Abatacept

Abatacept is an immunosuppressant for use in rheumatoid arthritis. Abatacept is a disease-modifying anti-rheumatic drug ( DMARD) used as a basic therapy for the treatment of rheumatoid arthritis.

Abatacept is a recombinant fusion protein consisting of the extracellular domain of human cytotoxic T-lymphocyte antigen-4(CTLA-4) and a modified Fc portion of human immunoglobulin G1 (IgG1).

Abatacept binds to CD80 and CD86 on the surface of antigen-presenting cells and thereby selectively modulates the costimulatory signaling pathway. In doing so, Abatacept impairs the response of naïve T lymphocytes more than that of memory T cells. According to studies, levels of inflammatory markers and interleukin-2 (IL-2) receptor as a marker of T-cell activation decreased in a dose-dependent manner.

Abatacept reduces the antigen-specific production of TNFα, interferon-γ and interleukin-2 by T lymphocytes and thus alters the inflammatory process.

Abatacept is approved in combination with methotrexate in adults for the treatment of rheumatoid arthritis. It is indicated for the: treatment of moderate to severe rheumatoid arthritis when previous treatment with at least one modifying antirheumatic drug (including methotrexate or a TNF-α inhibitor) has been unsatisfactory; and treatment of highly active and progressive rheumatoid arthritis not previously treated with methotrexate.

Alone or in combination with methotrexate, abatacept is also indicated in adults for the treatment of active psoriatic arthritis when previous treatment with DMARDs, including methotrexate, has been unsuccessful. Furthermore, the agent can be used in combination with methotrexate for the treatment of polyarticular juvenile idiopathic arthritis in children 6 years of age and older and adolescents. Abatacept is intended for the treatment of moderate to severe active forms of polyarticular juvenile idiopathic arthritis that do not respond adequately to other DMARDs, including at least one TNF inhibitor.

Off-label: The outcome of an open-label study evaluating the efficacy of Abatacept in alopecia areata remains to be seen (Mackay-Wiggan J et al. 2021).

Abatacept can be administered intravenously as a short infusion or subcutaneously as an injection. Intravenously, the substance is applied by means of a half-hour short infusion without premedication; the dosage is approximately 10 mg/kg body weight per infusion (< 60 kg: 500 mg, 60 - 100 kg: 750 mg, > 100 kg: 1000 mg). Infusions are given at baseline and after 2 or 4 weeks, then every four weeks.

The maximum dose of 1000 mg should not be exceeded.

Children and adolescents weighing less than 75 kg will receive 10mg/kg body weight. Those weighing 75kg and over will receive a dose according to the adult regimen.

Abatacept should be reapplied in adults and in children/adolescents two and four weeks after the first infusion and every 4 weeks thereafter.

There is insufficient experience for deviating doses (e.g., shortening or lengthening the infusion interval).

Subcutaneously, Abatacept can be injected weekly as a pre-filled syringe containing 125 mg of active ingredient. According to the product information, subcutaneous long-term therapy should also be started with an intravenously administered saturation dose (in the amount indicated above) if possible; the first subcutaneous injection should be given within 24 hours after the saturation infusion. When switching from intravenous to subcutaneous use, the first subcutaneous injection should be given at the time of the next scheduled infusion.

The combined use with MTX is specified in the label, for a recommendation of alternative DMARDs as combination partners, e.g. in case of MTX intolerance or contraindications, the previous experience is not sufficient, such combinations are also not approved. An application in combination with other biologics, especially TNF-alpha inhibitors, is not recommended due to increased side effect rates, especially infections. Abatacept also showed monotherapeutic efficacy in an early phase II study, but due to a lack of further experience it is not yet possible to assess whether monotherapy is an additional alternative in cases of MTX intolerance. There is no approval for this in Germany.

Side effects of Abatacept according to their frequency:

Very common:

• Upper respiratory tract infections.

Frequent:

• Lower respiratory tract infections
• Pneumonia
• Cough
• Urinary tract infections
• Herpes infections
• Influenza
• Headache
• Drowsiness
• Hypertension
• Abdominal pain, nausea, vomiting, diarrhea
• Dyspepsia
• ulceration of the mouth
• aphtous stomatitis
• liver dysfunction, increased transaminases
• fatigue, asthenia.

