The case of multiple changes in genetically engineered biological therapy in a child with juvenile idiopathic arthritis

Introduction

Juvenile idiopathic arthritis (JIA) is one of the most common pathologies within the structure of rheumatic diseases in children of different age groups. In Russia, the prevalence of JIA among the pediatric population reaches 62.3 per 100,000 children and continues to steadily increase [1, 2]. The significant rise in incidence, along with the high risk of disability and the impact on patients’ quality of life, defines the current research focus on approaches to the diagnosis and therapy of this disease [3].

In recent years, detailed studies of the pathogenesis of rheumatic diseases have achieved significant results. JIA belongs to the group of immune-mediated inflammatory diseases, the main pathogenetic mechanisms of which are autoimmune and autoinflammatory processes [4]. However, the mechanisms leading to the activation of autoimmunity and autoinflammation often remain unidentified. It has been established that in JIA, the synovial membrane of the joints undergoes leukocyte infiltration, hyperplasia, and chronic inflammation. Among the cells involved in the infiltrative growth are monocytes, which represent plastic and heterogeneous populations classified according to surface expression of CD14+ and CD16+ into “classical” (CD14+CD16−), “intermediate” (CD14+CD16+), and “non-classical” (CD14−CD16+) subtypes [4, 5]. Proinflammatory cytokines, such as interleukins (IL) 1, 6, 17, 18, and 23, play a crucial role in the pathogenesis of JIA. Of particular importance are IL-1 and tumor necrosis factor-alpha (TNF-α). In some patients with JIA, TNF-α and IL-1 were detected in the synovial fluid. Activated macrophages, monocytes, and synovial fibroblasts produce these cytokines, which in turn have a significant impact on cartilage destruction. Identification of this pathogenetic pathway in the development of JIA enabled the use of drugs capable of binding and neutralizing active proinflammatory cytokines [6]. Nevertheless, despite the recognition of the numerous aspects of pathogenesis, a unified concept has not yet been achieved, which results in the insufficient clinical efficacy of current therapeutic approaches.

Once diagnosed, therapy for JIA begins with the administration of nonsteroidal anti-inflammatory drugs (NSAIDs), along with cytostatic agents (most often methotrexate) and/or corticosteroids (methylprednisolone), including intra-articular injections [7, 8]. The development and introduction of genetically engineered biological agents (biologics/GEBAs) for the treatment of rheumatic diseases had a significant impact on the course, prognosis, and life prospects of patients with JIA [9]. Clinical outcomes improved substantially, and disease control and remission became achievable in the majority of patients receiving biologic therapy. However, in a significant proportion of patients, disease activity persists, necessitating a reassessment of drug combinations.

The authors present a clinical case involving multiple changes of biologic agents in a child with JIA characterized by a severe progressive course, ANA-positive status, and HLA-B27 association.

Clinical Case

Patient K., born in 2013, was first hospitalized in the pediatric department of the Rostov State Medical University clinic in July 2019 with complaints of persistent clinical and laboratory activity of arthritis despite ongoing therapy.

The girl first fell ill in April 2016, when she developed pain in the right knee joint, gait disturbance, and pain in the left hip joint. At her place of residence, she was followed by an orthopedic surgeon and pediatrician and received anti-inflammatory therapy; however, the hip pain persisted. In October 2016, she was first examined at the Regional Children’s Hospital: ESR – 24 mm/h, CRP – normal, ASLO – normal, LDH – 451 U/L, Mantoux test and Diaskintest negative, CT scan of the hip joints – a destructive area with cortical layer disruption in the left ischial bone measuring 7.0 × 4.0 × 3.0 cm with a dense sclerotic rim. She was discharged with the diagnosis: “Lesion of the left hip joint, unspecified.” Therapy with Ibuklin provided a short-term effect. She was re-hospitalized at the Regional Children’s Hospital with the diagnosis: “Chronic osteomyelitis of the left ischial bone of unclear etiology, persistent arthrogenic contracture of the left hip joint.” Despite treatment (Lendacin 0.5 g/day, Ibuklin), hip pain persisted.

In April 2017, the girl underwent examination and treatment in the pediatric traumatology department. CT of the hip joints revealed asymmetry of the acetabula (the left wider than the right), increased volume of periarticular soft tissues of the left joint, and thickening and shortening of the neck of the left femur. Based on these findings, Perthes disease could not be excluded. As a result of treatment with lincomycin 30% (2 mL daily, course of 6 doses) and ibuprofen (5 mL twice daily), the joint syndrome became less pronounced; however, pain and swelling developed in the right ankle joint.

