Abstract
Background/Aim: Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with the functional impairment of multiple joints and the destruction of bone and cartilage. Methotrexate (MTX) is a first-line drug commonly used to treat RA; however, even low doses of MTX can potentially cause rare but severe adverse reactions, such as neutropenic enterocolitis (NE), a life-threatening disease characterized by intestinal mucosal damage and immunodeficiency. Case Report: Here, we report on an 82-year-old RA patient who developed life-threatening NE after ten years of low-dose MTX treatment. The condition of the patient rapidly worsened, requiring emergency electrical cardioversion and intravenous treatment with immunoglobulin (IVIG). Immunophenotypic responses were analyzed before and after treatment to evaluate therapeutic efficacy. Conclusion: This case highlights the importance of monitoring elderly patients with RA receiving low-dose MTX treatment for the potential accumulation of MTX toxicity. Our findings also illustrate the importance of providing timely IVIG therapy for MTX-induced NE.
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic progressive synovitis and the destruction of cartilage and bone in multiple joints, leading to frequent recurrence and joint dysfunction. The global incidence of RA is roughly 1% (1). The typical approach to treating RA involves corticosteroids and disease-modifying antirheumatic drugs (DMARDs), such as methotrexate (MTX) (2). MTX is a common anti-metabolic drug and immunosuppressant used to treat cancer and autoimmune diseases, such as psoriasis and inflammatory myopathies (3, 4). Low-dose MTX is considered a first-line agent for the treatment of early and established RA, due to its high potency, good efficacy, and limited toxicity (3, 4); however, even low doses can have rare but severe adverse effects, including mucositis, pulmonary involvement, hepatotoxicity, myelosuppression, leukoencephalopathy, mucosal necrosis, and neutropenic enterocolitis (NE) (3, 5-7).
NE is a rare life-threatening condition, characterized by intestinal mucosal injury, neutropenia, and immunodeficiency, leading to intestinal edema, engorged vessels, and a disrupted mucosal surface, rendering the intestine susceptible to intramural bacterial invasion (8). NE can result in perforation and/or sepsis, with mortality rates ranging from 30% to 50% (9). There is at present limited research pertaining to the treatment of NE. Available treatments include conservative therapy, antibiotic treatment, and bowel rest (10).
This article reports on an 82-year-old patient with RA who developed life-threatening NE after receiving low-dose MTX treatment over a period of ten years. The patient developed severe NE due to MTX-induced immunodeficiency absolute neutrophil count (ANC) of 0, which resulted in sepsis and rapid disease progression. Upon hospital admission, the patient required urgent treatment using electrical cardioversion. Intravenous immunoglobulins (IVIG) are protein antibodies produced by plasma cells and biological agents for the management of various immunodeficiency disorders as well as autoimmune, infectious, and inflammatory conditions (11, 12). In this case, IVIG therapy was shown to have significant therapeutic effects, as evidenced by a rapid improvement in the patient’s condition.
Case Report
An 82-year-old female patient had been diagnosed with RA ten years prior to the events in this paper. In the intervening years, the patient had been receiving treatment with prednisone (5 mg/day), low-dose MTX (10 mg/week), and folic acid (5 mg/day). Throughout the ten-year period, the patient’s renal function was as follows: blood urea nitrogen (BUN) (Mean±SD=17.83±2.14), creatinine (Mean±SD=0.92±0.04), estimated glomerular filtration rate (eGFR) (Mean±SD=66.32±4.76), and creatinine clearance (CCr) rate (Mean±SD=30.06±1.86). In early 2023, the patient underwent trans-arterial embolization (TAE) due to gastric ulcer and duodenal bleeding, prompting the cessation of MTX treatment. Four months after these events, MTX treatment was resumed with a weekly dose of 7.5 mg. At two months after resuming MTX treatment, the patient was admitted to the emergency department due to fever (up to 38.9°C), diarrhea, and tarry stool persisting for two days. A physical examination revealed pale conjunctiva, ulceration of gingiva and oral mucosa (Figure 1A), dyspnea, chest tightness, palpitation, and arrhythmia. Blood tests revealed pancytopenia [white blood cell (WBC) count of 270/μl, hemoglobin (Hb) level of 6.2 g/dl, and platelet count of 5,000/μl], with undetectable absolute neutrophil and lymphocyte counts, as well as hypoalbuminemia (3.2 g/dl) and elevated C-reactive protein (CRP) levels (25.95 mg/dl) (Table I). BUN levels (45 mg/dl) and creatinine levels (1.4 mg/dl) indicated acute kidney injury (AKI) (Table I). Contrast-enhanced computed tomography (CECT) of the abdomen revealed thickening of the duodenum wall, ascending colon and distal ileum, and submucosal edema (Figure 1B), supporting the diagnosis of NE (8).
