Management of Rheumatoid Arthritis in a Patient with Aplastic Anemia and Ulcerative Colitis: A Case Report

Introduction

Rheumatoid arthritis (RA) is one of the most common systemic autoimmune diseases, affecting 0.5% to 1% of the general population worldwide [1]. It is characterized by inflammatory arthritis and extra-articular manifestations. RA is a chronic, incurable condition, and the primary goal of treatment is to achieve sustained clinical remission and optimize quality of life [2].

The primary approach to treating RA is early diagnosis and earlier intervention with disease-modifying antirheumatic drugs (DMARDs) to prevent joint damage and functional disability [3]. Nonsteroidal anti-inflammatory drugs and corticosteroids have a short onset and can decrease pain. However, nonsteroidal anti-inflammatory drugs alone do not change the course of the disease. Corticosteroids can offer a more significant benefit, although the risks associated with long-term use, including osteoporosis, make them an unfavorable option for long-term management [4].

As cartilage damage and bony erosions frequently occur within the first 2 years of the condition, rheumatologists promptly initiate DMARD treatment once the diagnosis is confirmed. Only DMARD agents have been shown to alter the disease course, improve radiographic outcomes, and prevent disabilities. Many DMARDs for RA have been identified, including methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide. Other classes of drugs include tumor necrosis factor (TNF) inhibitors, interleukin (IL)-6 inhibitors, IL-1 inhibitors, T-cell stimulation, and Janus kinases (JAK) inhibitors [5].

The American College of Rheumatology recommends early and aggressive treatment with conventional synthetic DMARDs, such as hydroxychloroquine, methotrexate, leflunomide, and sulfasalazine, followed by biological DMARDs or targeted synthetic DMARDs in cases of inadequate response. Biological DMARDs include TNF inhibitors (eg, etanercept, adalimumab, infliximab, certolizumab pegol, golimumab), IL-6 receptor inhibitors (eg, tocilizumab, sarilumab), B-cell depleting agents (eg, rituximab), T-cell costimulation modulators (eg, abatacept), and IL-1 inhibitors (eg, anakinra). Targeted synthetic DMARDs include JAK inhibitors (eg, tofacitinib, baricitinib, upadacitinib, filgotinib). New guidelines suggest hydroxychloroquine as a preferred initial therapy for patients with low disease activity, due to its favorable adverse effect profile. Methotrexate is preferred initial therapy for those with moderate to high disease activity [3].

Many DMARDs can cause cytopenia and immunosuppression, which can be very dangerous in patients with pre-existing aplastic anemia [5]. The approach to inflammatory arthritis in a patient with aplastic anemia has not been previously reported, and no protocol for this condition has been established. The coexistence of RA and aplastic anemia is exceedingly rare and has been described only in isolated case reports. Most available reports describe aplastic anemia as a treatment-related complication of RA therapies, rather than as a pre-existing comorbidity, further underscoring the novelty of this case [6,7]. This combination presents unique therapeutic challenges, as both conditions independently increase the risk of cytopenia and immunosuppression, and evidence-based treatment guidelines for managing this overlap are lacking.

Here, we report the management of newly diagnosed RA in a patient with aplastic anemia, highlighting the complexities and considerations involved in treating such patients.

Case report

A 54-year-old woman was referred to the Rheumatology Department for a recurrent left knee effusion and morning stiffness increasing in severity. A year prior, arthrocentesis from the left knee showed a hazy yellow synovial fluid, with 9972/mm3 white blood cell count and 80 polymorphonuclear cells, which had negative crystal, culture, and microbiology results. The fluid aspirate was group 2 inflammatory. The stiffness was primarily localized to the hands and treated with low-dose corticosteroids from her primary care provider, to which she responded well. Additionally, she had a history of ulcerative colitis (she underwent total colectomy in 2007 and no longer required maintenance medications for ulcerative colitis), and received a diagnosis of aplastic anemia 6 years prior to this encounter. She had previously trialed hydroxychloroquine (Plaquenil), which was ineffective. She reported having reactions to multiple anti-inflammatory drugs, including balsalazide disodium (Colazal) and mesalamine (Asacol), and was hesitant about starting new medications, due to her history of drug-induced thrombocytopenia.