In May 2017, on objective examination by a rheumatologist, swelling and deformity of the proximal interphalangeal joint of the 5th finger of the left hand were noted, as well as marked limitation of movement in both hip joints (predominantly on the right), moderate swelling, and mild restriction of movement in the right ankle joint. Regular NSAID therapy led to a decrease in the severity of the articular syndrome, with no fever. Considering the increase in laboratory activity and MRI findings of the hip joints, the diagnosis was established: Juvenile chronic (rheumatoid) arthritis, polyarticular, seronegative, activity grade II, radiographic stage II, functional class III. Therapy with methotrexate 10 mg intramuscularly once a week was initiated. Since June 2019, the methotrexate dose was increased to 12 mg per week due to gradual swelling in the left knee joint, and naproxen 0.25 mg was added to the therapy.

During the first hospitalization in the pediatric department of the Rostov State Medical University clinic in July 2019, examinations revealed high disease activity (ESR increased to 39 mm/h, fibrinogen to 4.8 g/L, CRP to 24 mg/L, CIC level to 91 U, ultrasound signs of arthritis and synovitis of the left knee, left hip, and right ankle joints, and radiographic signs of deformity of the 5th finger of the left hand). Considering the progressive and aggressive course of the disease, a decision was made to initiate therapy with the biologic agent tocilizumab (Actemra) at a dose of 10 mg/kg once every 28 days. While receiving this therapy, the patient’s condition remained stable.

However, in October 2019, during an episode of acute respiratory viral infection, pain and swelling intensified in the left knee and right ankle joints, as well as in the proximal and distal interphalangeal joints of the 5th finger of the left hand. Laboratory tests showed high inflammatory activity, which persisted after the scheduled administration of tocilizumab. In this regard, the patient received pulse therapy with Solu-Medrol 250 mg/day intravenously (3 infusions) and Privigen 25 mL intravenously (2 infusions). Nevertheless, within a few days, the articular syndrome worsened. A decision was made to adjust therapy: tocilizumab was discontinued, and the soluble TNF-alpha receptor inhibitor etanercept (Enbrel) was prescribed at 0.8 mg/kg once every 7 days in combination with methotrexate. This provided stabilization of the child’s condition.

In April 2020, the girl again began to complain of increased swelling and pain in the left knee joint. She was hospitalized in the pediatric department of Rostov State Medical University, where scheduled administration of etanercept and a single intravenous infusion of Solu-Medrol 250 mg were performed. Given elevated AST (110.9 U/L) and ALT (141.7 U/L) levels, methotrexate administration was postponed and resumed at the next hospitalization.

Despite the ongoing therapy and the addition of NSAIDs (diclofenac, nimesulide), swelling of the soft tissues of the left knee joint persisted, pain syndrome became more pronounced, gait changed, morning stiffness appeared, and body temperature rose to febrile values. MRI of the left knee joint revealed signs of productive synovitis. The child was referred for hospitalization at the V.A. Nasonova Research Institute of Rheumatology to determine further treatment strategy.

During her stay in the pediatric rheumatology department of the V.A. Nasonova Research Institute of Rheumatology, ultrasound of the ankle joints (signs of synovitis, more pronounced on the right), ultrasound of the knees (synovitis of the left knee joint with marked synovial proliferation, increased vascularization, minimal synovitis of the right knee, Baker’s cyst on the left), and ultrasound of the hips (no signs of synovitis, bilateral femoral head flattening) were performed. X-rays of the hands and wrists showed early signs of arthritis. Considering the chronicity of the disease, its rapid progression, refractoriness to therapy (adequate doses of methotrexate and two biologic agents – tocilizumab and etanercept), high clinical and laboratory activity, and poor prognostic factors, the decision was made to initiate therapy with the biologic agent adalimumab (Humira). The first injection in August 2020 (20 mg) was well tolerated and initially effective, leading to a reduction in exudative joint changes and improvement in functional status.

The next administration of adalimumab took place in September 2020 in the pediatric department of Rostov State Medical University. However, three days after the injection, the patient’s condition worsened: impaired gait (limping on the left leg) and increased swelling of the left knee joint were observed. At the subsequent hospitalization, knee joint puncture with injection of diprospan and evacuation of 40 mL of synovial fluid was performed. After discharge, joint symptoms regressed but recurred by December 2020, triggered by prolonged respiratory viral infections and irregular therapy. In February 2021, due to severe pain, swelling of the left knee joint, and impaired gait, pulse therapy with intravenous methylprednisolone 500 mg/day for three days was administered, followed by oral methylprednisolone 20 mg/day, with continuation of adalimumab every 14 days. Symptoms improved temporarily, but within two weeks after corticosteroid withdrawal, swelling of the left knee joint, stiffness, and gait disturbance recurred.