Occasional:

• Dental infections
• Onychomycosis
• Sepsis
• musculoskeletal infections
• Pyelonephritis
• Rhinitis
• Ear infections
• thrombocytopenia, leukopenia
• Hypersensitivity
• depression, anxiety
• Sleep disorders
• Migraine
• Paresthesia
• conjunctivitis, dry eyes
• reduced visual acuity
• Vertigo
• palpitations, tachycardia, bradycardia
• hypotension
• hot flushes, flush
• Vasculitis
• worsening of chronic obstructive pulmonary disease, bronchospasm
• Dyspnea
• gastritis
• increased tendency to bruising
• alopecia
• hyperhidrosis
• arthralgia, pain in the limbs
• amenorrhea, menorrhagia
• flu-like symptoms
• weight gain.

Rare:

• Tuberculosis
• Bacteremia
• gastrointestinal infections
• Pelvic inflammatory disease
• lymphoma
• malignant neoplasms of the lung
• Kaposi's sarcoma (Olivo D et al 2017).

Integumentary side effects:

Very common: Exanthema

Occasional: abscesses of the skin, dry skin, pruritus, urticaria, psoriasis, acne, erythema, (viral) papillomas of the skin

Increased tumor risk: Compared to other DMARDs, the use of Abatacept was associated with an increased incidence of overall cancer. There was a significantly increased incidence of non-melanoma skin cancer (mainly basal cell carcinoma ). There was no significant difference for other types of carcinoma (Montastruc F et al. 2019). However, this statement is not unchallenged (Simon TA et al.2019).

Particularly unfavorable with regard to susceptibility to infection is the combination with a biologic, especially TNF alfa blockers, e.g. etanercept, adalimumab, infliximab, which is therefore not recommended.

Combination with other drugs: Methotrexate, NSAIDs and corticosteroids showed no effect on abatacept clearance in pharmacokinetic studies. There are no major safety concerns with the use of abatacept in combination with sulfasalazine, hydroxychloroquine, or leflunomide.

Combination with other drugs affecting the immune system: Con comitant use of Abatacept and immunosuppressive or immunomodulatory biologics could potentiate the effect of Abatacept on the immune system. Insufficient data are available to assess the safety and efficacy of Abatacept in combination with anakinra or rituximab.

Vaccinations: Due to lack of data on safety, live vaccines should not be given concomitantly with Abatacept or within 3 months of discontinuation. The efficacy of immunizations may be attenuated. Some clinical data suggest that while Abatacept may attenuate the effectiveness of the immune response, the ability to mount a positive immune response is not significantly inhibited.

Combination with TNF antagonists: There is limited experience in the use of abatacept in combination with TNF antagonists. Concurrent treatment with Abatacept and a TNF antagonist is not recommended (risk of serious infections).

hypersensitivity to the active substance

severe infections (sepsis, severe opportunistic infections).

Orencia® (Bristol-Myers Squibb)

There is limited experience in the use of abatacept in combination with TNF antagonists. Patients treated concomitantly with Abatacept and TNF antagonists experienced more infections (including more serious infections) than patients treated with TNF antagonists alone. Concurrent treatment with Abatacept and a TNF antagonist is not recommended.

1. Blair HA et al.(2017) Abatacept: A Review in Rheumatoid Arthritis. Drugs 77:1221-1233.
2. Furst DE, Breedveld FC et al. (2006) Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2006.Ann Rheum Dis 65(Suppl 3): iii2-15.
3. Kuek A, Hazleman BL, Ostör AJ (2007) Immune-mediated inflammatory diseases (IMIDs) and biologic therapy: a medical revolution. Postgrad Med J 83:251-260
4. Montastruc F et al (2019) Abatacept initiation in rheumatoid arthritis and the risk of cancer: a population-based comparative cohort study. Rheumatology (Oxford) 58:683-691.
5. Mackay-Wiggan J et al.(2021) An open-label study evaluating the efficacy of abatacept in alopecia areata. J Am Acad Dermatol 84: 841-844.

6. Olivo D et al (2017) Kaposi's sarcoma after T-cell costimulation blockade with abatacept in rheumatoid arthritis: a case report. J Clin Pharm Ther 42:367-369.

7. Renert-Yuval Y et al.(2017) The Changing Landscape of Alopecia Areata: The Therapeutic Paradigm. Adv Ther 34:1594-1609.
8. Simon TA et al.(2019) Comparative risk of malignancies and infections in patients with rheumatoid arthritis initiating abatacept versus other biologics: a multi-database real-world study. Arthritis Res Ther 21:228.