The patient’s vital signs were stable on initial presentation, and her body mass index was 28.78. She reported having active joint pain. On musculoskeletal examination, she had tenderness and swelling in both hands, knees, and ankles. A physical examination of those joints showed mild restriction of motion and synovitis. The patient was started on a prednisone 20 mg taper for symptomatic management.

X-rays of her knees revealed a mild bilateral, left greater than right, medial compartment, with degenerative joint disease present. X-rays of her hands and ankles were unremarkable.

Laboratory examination revealed an elevated erythrocyte sedimentation rate (ESR) of 72 mm/h. Serum 14-3-3 ETA was within the reference range at <0.20 ng/mL. Rheumatoid factor was <10 IU/mL, and anti-cyclic citrullinated peptide antibodies were negative.

The patient’s white blood cell count was 4.3×103/μL, with 72.9% neutrophils and 16.8% lymphocytes. Hemoglobin was 8.8 g/dL, and the platelet count was 22×103/μL. Liver and renal function tests were within the reference range.

A bone marrow biopsy from 2016 showed mild hypocellularity. A repeat biopsy in 2019 confirmed hypocellular bone marrow. Flow cytometry demonstrated a myeloid-predominant marrow. The results of an infectious workup were all negative.

Based on the physical examination, imaging, and elevated ESR, the patient received a diagnosis of seronegative RA. Following a discussion with her hematologist, she was started on hydroxychloroquine. Although the patient had previously experienced limited response to hydroxychloroquine when used in the context of ulcerative colitis, it was selected again for RA, due to its relatively favorable hematologic safety profile in patients with underlying aplastic anemia. Hydroxychloroquine was favored over methotrexate due to the antimetabolic nature of methotrexate and concerns for exacerbated pancytopenia. Abatacept was also not preferred due to concerns about T-cell suppression.

During the following 6 months, the patient showed improvement on hydroxychloroquine 400 mg/day and was tapering off prednisone. She then presented with worsening tenderness and swollen bilateral hands and right knee. She shared that the pain significantly worsened after discontinuing prednisone. Her blood work also showed significantly decreased platelets of 17×103/μL. She received a platelet infusion from her hematologist, and hydroxychloroquine was discontinued. An ultrasound of her wrist was performed, showing active synovitis.

TNF inhibitors were contraindicated in this patient, due to the risk of worsening aplastic anemia. JAK inhibitors, while not formally contraindicated, were deferred, given that IL-6 inhibitors had a longer safety record in this population and were showing clinical efficacy in this case. Sulfasalazine, although not strictly contraindicated, was avoided due to the risk of drug-induced aplastic anemia, which, although rare, has been reported. Following the development of thrombocytopenia on hydroxychloroquine, an IL-6 inhibitor was selected as the next-line agent, given its efficacy in RA and relative safety profile in this patient population.

Sarilumab, an IL-6 inhibitor, in 150 mg subcutaneous injections were initiated biweekly. The patient initially reported improvement but, after 5 months, experienced recurrent joint pain, iron deficiency anemia, and thrombocytopenia. Iron supplementation (325 mg) was prescribed, and the sarilumab dosing interval was adjusted to every 3 weeks.

Three months later, the patient returned with extremity edema and bilateral tender, swollen joints, particularly in the hands and right knee. Sarilumab was discontinued, and prednisone 10 mg daily was initiated. Tocilizumab, an IL-6 inhibitor, in 162 mg subcutaneous injections biweekly was prescribed.

Seven months later, the patient reported persistent pain and stiffness, noting nonadherence to tocilizumab, due to discomfort with self-injections. Treatment was transitioned to monthly intravenous (i.v.) tocilizumab at 8 mg/kg.

Ten months after initiating i.v. tocilizumab, the patient reported significant clinical improvement, with no active inflammation or joint pain at presentation. This improvement may be attributed to both the increased bioavailability of the i.v. formulation, compared with the subcutaneous injection, and improved adherence. The patient previously struggled with self-administering subcutaneous injections, which may have contributed to suboptimal drug levels and disease control. Intravenous administration ensures full drug delivery and removes the barrier of self-injection, leading to more consistent therapeutic effects.

