Kohl, Nick_Senior Thesis 2026

Uses of Adalimumab and its Future Application to the Treatment of Autoimmune Disease Nick Kohl Senior Thesis | 2026

Uses of Adalimumab and Its Future Application to the Treatment of Autoimmune Disease Nick Kohl∗ Boston University Academy E-mail: nickkohl@bu.edu Abstract This paper is a thorough literature review about the previous uses of the monoclonal antibody adalimumab, particularly in the treatment of autoimmune diseases. After being approved for the treatment of rheumatoid arthritis, its uses only grew, now encompassing inflammatory bowel disease, uveitis, and hidradenitis suppurativa. In addition to its on-label uses, it has been used to treat a variety of other diseases, almost always when first-, second-, and even third-line treatments fail. Understanding adalimumab comes down to understanding TNF-α, the cytokine it inhibits, and the drug’s pharmacological properties. TNF-α, a key inflammatory cytokine in the immune system, is implicated in the etiology of many diseases, especially autoimmune. Getting to the bottom of the cascade it is a part of helps shed light onto the path by which one’s immune system starts to malfunction and attack self tissues. Adalimumab’s

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pharmacology, encompassing how it is administered, by what means and how much the body distributes the drug into tissues, how fast it takes to work, what it specifically acts on within the body, and how long and through which organs it gets eliminated, is integral to understanding the precise way it interacts with TNF-α, thereby interfering with the inflammatory, disease-causing process.

Introduction Autoimmune diseases, diseases defined by the immune system mistakenly attacking one’s own tissues, affect about 8% of the US population, and 5-8% of the world’s population.1,2 These diseases have a heavy burden on quality of life and may cause life-threatening symptoms.3 Currently, autoimmune diseases (across various organs) are treated most commonly by Janus Kinase (JAK) inhibitors, as well as inhibitors of cytokines (Tumor Necrosis Factor [TNF], Interleukins [IL]) and other immunomodulatory drugs.2 Despite the efficacy of these modes of treatment, challenges arise. The first challenge comes with the highly variable nature of the immune system: patients can react very differently to the same treatment, requiring a unique treatment plan for each individual. The second challenge comes from the interconnected nature of immune processes.2 Affecting one cytokine or signaling molecule inevitably affects others, and this cascade can be hard to predict in advance. As a result, the treatment of autoimmune diseases is a difficult problem being studied today.

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Arthrides Rheumatoid arthritis (RA) is an autoimmune condition characterized primarily by inflammatory arthritis, as well as extra-articular, systemic symptoms.4 The arthritis is usually symmetric and starts in peripheral joints before moving to proximal joints. Over time, cartilage in the joints becomes eroded, leading to arthralgia, mechanical issues, and bony erosions if left untreated. Worldwide, the incidence rate of RA is 0.24%. In the US, there is a gender gap: the RA rate in women is 3.6% versus the 1.7% in men.

There is a genetic component in RA; a 2013 Swedish study showed a 40% rate of heritability, and this was especially the case for seropositive and early-onset RA. Psoriatic Arthritis (PsA) is a chronic inflammatory arthritis that shares features with RA and spondyloarthritis (SpA).5 The rate of PsA in psoriasis (Ps) patients is about 20%, compared to the 0.05-0.25% rate in the general population.

Specifically, it is associated with more severe psoriatic symptoms, as well as scalp psoriasis, intergluteal and perianal psoriasis, and nail pitting. PsA is usually seronegative, though some patients will have positive rheumatoid factor (RF) or anti-cyclic citrullinated peptide (anti-CCP) titers. The exact etiology is multifaceted, but there is a definite genetic component. 20% of PsA patients with axial skeletal symptoms have the HLA-B27 gene. This cohort tends to appear clinically similar to ankylosing spondylitis (AS) patients (where 90% of AS patients have this gene, too). Akin to the Koebner phenomenon in Ps–where skin trauma triggers the formation of lesions–there is evidence for a “deep” Koebner phenomenon in PsA, where joint trauma triggers arthritis symptoms. In PsA, activated macrophages and Dendritic 3

Cells (DCs) produce IL-23, key to its pathogenesis. Unlike RA, where the prominent feature is synovitis, enthesitis is the prominent feature of PsA. For this reason, distal arthritis is more common in PsA than in RA; There are many entheses, but not much synovial tissue in distal joints.

