|Year : 2015 | Volume
| Issue : 1 | Page : 7-11
Kinjal Deepak Rambhia, Uday Sharadchandra Khopkar
Department of Dermatology, Seth GS Medical College, KEM Hospital, Parel, Mumbai, Maharashtra, India
|Date of Web Publication||1-Dec-2015|
Kinjal Deepak Rambhia
B-105 Kalpataru Classic, Chincholi Bunder Road, Malad West, Mumbai - 400 064, Maharashtra
Source of Support: None, Conflict of Interest: None
Adalimumab is a biological agent which acts by inhibiting tumor necrosis factor-alpha. It has been used for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, and moderate to severe chronic plaque psoriasis. Various studies show good efficacy in psoriasis cases, unresponsive or partially responsive to other systemic therapies and even cases of resistance to other biologics. It has helped reduce the morbidity significantly and improved the quality of life of psoriatics. Although majority of the experience of this drug is from its use in rheumatoid arthritis, this biologic has generally been considered safe even for psoriasis and other dermatologic conditions.
Keywords: Adalimumab, arthritis, biologic, dermatology, psoriasis, tumor necrosis factor-alpha
|How to cite this article:|
Rambhia KD, Khopkar US. Adalimumab. Indian J Drugs Dermatol 2015;1:7-11
| Introduction|| |
Adalimumab is the first fully human IgG1 monoclonal antibody targeting the tumor necrosis factor-alpha receptor. It was introduced in the year 2003 and is being used for various dermatological and nondermatological indications. Among the dermatologic conditions, it is approved for the treatment of moderate to severe chronic plaque psoriasis.
| Pharmacokinetics|| |
Adalimumab, initially named as D2E7, is a protein comprising 1330 amino-acids with a molecular weight of 148 kilodaltons. It is a purely human IgG1 monoclonal anti-tumor necrosis factor (TNF)-alpha antibody which is administered subcutaneously as a 40 mg dose once every 2 weeks. It has high affinity and selectivity for TNF-α and acts on the soluble as well as the membrane bound TNF-α. Its bioavailability following a single subcutaneous injection is 64%. It is slowly absorbed mainly through the lymphatics with peak concentrations at 1–2 weeks. The half-life of the drug is 14 days. The therapeutic effects of this injection are usually seen within 24 h to 1 week with maximum effect being observed at 2 weeks. The mean steady state trough level was 5 mg/ml when adalimumab was given every other week.
| Mechanism of Action|| |
TNF-α is a pro-inflammatory cytokine which is synthesized by antigen-presenting cells; activated macrophages, dendritic cells, and effector T-cells. TNF-α exerts various local and systemic effects in the development of inflammatory and autoimmune diseases by regulating numerous cellular and molecular signals which are implicated in the causation of inflammatory cascades of the autoimmune diseases. These pro-inflammatory cytokines in turn cause increased skin proliferation, T-cell activation, cell infiltration, and angiogenesis. Binding of adalimumab to TNF-α, prevents the interaction of the later with its receptors thereby reducing the inflammation [Figure 1].
| Indications|| |
Adalimumab is approved by the US Food and Drug Administration (FDA) for the use in:
- Rheumatoid arthritis
- Psoriatic arthritis 
- Juvenile idiopathic arthritis
- Ankylosing spondylitis
- Crohn's disease
- Ulcerative colitis
- Moderate to severe chronic plaque psoriasis.
Apart from psoriasis, other dermatologic indications where adalimumab has been used include:
- Hidradenitis suppurativa 
- Neutrophilic dermatosis – pyoderma gangrenosum, Behcet's disease
- Wegener's granulomatosis
- Sarcoidosis 
- Multicentric reticulohistiocytosis
- Alopecia areata.
| Dosing|| |
Adalimumab is given as an initial dose of 80 mg subcutaneous injection, second dose of 40 mg after 1 week, and thereafter 40 mg every other week. If no response is seen in 12–16 weeks, treatment may be reconsidered. In patients who respond, treatment may be continued as per the clinical response.
| Contraindications|| |
- Hypersensitivity to the drug
- Neurological disorders
| Adverse Effects|| |
Various clinical trials have shown that adalimumab is usually well-tolerated. The adverse events noted were mild and did not require discontinuation of the therapy. Development of serious adverse reactions was rare. A comparison of the TNF-α antagonists is shown in [Table 1]. The adverse reactions described with the use of adalimumab include:
Local injection site reactions
The most common adverse events after adalimumab injections were injection site reactions. They are usually mild and transient, being characterized by pruritus, pain, erythema, and urticarial plaques. In clinical trials, these reactions were observed in 20.3% of patients treated with adalimumab in contrast to 13.8% of patients treated with placebo. These reactions, being mild, do not usually require any treatment.