Clinical course of the patient condition: (A) Images captured in the emergency department, showing ulceration of the gingiva and oral mucosa; (B) Transverse section of contrast-enhanced computed tomography (CECT) revealing circumferential thickening of duodenum walls (arrow) and ascending colon (triangle) as well as the presence of submucosal edema and pericolic infiltration (arrow); (C) The changes in blood urea nitrogen (BUN), creatinine (Cr), estimated glomerular filtration rate (eGFR), and creatinine clearance (CCr) levels from the patient’s last admission to the point of achieving a stabilized clinical condition during this hospitalization. BUN levels are depicted in blue, creatinine levels in orange, eGFR levels in red, and CCr levels in green. The purple arrow indicates the patient’s hospitalization status and urgent medical treatments received; (D) Record of temperature (Tem), pulse, and respiratory rate (RR) from the onset of disease to the point at which the clinical condition of the patient stabilized. The green arrow indicates the initiation of IVIG treatment. CPR: Cardiopulmonary resuscitation; IVIG: intravenous immunoglobulin; CVVH: continuous venovenous hemofiltration.
Blood investigations before and after intravenous immunoglobulin (IVIG) treatment.
Upon admission, the patient presented symptoms of dyspnea, abdominal distension, abdominal pain, tachycardia (140-182 beats per min), and hypertension (182/77 mmHg). A physical examination revealed notable tenderness in the right lower abdomen with dullness on percussion. Laboratory data revealed thrombocytopenia and anemia [PLT 5,000/μl, red blood cell (RBC) 2.08×106/μl, Hb 6.2 g/dl, hematocrit (HCT) 19.1%] as well as metabolic acidosis (vein blood gas pH 7.273, HCO3 21.4 mmol/l). The patient subsequently received a transfusion of packed red blood cells and platelets that had been processed for the removal of leukocytes. Chest X-rays revealed left pleural effusion, ruling out MTX pneumonia. Attending staff observed a rapidly degenerating condition and biochemical abnormalities, including hypokalemia (K 2.6 mmol/l) and hyperchloremia (Cl 113 mmol/l) as well as elevated creatine kinase (CK, 1,575 U/l) and troponin I (292 pg/ml). This prompted the transfer of the patient to the intensive care unit (ICU) for mechanical ventilation, and various cultures were obtained, including blood, sputum, stool, urine, and fungus culture. Additionally, tests for Clostridium difficile toxin (CDI), tuberculosis (TB), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) were conducted, all of which yielded negative results. Throughout the hospitalization, a series of prophylactic antibiotics were administered, including cephalosporine, meropenem, myfungin, and Tazocin, but the infection could not be controlled. The unstable condition of the patient precluded gastroscopy or bone marrow biopsy due to the risk of infection. Abnormal electrocardiogram (EKG) signals, including paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation (AF) with a rapid ventricular response (RVR), and sinus tachycardia, prompted 13 sessions of electrical cardioversion, which stabilized the heart rate. Nonetheless, laboratory data revealed a rapid deterioration in renal function (BUN: 152 mg/dl, creatinine: 4.0 mg/dl, eGFR: 11.6 ml/min, CCr: 6.6 ml/min) (Figure 1C). The patient also presented severe diarrhea, and abdominal ultrasound analysis revealed intestinal edema with elevated levels of procalcitonin, indicative of a severe infection. The patient was subsequently scheduled to undergo IVIG therapy and continuous venovenous hemofiltration (CVVH) for a period of three days. The three-day course of IVIG therapy led to an overall improvement in the patient’s condition, including stabilized vital signs (Figure 1D) and a decrease in the frequency of diarrhea. Laboratory results at the completion of IVIG therapy were as follows: ANC (13,932/μl), WBC (15,480/μl), CRP (6.61 mg/dl), BUN (43 mg/dl), and creatinine level (0.8 mg/dl) (Figure 1C, Figure 2A, and Table I). A subsequent colonoscopy revealed evidence of colitis, including mucosal edema, fragility, and ulcerations in the ascending colon, further confirming the diagnosis of NE (Figure 2B). Biopsy results revealed ulceration with CMV infection and eosinophil infiltration of colonic tissue. This prompted physicians to prescribe treatment using Cymevene and total parenteral nutrition with bowel rest. The patient recovered well and was discharged from the hospital at 16 weeks after admission. Figure 2A presents the disease progression in this case.