Juvenile Idiopathic Arthritis (JIA), the most common rheumatological disorder in children, is a group of seven types of arthritis, each with their own symptoms and characteristics.6 It used to be known as Juvenile Chronic Arthritis and Juvenile Rheumatoid Arthritis, before being merged into JIA in 1995. The subtypes are oligoarthritis, RF-positive polyarthritis, RF-negative polyarthritis, systemic arthritis, psoriatic arthritis, enthesitis-related arthritis, and undifferentiated arthritis. The exact etiology is currently unknown, though antibiotic exposure, being born via C-section, and certain pathogens are possible risks. Certain HLA alleles are known to put one at risk for JIA. A US and Canada study found the rate of JIA to be 0.041 to 0.061 per 1000 children. Oligoarthritis is the most common subtype, representing about half of JIA cases. The next most common is RF-negative, followed by systemic arthritis. Most subtypes of JIA are characterized by an imbalance of Th1 and Th17 cells, showing it to be physiologically similar to both RA and PsA.6,7 In addition, the histopathological findings are similar to those in adults with RA.6 Typical RA treatment consists of various disease-modifying antirheumatic drugs (DMARDs): conventional DMARDs (hydroxychloroquine, methotrexate, leflunomide, sulfasalazine), biologics (e.g., TNF inhibitors, among others), and targeted synthetic DMARDs (i.e., JAK inhibitors).8 Patients who are not meeting their treatment 4

goals with methotrexate alone may benefit from adding on concurrent TNF inhibitor therapy. Treatment of moderate-to-severe JIA in patients over 2 years of age is similar: nonsteroidal anti-inflammatory drugs (NSAIDs), systemic and intra-articular corticosteroids, and various DMARDs, both biologic and conventional. Adalimumab is used to manage symptoms of PsA vis-à-vis improving physical function and stopping disease progression in adults.8 It is used either alone or in conjunction with nonbiologic DMARDs. Other nonbiologic treatments include methotrexate, sulfasalazine, cyclosporine, leflunomide, and apremilast.

Psoriasis Psoriasis is a chronic inflammatory dermatological condition, causing erythematous plaques with characteristic silver “scaling”, as well as extradermatological symptoms affecting the nails, eyes, and tongue.9 Plaque lesions, affecting 85-90% of psoriasis patients, occur most commonly on extensors of extremities (elbows, knees, back), as well as on the scalp. Less common psoriasis subtypes include guttate psoriasis, characterized by raindrop-shaped lesions appearing after strep infections, pustular psoriasis, presenting with sterile pustules on erythematous plaques, erythrodermic psoriasis, a serious exacerbation of plaque psoriasis caused by abruptly stopping corticosteroid treatment, and inverse psoriasis, a form characterized by smooth, erythematous lesions with clear-defined borders that occur on flexural surfaces. The treatment for mild to moderate cases is topical agents: moisturizers, retinoids, and corticosteroids.9 Phototherapy, including PUVA (psoralen and UVA light) and 5

NBUVB (narrowband UVB light), is also common and well-tolerated. In patients whose symptoms do not respond to topical agents and phototherapy, methotrexate and other systemic drugs (cyclosporine, retinoids, fumarates) are the next treatment line. If the patient does not respond to these systemic treatments, the next treatment line is biologic agents (TNF inhibitors, IL inhibitors).

Ankylosing Spondylitis Ankylosing Spondylitis is an autoinflammatory disease primarily affecting the axial skeleton, leading to symptoms such as pain, enthesitis, and physical impairment.10 Long-term effects include cervical flexion, reduced lumbar lordosis, posterior rotation of the pelvis, hip extension, knee flexion, ankle plantar flexion, and kyphosis. Effects on the hips occur in about 40% of patients. AS usually presents between the ages of 15 and 25, with males having a greater prevalence. AS is a type of spondyloarthritis, a group of conditions characterized by inflammatory back pain, asymmetrical oligoarthritis of the lower limbs, and potential for other autoinflammatory complications. There is a strong correlation with human leukocyte antigen B27 (HLA-B27). AS is specifically defined as radiographic axial spondyloarthritis (axSpA), due to characteristic radiological findings. First-line treatment for AS is NSAIDs for pain and inflammation management.10 In cases of peripheral AS, DMARDs such as methotrexate, hydroxychloroquine, and thalidomide are effective.

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Inflammatory Bowel Disease Crohn’s disease (CD) is an inflammatory disorder affecting the gastrointestinal (GI) tract, particularly the small intestine, and is one of two diseases known together as Inflammatory Bowel Disease (IBD).11 Common symptoms include diarrhea, abdominal pain, rectal bleeding, and weight loss. Patients also sometimes develop extraintestinal symptoms, often ones characteristic of other autoimmune diseases, such as spondyloarthritis, uveitis, and cutaneous symptoms. Patients with CD are at risk for developing intestinal strictures, possibly leading to bowel obstruction and perforation. First-line treatment is 6-Mercaptopurine (6MP) and azathioprine, corticosteroids, or mesalamine, with methotrexate.12 In more severe cases, biologics (infliximab, adalimumab, certolizumab pegol, vedolizumab, ustekinumab, risankizumab) can be used.