The bioavailability of a medication varies by route of administration; oral formulations typically have the lowest bioavailability, due to gastrointestinal metabolism, whereas i.v. administration provides nearly complete systemic availability. In this case, the switch to i.v. tocilizumab appeared to have enhanced drug efficacy, leading to better disease control. Laboratory findings further support this improvement, with a C-reactive protein level of <1 mg/L (reference range: 0–10 mg/L) and an ESR of 11 mm/h, indicating minimal inflammatory activity. However, the patient continued to have anemia (hemoglobin: 10.1 g/dL) and thrombocytopenia (platelet count: 15×103/μL), suggesting ongoing hematologic monitoring was required. Treatment decisions and outcomes are summarized in Table 1.

Discussion

Managing RA with concurrent hematological conditions presents a complex clinical challenge. In this case, we discussed the management of RA in a patient with aplastic anemia, to balance inflammation and symptom control while minimizing hematological complications.

Methotrexate, a traditional DMARD, was not recommended, due to the documented risk of pancytopenia exacerbation [8,9]. Hydroxychloroquine was selected due to its favorable hematological profile [10]. Although the patient had previously experienced limited response to hydroxychloroquine in the context of ulcerative colitis, it was selected for RA based on its safety profile in the setting of aplastic anemia. However, disease progression and hematological complications prompted a switch to IL-6 receptor antagonists. Other DMARDs were carefully evaluated but not pursued: TNF inhibitors were contraindicated due to risk of worsening aplastic anemia; JAK inhibitors, while not formally contraindicated, were deferred in favor of IL-6 inhibitors, given their longer safety record and established efficacy; sulfasalazine was avoided due to its known rare association with drug-induced aplastic anemia. The patient initially received subcutaneous IL-6 inhibitors but was nonadherent with injections; therefore, an i.v. route was started. Given emerging evidence that elevated IL-6 levels can contribute to the severity of aplastic anemia [11], targeting this pathway provided a rational therapeutic strategy to potentially benefit both RA disease activity and underlying hematologic abnormalities.

Despite initial improvement, the patient developed iron deficiency anemia and thrombocytopenia, requiring further therapy adjustments. This highlights the need for close monitoring of the hematological profile and rapid intervention. Based on our experience and existing RA monitoring recommendations, we suggest hematologic laboratory monitoring (complete blood count with differential) every 4 to 6 weeks during DMARD initiation and early treatment, and every 2 to 3 months once stable, with more frequent monitoring as clinically indicated in patients with pre-existing aplastic anemia.

Medication adherence was also a significant barrier to effective management in this case. The patient’s reluctance to self-administer subcutaneous injections and discomfort with needles underscores the importance of continuous patient education and shared decision-making in treatment selection and maintenance. Strategies to improve adherence can include proactive counseling about the importance of adherence, demonstration of injection techniques, and, when necessary, switching to alternative administration routes such as i.v. therapy to support consistent treatment delivery.

Few reports exist describing the management of RA in patients with concurrent aplastic anemia. To the best of our knowledge, this is among the first detailed case reports to describe treatment selection, monitoring, and outcomes in this rare clinical context. Published literature remains limited to isolated case reports without formal guidelines to inform therapeutic choices. This report contributes novel insights regarding the use of IL-6 inhibitors as a potentially safe and effective strategy in such patients.

This case highlights the significance of an adaptable approach to RA management in patients with multiple comorbidities. Inter-specialty collaboration and continuous monitoring were essential in managing this case. Furthermore, this experience illustrates the importance of integrating hematology, rheumatology, and patient-centered education into the treatment plan, to optimize outcomes. More research is needed to refine treatment strategies and improve outcomes in RA with concurrent aplastic anemia. Given the rarity of this overlap, prospective data and treatment guidelines are lacking; therefore, individualized therapy based on patient-specific hematologic and rheumatologic considerations remains essential.

Conclusions

This case demonstrates the successful management of newly diagnosed RA in the setting of complex hematologic comorbidities, such as aplastic anemia. The hematologic profiles of DMARDs were carefully considered to guide a treatment plan that minimized adverse effects and allowed for timely therapeutic adjustments. Intravenous tocilizumab ultimately demonstrated success in controlling disease activity and was well tolerated. The challenges and nuances in this case underscore the lack of formal, evidence-based guidelines for the treatment of RA with aplastic anemia. Further studies are warranted to evaluate the safety and efficacy of DMARD regimens in this patient population.