Progress of disease and course of clinical treatment: (A) Disease progression and clinical treatment course. The gray line indicates the overall disease progression. The hollow arrow indicates the time points for the onset of symptoms, changes in laboratory findings, and examinations. The blue line and arrow indicate variations in MTX dosage. The green line and arrow denote the medical treatments administered and hospitalization status; (B) Colonoscopic images obtained post-intravenous immunoglobulin therapy, exhibiting mucosal hyperemia, fragility, and ulcerations in the ascending colon. TAE: Trans-arterial embolization; ICU: Intensive Care Unit; CPR: cardiopulmonary resuscitation; A-colon: ascending colon; CMV: cytomegalovirus.
In this study, flow cytometry was used for immunophenotyping analysis before and after IVIG treatment to elucidate the treatment response (Table II). Whole blood analysis was conducted at three time points: prior to disease onset (−1.5 y), before IVIG treatment (pre), and after IVIG treatment (post). Immune cells were analyzed using a 3-laser 13-color CytoFLEX flow cytometer (Beckman Coulter, Brea, CA, USA). Briefly, whole blood samples were added to a DuraClone IM T cell subsets Tube (IM T DuraClone cell tube 25 tests; B53328-25 tests, RUO), a DuraClone IM Treg Tube (IM Treg DuraClone Tube 25 tests; B53346-25 tests, RUO), and a DuraClone IM B cell Tube (IM B DuraClone cell tube, 25 tests; B53318-25 tests, RUO), using the following pre-added antibodies: anti-human CD95-BV605 (Catalog number: 305628; BioLegend, San Diego, CA, USA), anti-human CD366-BV650 (Catalog number: 345028; BioLegend), anti-mouse/human killer-cell lectin-like receptor G1 (KLRG1)-BV785 (Catalog number: 138429; BioLegend), anti-human HLA-DR-BV650 (Catalog number: 307650; BioLegend), anti-human CD62L-BV605 (Catalog number: 304834; BioLegend), anti-human CD127-BV785 (Catalog number: 351330; BioLegend), and CD8-APC-Alexa Fluor 700 (Catalog number: A66332; Beckman Coulter). The detailed setting and cell gating are listed in Supplementary Data 1 to 4. Analysis was performed in strict adherence to the protocols outlined by the manufacturer. Raw data obtained via flow cytometry were analyzed using Kaluza 2.1.1 software. GraphPad Prism 8 (GraphPad, La Jolla, CA, USA) was used to create graphs for a comparison of data before and after treatment.
Immunophenotypic analysis before and after intravenous immunoglobulin (IVIG) treatment.
Ethics statement. This study was approved by the Institutional Review Board (IRB) of Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC and complied with relevant guidelines. The research method in this study involving human participants was in accordance with the ethical standards of the institution and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from the patient herself.
Discussion
The case presented in this report demonstrates the potentially life-threatening adverse effects of low-dose MTX therapy. The patient in this study exhibited multiple clinical presentations consistent with a diagnosis of NE (8), including fever, diarrhea, abdominal pain, neutropenia (ANC of zero), and thickening of the intestinal wall. Several risk factors contributed to the toxic effects of MTX in this patient, including advanced age and AKI. Drug-drug interactions can also contribute to delayed methotrexate excretion and subsequent nephrotoxicity (13). Research has shown that when using high-dose MTX in combination with Glycyrrhizin, one should consider the administration intervals to avoid unwanted interactions (13). Limited published data and clinical experience with such cases suggest that severe NE or MTX-induced mucosal necrosis may be common occurrences among elderly patients receiving low-dose MTX (5, 7, 14) (Table III). It is possible that these effects are attributable to the age-related decline in renal function, which presumably exacerbates the accumulation of MTX (15). Furthermore, age has been found to be associated with nonresponse status to RA treatment (16). Close monitoring is recommended for elderly RA patients receiving low-dose MTX treatment, and practitioners should consider the possibility of NE in cases involving the appearance of neutropenia and/or gastrointestinal symptoms.