Adalimumab is used in pediatric (≥ 6 years of age) populations for patients whose symptoms are not adequately controlled by steroids and exclusive enteral nutrition and/or immunomodulators, with the exception of patients who have complex perianal fistulas.8 In adults with moderate-to-severe CD, it is used as induction and maintenance therapy. Ulcerative colitis (UC) is an inflammatory disorder causing erosions of the colon wall, leading to bleeding.13 The etiology is unknown, though there is evidently a genetic component, as the disease occurs 4 times more often in first-degree relatives of UC patients.11 First-line treatment is enteral sulfasalazine and 5-aminosalicylates, which can induce remission within two weeks.13 If insufficient, enteral glucocorticoids may be used, followed by 6-MP and azathioprine or biologics (infliximab, adalimumab, golimumab, vedolizumab). TNF inhibitors are 7

a first-line treatment for induction and maintenance of remission in adults who have moderate-to-severe UC.8 Adalimumab is used in pediatric populations (≥5 years old) when 5-aminosalicylates/azathioprine are not effective, or who are unable to go off of corticosteroids when on 5-aminosalicylates/azathioprine. Colectomy is curative, though only indicated in patients for whom other treatments have been ineffective, those with colon cancer, or those with other life-threatening complications.13

Non-Infectious Uveitis Non-infectious uveitis (NIU) is a type of uveitis (inflammation of the uvea, the middle part of the eye) not associated with a pathogen.14,15 It is most often idiopathic, but is also associated with autoimmune and other inflammatory conditions such as JIA, IBD, and BD, among others. Depending on the affected area, different symptoms are present. Some common symptoms are blurry vision, floaters, eye pain, rubeosis, and photophobia. Uveitis, if left untreated, can lead to vision loss, accounting for 10% of blindness cases in the US. NIU’s etiology is not well-understood, though it is thought that naive T-cells, which would normally not be allowed through the blood-retinal barrier, may be able to “sneak through”, causing immune sensitivity to retinal proteins.15,16 First-line treatment for NIU is topical or intraocular corticosteroids, as well as methotrexate in some cases.17,18 Biologic treatments, often adalimumab, can be used with methotrexate for refractory uveitis.

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Hidradenitis Suppurativa Hidradenitis Suppurativa (HS) is an inflammatory dermatological condition formerly known as Acne Inversa.19,20 HS lesions include nodules, abscesses, and sinus tracts leading to severe, fibrotic scarring.20 The distribution of lesions on the body maps exactly onto the distribution of apocrine glands on the body: with lesions primarily occurring in the axillary and groin regions, and to a lesser extent in the mammary, perineal, and intergluteal regions.21 Individuals with HS are more likely to be obese, with increased skin area leading to increased sweat production and shear forces.20,21 Hormones, too, seem to play a part in its etiology, as women are 3 times more likely to develop HS than men, and because menstrual cycles seem to affect symptoms.20 HS is a part of the follicular occlusion tetrad, consisting of acne conglobata (AC), dissecting cellulitis, and pilonidal disease.17,19,20 HS treatment starts with addressing comorbidities that are known to worsen the syndrome, namely obesity and smoking.20 Analgesics, such as lidocaine, NSAIDs, and acetaminophen, are important to reduce pain from lesions.

Additionally, wound care is vital, covering the minimization of further skin trauma, intralesional steroids to control inflammation, and topical antibiotics. Topical clindamycin, in conjunction with systemic therapy, is the most effective first-line treatment. Systemic treatments involve oral tetracyclines, anti-androgens, and antidiabetics (i.e., metformin). If needed, other antibiotics (different tetracyclines, dapsone, rifampin) can be used. If both firstand second-line therapies fail, then biologics are the next treatment line, with adalimumab being the most 9

well-researched in HS. Adalimumab is indicated for use in those 12 years of age or older with moderate-to-severe HS.8

Acne Conglobata Acne Conglobata is a chronic inflammatory disease characterized by severe nodulocystic acne.17 The disease is disfiguring, due to extensive scarring from characteristic inflammation, burrowing abscesses, and healing of cysts and nodules. Acne cysts often discharge malodorous pus.17,19 Lesions, upon draining, usually crust over before scarring.17 The most common locations for lesions include the face, shoulders, back, buttocks, and chest. It may occur on its own or as a worsening of acne vulgaris.17,19 AC is more common in young adult males.17 The exact disease etiology is unknown, but there are several known risk factors. There appears to be a genetic component. There is also an association with anabolic androgenic steroid (AAS) use.17,19,22,23 There are androgen receptors in sebocytes and follicular keratinocytes, and as such, sebaceous glands are controlled primarily by androgens.17,22 Skin biopsy of individuals taking exogenous androgens showed hypertrophied sebaceous glands.23 It also seems that taking AAS increases the concentration of Cutibacterium acnes, a bacterium known to be involved in the etiology of acne, on the skin. First-line treatment for AC is oral isotretinoin, with or without corticosteroids.17 Antibiotics may also be used: tetracyclines at first and oral dapsone if other therapies prove ineffective.17,19 TNF-α inhibitors, including adalimumab, have been used in a handful of cases to successfully treat treatment-resistant AC, both on its own and in the context of systemic conditions.24,25 10

Behçet’s Disease Behçet’s Disease (BD) is a chronic, relapsing, systemic vasculitis affecting multiple organ systems.26 It is characterized by chronic aphthous ulcers (canker sores), along with ≥ 2 of genital ulcers, ocular lesions, specific skin lesions, and/or a positive pathergy test. There may also be vascular and/or central nervous system (CNS) involvement.