In July 2021, due to a lack of stabilization, therapy was switched to the TNF-α inhibitor golimumab. A short-term positive effect was noted, but 10 days after discharge, swelling of the left knee joint worsened, accompanied by impaired gait, forced bed rest, local hyperthermia, and febrile fever. On examination at the next hospitalization, the child’s condition was assessed as moderate: excessive subcutaneous fat with Cushingoid distribution, painful and restricted knee movement, right knee size 28.5×28.5×25 cm, left knee 30×31×25 cm, deformity of the fifth finger of the left hand, and limping on the left leg. Follow-up MRI of the left knee compared with the previous year showed significant regression of synovial thickening, edema, and effusion; synovial thickening persisted along the tibial epiphysis, articular surfaces remained relatively smooth, hyaline cartilage volume was preserved, and cartilage signal was homogeneous. The child was again referred to the V.A. Nasonova Research Institute of Rheumatology, where in September 2021, given high clinical and laboratory activity, poor prognostic factors, and progressive functional impairment, therapy with the JAK inhibitor tofacitinib at a dose of 7.5 mg/kg/day was initiated.

During treatment, laboratory activity (ESR, CRP) decreased, but persistent arthritis of the left knee joint remained, requiring puncture with intra-articular kenalog injection. Tofacitinib therapy was continued; however, arthritis with contracture of the left knee persisted, confirmed by radiography (Fig. 1).

In November 2022, due to the clinical course, history of dactylitis of the fifth finger of the left hand, and high laboratory activity (ESR 58 mm/h, CRP 23 mg/L), secukinumab therapy was initiated at a dose of 75 mg on weeks 0, 1, 2, and 3, followed by monthly administration. The patient continued treatment regularly; local activity was almost completely controlled, although moderate functional impairment in the left knee joint persisted (Fig. 2).

Discussion

The presented clinical case is of particular interest due to the choice of baseline therapy for JIA in relation to the lack of efficacy or loss of efficacy of various biologic agents. In the Russian Federation, the following classes of biologics are currently approved: tumor necrosis factor α inhibitors (etanercept, infliximab, adalimumab), IL-1 receptor inhibitors (canakinumab), IL-6 receptor inhibitors (tocilizumab), IL-17 inhibitors (secukinumab), anti-B-cell therapy (rituximab), T-cell activation blocker (abatacept), and JAK kinase inhibitors (tofacitinib, TOF) [10]. However, despite the widespread use of biologics in pediatric arthritis treatment protocols and their proven efficacy, a satisfactory therapeutic result is not always achieved. In our patient, the use of different classes of biologics provided a positive but short-term effect. Over the course of four years, five switches of biologic agents were performed, including both different classes and agents within the same class: 2019 – tocilizumab (IL-6 receptor inhibitor), 2019 – etanercept (TNF-α inhibitor), 2020 – adalimumab (TNF-α inhibitor), 2021 – golimumab (TNF-α inhibitor), 2021 – tofacitinib (JAK kinase inhibitor), and 2022 – secukinumab (IL-17 inhibitor).

The achievement of a positive therapeutic effect after switching within the same class is associated with differences in molecular structure, mechanisms of action, pharmacodynamics, and pharmacokinetics. However, if therapy with one biologic agent is discontinued due to adverse effects, treatment should be continued with a drug from a different class. In cases of primary inefficacy, a positive outcome may be achieved through dose adjustment, modification of the administration regimen, or combination with methotrexate. During treatment, the development of neutralizing antibodies to individual biologics in some patients may result in secondary inefficacy or loss of response [11].

In this patient, each new biologic initially produced a positive effect manifested by clinical improvement, reduction of pain syndrome, and decreased laboratory activity. Biologic therapy was not associated with adverse events. However, this case clearly illustrates the phenomenon of loss of therapeutic efficacy (“escape effect”) during biologic treatment.

Conclusion

The presented clinical observation highlights the challenges of selecting a specific drug for the targeted therapy of JIA. The introduction of biologic agents into treatment guidelines for rheumatic diseases has had a significant impact on the clinical course and prognosis of this group of pathologies. However, despite the strong evidence base supporting the use of biologics in JIA treatment, therapy selection remains highly personalized and may require modification depending on the observed clinical response.