Summary of four cases of methotrexate (MTX)-induced neutropenic enterocolitis (NE) in patients with rheumatoid arthritis (RA).
Our findings also demonstrate the feasibility of using IVIG therapy to treat severe MTX-induced NE. The current case presented MTX-induced immunodeficiency (ANC=0), which allowed the development of severe NE, leading to sepsis and rapid disease progression. This event highlights the importance of prompt and effective treatment for severe NE. Existing treatments are limited to conservative therapy, antibiotic treatment, and bowel rest (10). In the current case, conservative management permitted the rapid deterioration of the patient’s condition; however, IVIG therapy prompted a rapid improvement, including a decrease in diarrhea frequency and the stabilization of vital signs (Figure 1D). IVIG treatment also promoted improvements in laboratory data (Table I), as follows: ANC (13,932/μl), WBC (15,480/μl), BUN (43 mg/dl), creatinine levels (0.8 mg/dl), and CRP levels (6.61 mg/dl). IVIG is a biologic agent comprising protein antibodies produced by plasma cells, which have been shown to have immunomodulatory effects involving the regulation of B and T lymphocytes, the neutralization of pathogenic autoantibodies, and anti-inflammatory effects via interactions with cytokines, chemokines, and other factors. IVIG is used to treat a variety of immunodeficiency conditions as well as autoimmune, infectious, and inflammatory diseases (11, 12). Note that in the current study, IVIG therapy was implemented in conjunction with CVVH to prevent potential adverse effects, including increased blood viscosity, which could lead to thrombosis and/or renal impairment. Overall, IVIG treatment represents a promising new therapeutic option for NE.
We evaluated the efficacy of IVIG therapy by observing changes in immunophenotypes (Table II). Our analysis revealed a significant increase in lymphocytes and their T cell subgroups after treatment. In terms of lymphocyte percentages, IVIG treatment led to a significant decrease in the relative percentage of B cells, despite a remarkable increase in absolute counts. This inconsistency can be attributed to the low baseline number of lymphocytes, which made the pre-treatment percentage of B cells appear erroneously high. In the subsequent analysis of T cell subgroups, Th, Treg, and Tc cells all presented significant increases after therapy. Note that the initial expression of plasmablasts and plasma cells (i.e., before treatment) was zero; however, both values presented significant increases after IVIG therapy. These findings suggest that the therapeutic effects of IVIG therapy on neurological events involve the modulation of immune cells (i.e., immunomodulatory effects).
Conclusion
To conclude, it is important to monitor elderly patients with RA receiving long-term low-dose MTX therapy in terms of renal function and potential adverse reactions, such as NE. Our findings indicate that IVIG is a feasible treatment option for potentially fatal NE.
Acknowledgements
This study was supported by Undergraduate research fellowship, Ministry of Science and Technology (110-2813-C-016-003-B), Ministry of Science and Technology (MOST 109-2314-B-016-052 and MOST 111-2314-B-016-026), National Science and Technology Council (NSTC 112-2314-B-016-033) and Tri-Service General Hospital (TSGH-E-111215) in Taiwan, R.O.C.
Footnotes
Authors’ Contributions
Treatment of patients, data collection and assessment: SWL, TYH, FCY, FCL. Manuscript writing, discussion, revision: SWL, JWL, YJH, FCL. Study conception and design: SWL, JWL, YJH, TYH, FCY, FCL.
Supplementary Material
Supplementary material can be found at: https://figshare.com/s/6308c9a23dfd82a20c55
Conflicts of Interest
The Authors declare that they have no conflicts of interest in relation to this study.
- Received September 12, 2023.
- Revision received September 29, 2023.
- Accepted October 3, 2023.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