BD is associated with the histocompatibility complex antigen HLA-B51 gene. The exact etiology of BD is unknown, but the disease is characterized by hyperfunction of neutrophils, causing tissue damage and vasculitis. In patients with active BD, a greater number of peripheral blood cells were found to secrete Interferon (IFN)-γ, IL-12, and TNF-α. For example, γδ T-cells and monocytes were found to have increased expression of TNF-α. Additionally, ulcerative lesions in patients with ulcerative BD have shown increased expression of TNF-α mRNA. After treatment, the increased expression stops, suggesting TNF-α plays a role in the disease.

Typical treatments include various immunosuppressive therapies (colchicine, cyclosporine A, cyclophosphamide, methotrexate, azathioprine), though these are not effective at reducing disease activity. Adalimumab and other TNF-α inhibitors, namely infliximab, have been used in the treatment of BD. For ocular manifestations of BD, the American Uveitis Society has proposed adalimumab and infliximab as first-line treatments.

Pyoderma Gangrenosum Pyoderma Gangrenosum (PG) is a type of neutrophilic dermatosis occurring overwhelmingly in adults, and often 11

alongside another systemic disease, such as RA or IBD, or various malignancies.27,28 The characteristic ulcer is painful, with dusky, necrotic edges.28 The etiology is not fully understood, though immune system dysfunction and genetics are thought to play a role. Lesions have been found to have higher levels of clonal T-cells and IL-23, both of which play a role in inflammation. Mutations in JAK2, too, have been found in association with PG. Typical treatment is variable, based on underlying diseases and rate of progression. For actively progressing disease, systemic corticosteroids and cyclosporine are used. For more contained disease, treatments tend to be intralesional. TNF inhibitors, including adalimumab, have been successfully used in the treatment of PG.28,29 In one case, a woman with PG whose treatments had been so far ineffective for the past 5 years started adalimumab therapy.

She had a loading dose of 80 mg, a second dose a week later of 40 mg, followed by maintenance doses of 40 mg biweekly.29 Her lesions were nearly completely healed after 64 weeks.

Granulomatosis with Polyangiitis Granulomatosis with Polyangiitis (GPA), formerly known as Wegener’s granulomatosis, is a rare type of vasculitis called an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).30,31 The disease is characterized by necrotizing granulomas (localized collections of immune cells, built up from persistent inflammatory stimulation) and vasculitis of small blood vessels, primarily in the upper respiratory tract, lungs, and kidneys.31,32 PG’s etiology is multifaceted, but ANCAs are known as being the drivers of 12

inflammation in GPA.31 There are 2 main types of ANCAs involved in GPA– anti-proteinase 3 (PR3) and anti-myeloperoxidase (MPO). The binding of ANCA to PR3 causes neutrophils to degranulate and adhere to the endothelium, damaging it and secreting other cytokines, such as IL-8. Certain pathogens, too, are implicated in the disease, notably the bacterium Staphylococcus aureus and viruses such as Hepatitis C Virus (HCV), Epstein-Barr Virus (EBV), and others.

Both life-threatening and non-life-threatening disease is treated with glucocorticoids and rituximab. Severe disease may also call for cyclophosphamide, and in less severe cases, methotrexate and mycophenolate mofetil can be used in lieu of rituximab.

One study analyzing the safety and efficacy of biologic therapies for GPA found that in the group treated with TNF inhibitors (n = 20), 10% had remission, 30% partial response, and 60% treatment failure at 6 months, and 25%, 20%, and 55%, respectively, at 12 months.31 This indicates that TNF inhibitors may not be optimal for treating GPA, as a <50% remission and partial response rate is unacceptable.

