmildupperrespiratorytractinfectionsmanagedonan outpatientbasisandagreedtocontinuethetreatmentbutnotwithaggressivediagnostic tests. 4.Discussion Inthe21stcentury,neutropeniainRApatientsisacommonfinding,withvalues between0.5%to37%(1–3).InoursampleofRApatients,itwas18.5%(14.0–25.6%),in agreementwiththesevalues.WiththeintroductionoftheT2Tstrategysince2010[11],the characteristicsandconsequencesofneutropeniainRApatientshavechanged.Recent studiesreportthatinearlyRAwithoutDMARDtreatment,neutropeniaoccursuncommonly(inlessthan1.5%ofcases),andcongenitalneutropeniashouldberuledout[1–4]. InestablishedRA,theprevalenceismuchhigher,andthemaincauseofneutropeniais treatmentwithDMARDs,mainlybDMARDswithprevalencesof14.3%to19%,followed byRAactivity.Ourretrospectiveseriesincludedpatientswithameanof61years,longlastingdiseaseandahighproportionofRFandACPApositivity,andthefrequencyand causesofneutropeniawerelikethoseinotherstudies[1–3].Betweenthebiologics,those mostcommonrelatedwithneutropeniawereIL6idrugs,mainlytocilizumabfollowedby rituximab,andlastly,byTNFidrugs.scDMARDswerethesecondmostcommoncause ofneutropeniaafterbDMARDs,mainlymethotrexate.AndJAKiwerethethirdgrouprelatedtoneutropenia[1–3].Thesefindingswereverysimilartoours,with79%ofepisodes ofneutropeniaforbDMARDsmainlyinvolvingIL6i(59%tocilizumaband9%sarilumab), followedbyTNFidrugsin24%(18%etanercept,9%adalimumaband4%infliximab),and JAKiin3%.Mayberituximabwasthelastduetothelowprevalenceofuseofrituximab inourcohort.Inourseriesandintherecentliterature,nocaseswererelatedtoNSAIDs, maybebecausetheprevalenceofuseofNSAIDshasreduced,accordingto Figure 4. Flow cytometry dot plots that show absence of clonal expansion of NK cells expressing or not CD8+. She accepted treatment with biannual rituximab. Until the last review, she had received two cycles of 1000 mg IV (day 0 and day 15), with the last one in March 2024, without complications. There was evidence of improvement in inflammatory activity DAS28PCR, 1.8, anemia and thrombocytopenia, but so far, not for the remaining laboratory parameters. She had Hb 14.5 g/dL, total leukocytes 2000 × mm 3 , total neutrophils 1060 × mm 3 , platelets 53,000 × mm 3 , ESR 121 mm/h, CRP 1.3 mg/L, RF 4935 UI/mL and ACPA > 340 U/mL. She had had mild upper respiratory tract infections managed on an outpatient basis and agreed to continue the treatment but not with aggressive diagnostic tests. 4. Discussion In the 21st century, neutropenia in RA patients is a common finding, with values between 0.5% to 37% (1–3). In our sample of RA patients, it was 18.5% (14.0–25.6%), in agreement with these values. With the introduction of the T2T strategy since 2010 [ 11 ], the characteristics and consequences of neutropenia in RA patients have changed. Recent studies report that in early RA without DMARD treatment, neutropenia occurs uncommonly (in less than 1.5% of cases), and congenital neutropenia should be ruled out [ 1 – 4 ]. In established RA, the prevalence is much higher, and the main cause of neutropenia is treatment with DMARDs, mainly bDMARDs with prevalences of 14.3% to 19%, followed by RA activity. Our retrospective series included patients with a mean of 61 years, longlasting disease and a high proportion of RF and ACPA positivity, and the frequency and causes of neutropenia were like those in other studies [ 1 – 3 ]. Between the biologics, those most common related with neutropenia were IL6i drugs, mainly tocilizumab followed by rituximab, and lastly, by TNFi drugs. scDMARDs were the second most common cause of