TNF-α and the Immune System Monoclonal Antibodies Monoclonal antibodies stand in contrast to small-molecule drugs: they’re large (>1 kDa), have complex and often poorly-defined structures, and are heterogeneous mixtures.33,34 Monoclonal antibodies, in comparison to small-molecule drugs, have several downsides: they’re difficult and expensive to produce, there is much variety in their structure, and they’re immunogenic (though this, in 13

some instances, is ideal). However, there are also several upsides: they’re extremely targeted, they do not often have metabolic interactions, and they have long half-lives.34 Monoclonal antibodies are administered parenterally, because of the heat-sensitive nature of proteins and their inability to be metabolized by the liver and kidneys, and their distribution in the lymphatic system.33,34

History TNF-α was first identified, albeit not explicitly, and used in the late 1800s by a Dr. William Coley, who found that dead bacteria and their metabolic products regressed tumors in patients with inoperable neoplasias.35 At the time, they were called “Coley’s toxins”. Later, in the 1970s, TNF-α was identified by cancer immunologist Lloyd Old, who was also the first to identify “killer” T cells (cytotoxic T lymphocytes or CTLs) and “helper” T cells (CD4+ T cells), and his colleagues. They found that TNF-α induced necrosis of certain tumors in rodents.35,36 The connection to chronic diseases was found in the 1980s, when Cerami and colleagues described a seemingly different molecule contributing to the wasting seen in chronic diseases, catechin, which was later found to be identical to TNF-α.35 TNF-α was able to be studied starting in 1984, when Goeddel and colleagues cloned both it and a related molecule, TNF-β (aka lymphotoxin).

Role in the Immune System TNF-α is most commonly secreted by macrophages, T-cells, and natural killer cells.7 It is a homotrimer protein, meaning it consists of 3 identical subunits, and it is made 14

up of 157 amino acids (Figure 1). It exists in two forms: transmembrane TNF-α (tmTNF-α) and soluble TNF-α (sTNF-α). tmTNF-α is converted to sTNF-α by TNF-α-converting enzyme (TACE). In the body, there are two specific receptors: TNF receptors 1 and 2 (TNFR1/2), or p55 and p75, respectively.37 tmTNF-α can act on both TNFR1 and TNFR2, though it mostly works through TNFR2.7 sTNF-α acts on both TNFR1 and TNFR2. TNFR1, unlike TNFR2, is ubiquitous in human tissues and is the key receptor in TNF-α’s signaling. Additionally, TNFR1 has the death domain (DD), a sequence of 70 amino acids that signals for apoptosis, whereas TNFR2, lacking a DD, cannot directly signal for apoptosis.35 TNFR2 is primarily involved in tissue regeneration, cell proliferation, and cell survival, while also triggering inflammation and defense against pathogens.7 The activation of TNFR1 then triggers the formation of various complexes, numbered I,

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Figure 1: Protein Structure of TNF-α. Each trimer is in its own color.

Image Credit: Bank, R. P. D. RCSB PDB - 1TNF: THE STRUCTURE OF TUMOR NECROSIS FACTORALPHA AT 2.6 ANGSTROMS RESOLUTION. IMPLICATIONS FOR RECEPTOR BINDING. https://www.rcsb.org/structure/1TNF (accessed 2026-03-15).38

IIa, IIb, and IIc.7 When TNF-α binds to TNFR1, TNFR1 undergoes a conformational change in its DD.39 At that point, both TNFR1-Associated Death Domain (TRADD) and receptor-interacting serine/threonine protein kinase 1 (RIPK1) form complex I. Complex I is responsible for initiating inflammation, cell survival, and proliferation, and the immune system’s response to pathogens.7 The formation of complex I relies on the ubiquitination of 16

Figure 2: The cascade set off by TNF-α and its various effects. Image Credit: Jang, D. et al. The Role of Tumor Necrosis Factor Alpha (TNF-α) in Autoimmune Disease and Current TNF-α Inhibitors in Therapeutics.

Int J Mol Sci 2021, 22 (5), 2719. https://doi.org/10.3390/ijms22052719.7

RIPK1; when this does not occur, it is able to dissociate from complex I and form complex IIb.39 The formation of complexes IIa and IIb (apoptosome) (Figure 2) results in apoptosis.7 To stop the formation of complex IIc, a complex of caspase-8 or pro-caspase-8 with FLICE-like inhibitory protein long (cFLIPL) needs to cleave RIPK1 and 3.39

Role in Autoimmune Disease In RA, TNF-α is secreted from Th1 cells and macrophages. It then activates synovial fibroblasts, as well as promoting epidermal hyperplasia and the recruitment of inflammatory cells.7 Activated fibroblasts then overexpress cathepsins and matrix metalloproteinases (MMPs), which break down collagen and other parts of the extracellular matrix (ECM). The end result is cartilage and bone 17

degradation, eroding the joint on the whole. In PsA, TNF-α activates DCs and macrophages, causing them to oversecrete TNF-α and IL-23. IL-23 then allows for the overproduction of IL-17. IL-17 and TNF-α work to activate keratinocytes, causing epidermal hyperplasia and recruiting further inflammatory cells. TNF-α also promotes antiapoptosis of keratinocytes, eventually leading to the formation of microabscesses in psoriasis. In Ps, stressed keratinocytes oversecrete TNF-α, IL-1, and IL-6, which activate DCs. Activated DCs produce IL-12 and IL-23, which differentiate T cells, which then secrete TNF-α, IFN-γ, and IL-17. DCs are continuously activated by TNF-α, keeping this process going. The ultimate result is the overproliferation of keratinocytes, acanthosis, parakeratosis, and hypogranulosis. In both UC and CD, Th1 secretes TNF-α, IL-1, IL-6, and IL-17, which end up accumulating intestinal fibroblasts, neutrophils, and macrophages. Intestinal fibroblasts become fibrosis, forming strictures in the intestines. Neutrophils and macrophages degrade the ECM, and macrophages also cause epithelial damage, endothelial activation, and vascular disruption. Finally, in NIU, macrophages produce TNF-α, IL-6, IL-10, IL-12, and IL-23 excessively, eventually leading to activated Th1 and Th17 cells infiltrating the uvea. There, the cells damage the blood-retinal barrier, recruit further inflammatory cells, and trigger retinal vasculature, with the end result that the uvea may eventually be destroyed.

Significance Evidently, TNF-α is crucial to the etiology of several autoimmune diseases. In addition to the diseases covered 18

here, it is also a key part of the etiology of diseases such as lupus erythematosus and sarcoidosis.40,41 It stands to reason, then, that TNF inhibitors hold potential for the treatment of a wide variety of autoimmune and related diseases. Adalimumab, as a well-tolerated and widely used drug in this class, should be further considered for potential applications in other diseases.

About Adalimumab Adalimumab (C6428H9912N1694O1987S46) is a large protein (Figure 3) consisting of 1330 amino acids with a mass of 148 kDa and a pH of 5.2.37,42 Adalimumab belongs to a class of drugs called monoclonal antibodies, as well as the class known as disease-modifying anti-rheumatic drugs (DMARDs). More specifically, it is a tumor necrosis factor alpha (TNF-α) inhibitor. Adalimumab was first approved for RA by the FDA in 2002.8,27 It was the third TNF-α inhibitor developed.27

Manufacturing Adalimumab is a recombinant, fully human IgG1-derived antibody expressed in a Chinese Hamster Ovary (CHO) cell line.37,44 Mammalian cells are common for the production of clinical proteins, because they are more effective at correct protein folding, assembly, and post-translational proteolysis than other cell types.45 The recombinant gene and the transcriptional elements are added to the

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Figure 3: Protein Structure of adalimumab. Alpha helices are in blue, beta pleated sheets are in red, and coils are in yellow. Image Credit: condray, cass.

Adalimumab.

NIH 3D. https://3d.nih.gov/entries/3DPX-016551 (accessed 2026-03-15).43

mammalian cells. Another gene is also added that selects for the survival of cells with the recombinant gene in them.

The non-selected cells are killed, leaving only the cells with the target gene in them. Cells are subsequently cloned.45 The resulting antibody has a human IgG1 constant region and human-derived light and heavy chain variable regions.45

Pharmacokinetics Adalimumab is delivered either as an autoinjector (commonly known as a “pen”) or as a prefilled syringe in a 20

concentration of 100 mg/mL.37 It is designed to be administered subcutaneously. For adults and children 12 years of age and older, 40 mg biweekly is the dose for most indications. For adults with IBD, the initial dosage is 160 mg, followed by an 80 mg dosage, followed by the standard dosage.27,37 For plaque psoriasis and adult uveitis, the initial dosage is 80 mg, followed by the standard dosage, started one week after the initial dose.27 For HS, the initial dosage is 160 mg, followed by an 80 mg dosage, followed by 40 mg administered weekly.27 For pediatric JIA/NIU, dosages range from 10-40 mg biweekly, depending on weight.27,37 Patients with RA who are not also taking other DMARDs may take 40 mg weekly, or 80 mg biweekly for increased efficacy.37 The mean bioavailability of adalimumab, an important parameter when considering the efficacy of a particular Route of Administration (RoA) of a drug, of a single 40 mg SC dose is 64%.37,46,47 The bioavailability, sometimes called the absolute bioavailability, of a drug at a particular dosage and route of administration is a measure of how much of the administered drug reaches systemic circulation, at which point it can take effect.46,47 It is calculated as the ratio of the Area Under Curve (AUC) serum concentration after the administration of a drug by one RoA to the AUC serum concentration after IV administration, which is always assumed to be 100%. The maximum serum concentration in those not also taking MTX is 4.7 ± 1.6 mcg/mL, and it was reached on average in 131 ± 56 hours in healthy subjects.37 In those taking methotrexate, plasma concentration reached 8-9 mcg/mL.27 A biweekly 80 mg dose produces comparable serum concentrations to a weekly 40 mg dose. Therapeutic proteins seem to be metabolized in the same way 21

endogenous proteins are.33 Unlike small-molecule drugs, Monoclonal antibodies are not usually metabolized by CYP450-mediated pathways or using processes that utilize cell membrane transporters.27,34 Despite this, Adalimumab may impact the metabolism of other drugs; see “Drug Interactions”.

Mechanism of Action Adalimumab inhibits the interaction of TNF-α with its surface cell receptors, TNFR1 (p55) and TNFR2 (p75).27,37 In addition, in the presence of a complement, adalimumab destroys TNF expressed on cell surfaces.37

Adalimumab in Treatment TNF inhibitors, such as adalimumab, have been previously shown to be effective in treating AS.10,48 One paper found that in multiple double-blind, placebo-controlled trials, adalimumab significantly improved rates of both functional disability and inflammation, even with those who had total spinal ankylosis (though this finding was not statistically significant).48 In the area of extra-articular AS manifestations, adalimumab was found to significantly reduce the frequency and severity of uveitis flares, with one study reporting a near half reduction.10 In patients with psoriasis and AS, adalimumab has been shown to treat both simultaneously. Similarly, in patients with IBD, adalimumab treatment has been shown to foster healing of intestinal mucosa. Interestingly, in one study, adalimumab treatment was more effective in younger populations, those with higher C-Reactive Protein (CRP) levels, naivety to TNF treatment, and the presence of HLA-B27.10,48 Long-term, adalimumab use seems to be effective: in a study over five 22

years with 125 participants, over 70% reached significant milestones, while just over half reached partial remission and inactive disease.10 A randomized, double-blind, placebo-controlled UK study comparing the effects of methotrexate monotherapy to methotrexate with adalimumab in patients with JIA-related uveitis found that patients taking both adalimumab and methotrexate were 75% less likely to experience treatment failure.22 In addition, patients on concomitant therapy were significantly more likely to experience greater disease control at 3 and 6 months, higher rates of remission at 3 and 6 months, and reduced corticosteroid usage.

When looking at 47 cases of patients with Behçet’s uveitis, the authors found that 42 (89%) patients responded well, 2 (4%) had a partial response, and 3 (6%) had no response.26 While there have been no randomized controlled studies of adalimumab’s use in intestinal manifestations of BD, a nonrandomized clinical trial showed that adalimumab was effective for both the treatment of intestinal BD and other manifestations (aphthous ulcers, erythema nodosum). Treatment of intestinal BD is important due to the risk of life-threatening complications, such as bowel perforation and acute intestinal bleeding.

Safety Infections Taking adalimumab puts one at risk for developing more severe infection, as well as opportunistic diseases (e.g., histoplasmosis).37 Contracted infections are more likely to be disseminated as opposed to localized. It is important to 23

exercise caution when treating patients with already compromised immune systems, who have chronic or recurring illnesses, who live in an area where tuberculosis (TB) or other opportunistic infections are endemic, or those with a history of TB. Outcomes are improved when patients with latent TB are treated before adalimumab therapy is commenced. Similarly, the use of adalimumab may increase the risk of reactivating Hepatitis B (HBV) in those carrying the virus. Some cases of reactivation have been fatal. Most cases have been in those taking concomitant immunosuppressants. It is important to screen patients for HBV and to monitor those with a history of or at risk for infection.

Cancer Adalimumab therapy should be carefully considered in patients with, or with a history of, malignancies, with the exception of non-melanoma skin cancer (NMSC).37 In the controlled portion of 39 clinical studies studying adalimumab’s use in RA, PsA, AS, CD, UC, Ps, HS, and NIU, malignancies, other than NMSCs (namely basal and squamous cell carcinoma), were observed at a rate of 0.7 per 100 patient-years among 7973 adalimumab patients versus a rate of 0.7 per 100 patient-years among 4848 control-treated patients. Average treatment duration was 4 months for both cohorts. In 52 global controlled and uncontrolled studies of adults being treated with adalimumab for RA, PsA, AS, CD, UC, Ps, HS, and NIU, the most common malignancies, except for lymphoma and NMSC, were of the breast, colon, prostate, lung, and melanoma, the rates of which are comparable to the general U.S. population.

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NMSC occurred in the controlled portion of 39 clinical trials looking at adults with RA, PsA, AS, CD, UC, Ps, HS, and NIU at a rate of 0.8 per 100 patient-years in the adalimumab-treated group, versus 0.2 per 100 patient-years in control-treated patients. As a result, clinicians should examine all patients, and particularly patients with previous immunosuppressant therapy, and Ps patients who have been treated with PUVA. In the controlled portion of 39 clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS, and NIU, there were 2 cases of lymphoma among 7973 adalimumab-treated patients, and 1 lymphoma case among 4848 control-treated patients.37 In 52 clinical trials studying 24,605 adult patients, with RA, PsA, AS, CD, UC, Ps, HS and NIU and over 40,215 patient-years of adalimumab with a median duration of 0.7 years, the observed rate of lymphoma was 0.11 per 100 patient-years, three times the rate in the general US population, controlled for age, gender, and race. However, it should be considered that because RA and others are chronic inflammatory diseases and often involve treatment with other immunosuppressive drugs, patients may be at a higher risk than the general population for lymphoma already. Similarly, RA patients already have about twice the risk of developing leukemia compared to the general population.

In pediatric populations (defined as having initiated treatment before age 18), there have been some sometimes-fatal malignancies reported.37 About half of the malignancies were lymphomas, while the other half were a variety that included some that are rare in children and some already known to be associated with immunosuppression. In a cohort of patients, mostly young 25

men with IBD taking TNF inhibitors at the same time as or after azathioprine or 6-mercaptopurine (6–MP), developed hepatosplenic T-cell lymphoma. These patients’ diseases were aggressive and often fatal.

Other Diseases Other TNF inhibitors have been linked to cases of worsening or new-onset congestive heart failure (CHF).37 Adalimumab has not been studied in CHF, but another TNF inhibitor has been linked to adverse events in CHF, so caution should be exercised in those with CHF and at risk for CHF. A possible side effect of TNF inhibitor therapy is the development of autoantibodies and antidrug antibodies.37 Anti-drug antibodies occur when the immune system recognizes the drug (generally a monoclonal antibody) as a foreign entity and then produces antibodies to destroy it.

This can potentially affect treatment efficacy or harm the patient.49 Anti-adalimumab antibody development was not found to be associated with safety in three clinical trials.37 In studies looking at anti-adalimumab antibody development in RA, JIA, and PsA, there was a higher incidence of antibody development with adalimumab monotherapy compared to concomitant methotrexate therapy. Autoantibodies may result from adalimumab therapy and may rarely lead to a lupus-like syndrome. In RA controlled trials, 12% of patients of the adalimumab group and 7% of the control group developed a positive Anti-Nuclear Antibody (ANA) at week 24 after a baseline negative ANA. Two patients out of the 3046 treated with adalimumab developed symptoms of a new-onset 26

lupus-like syndrome. These patients did not develop lupus nephritis or CNS symptoms. Symptoms dissipated upon cessation of adalimumab therapy.

Use of TNF inhibitors, including adalimumab, has been associated with rare cases of new-onset or exacerbation of CNS demyelinating diseases, including multiple sclerosis, optic neuritis, and Guillain-Barré Syndrome.37 Caution should be exercised in those with a history of such diseases. It should be noted, also, that there is a known connection between intermediate uveitis and central demyelinating disorders.

TNF blockers, including adalimumab, have had rare reports of hematological abnormalities, including pancytopenia, aplastic anemia, and various cytopenias.37 The connection between adalimumab and hematological abnormalities is currently unknown. Those who develop hematological complications should consider ceasing adalimumab therapy. Interestingly, in a study looking at patients with moderate-to-severe HS, 42.4% of 594 patients with baseline labs had some sort of hematologic abnormality.50 Participants were then treated with either 40 mg adalimumab or a placebo. Patients treated with adalimumab showed significant improvements in bloodwork (hemoglobin levels, white blood cell count, platelet count), whereas placebo recipients showed no significant improvement.

Drug Interactions The use of TNF blockers, including adalimumab, with abatacept or anakinra is contraindicated, as concomitant use has been associated with even higher rates of severe 27

infection in RA.37 Concomitant use of Anakinra, an IL-1 antagonist, has also been associated with a greater risk of neutropenia, with no benefit above TNF inhibitor monotherapy for RA. Likewise, concomitant use of other immunomodulatory drugs requires caution. Patients on adalimumab are free to take concurrent vaccines, with the exception of live vaccines. Patients should be brought up-to-date on vaccinations before initiating adalimumab therapy.

Chronic inflammatory diseases can cause elevated cytokines, suppressing the production of CYP450 enzymes.

Reducing cytokines using a drug such as adalimumab may then have effects on CYP450 enzymes, and as such, patients undergoing concurrent treatment with CYP450 substrates should be monitored for changes in drug concentration.27,51

Conclusion TNF-α is a cytokine key to the etiology of many diseases which impose a heavy burden onto those affected by them.

Future research should study adalimumab’s usage in further diseases or in different dosages/forms.

Adalimumab also need not be the final product: more innovation in the pharmaceutical field can lead to more readily available and better drugs. Improvements are always able to be made to safety and efficacy. Further elucidating the etiology of diseases is also an important step in treating them more effectively. One limitation, of course, of this paper is that it is a literature review. In the future, I hope to contribute personally to this field by means of my own research.

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Acknowledgement The author thanks Dr. Elizabeth Karnaukh, my advisor, for guiding me through this process and teaching me so much.

The author also thanks Camilo Gutiérrez-Lara for peer editing this paper and his generally invaluable advice.

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