Anaphylaxis and angioedema have been reported following treatment with adalimumab.
| Cutaneous Adverse Events|| |
Skin infections, allergic rash, urticaria, drug eruptions, eczematous and psoriasiform eruptions, vasculitis, ulcers, actinic keratoses, tumors, treatment-related plaque psoriasis, and pustulosis  have all been described.
| Infections|| |
Patient taking adalimumab are at a risk of developing infections. TNF-α is a molecule which plays a key role in maintaining the body's immune system. It is a key signaling molecule in the immune response to combat infections. Blockage of this pathway by anti-TNF-α (adalimumab) results in an increased predilection for the development of serious infections. The incidence of serious infections is 1.7%. The most frequent infections observed in clinical studies were rhinitis, upper respiratory tract infections, bronchitis, and urinary tract infections. It also increases the predisposition to rare infections such as fungal pneumonia, septic arthritis, and pyelonephritis. Re-activation of hepatitis B may also occur while on adalimumab treatment.
It may cause progression of latent tuberculosis to overt tuberculosis, new-onset tuberculosis, or dissemination of tuberculosis. Re-activation of latent tuberculosis usually occurs within the first 8 months of treatment. Hence, it is recommended to do a complete blood count, erythrocyte sedimentation rate (ESR), tuberculin skin test, and chest radiograph prior to the treatment with adalimumab. Interferon gamma release assays (IGRAs) such as QuantiFERON-TB test, the QuantiFERON-TB Gold test (QFT-G), and the T-SPOT TB approved by the US FDA can also be used to aid in the diagnosis of latent and active tubercular infection. In the presence of any of these tests being positive, initiating patients on adalimumab is not recommended.
Other opportunistic infections that have been occasionally reported to occur in patients on adalimumab are:
Bacterial: Listeriosis, legionella pneumonias, and  mycobacterial infections.
Fungal: Aspergillosis, blastomycosis, coccidioidomycosis, candidiasis, histoplasmosis, pneumocystosis, and paracoccidioidomycosis.
| Malignancies|| |
Patients treated with adalimumab are at an increased risk to develop malignancies including lymphomas (Hodgkin's and non-Hodgkin's lymphoma) and nonmelanoma cancers (basal cell carcinoma and squamous cell carcinoma). There are reports of hepatosplenic T-cell lymphoma in patients of Crohn's disease treated with adalimumab. Patients with psoriasis and rheumatoid arthritis, especially those with chronic or severe disease, who have been on immunosuppressants, have an additional risk of developing lymphomas than the general population even in the absence of treatment with adalimumab.
| Neurological Reactions|| |
The use of adalimumab has been associated with increased number of cases of new-onset or exacerbation of previous demyelinating disorder including multiple sclerosis, optic neuritis, and Guillan–Barre syndrome. Hence, adalimumab therapy should be avoided in patients with a personal history of or a first-degree relative with a demyelinating disorder. If neurological symptoms suggestive of demyelination develop during therapy, treatment should be withdrawn.
| Hematological Abnormalities|| |
Infrequent occurrence of thrombocytopenia, leukopenia, and aplastic anemia has been reported with the use of adalimumab. However, the exact causal relationship of these reports is not yet clear. All patients on adalimumab therapy must be advised to seek medical attention if they develop fever, bruising, or bleeding.
| Congestive Heart Failure|| |
It is known to cause worsening of symptoms in congestive heart failure, and cases of new-onset congestive heart failure have also been observed in clinical studies. Hence, caution must be exercised in treating heart failure patients with adalimumab and they should be monitored carefully.
| Hepatotoxicity|| |
There are conflicting reports of the possible role of adalimumab in causing hepatotoxicity and increased risk of re-activation of hepatitis B and hepatitis C re-activation.
| Drug Induced Lupus|| |
Between 3% and 12% of patients treated with adalimumab may develop antibodies to nuclear and double stranded DNA. However, the development of systemic lupus erythematosus and lupus-like syndrome is quite rare. The formation of autoantibodies could be explained by a shift from Th1 to Th2 cytokine production, increase in apoptosis of T-cells followed by subsequent presentation of nuclear antigens, and reduction in the C-reactive protein (CRP) levels which interfere with the removal of nuclear debris.
| Drug Interactions|| |
- Concomitant use of anakinra (a recombinant human interleukin-1 receptor antagonist) does not have an additional benefit as compared to the individual agents and there is an increased risk of serious infections and neutropenia
- Live and live-attenuated vaccines should be avoided when a patient is on adalimumab therapy.
| Monitoring|| |
Before initiating adalimumab therapy, the following should be advised:
- Complete blood count
- ESR, CRP
- Liver function tests
- Urine routine and microscopy
- Mantoux test, IGRA such as QFT-G test
- Chest radiograph
- Hepatitis B surface antigen, anti-Hepatitis B core IgM antibody, anti-Hepatitis C antibody, and ELISA for human immunodeficiency virus.
On treatment initiation, the patient should be monitored for the development of signs and symptoms of infections. If infections develop, consider appropriate diagnostic tests and institute appropriate treatment.
| Use in Specific Conditions|| |
Pregnancy category: B 
Adalimumab is an IgG1 antibody and is transported across the placenta with the largest amount of transfer in third trimester of pregnancy. However, there is a paucity of well-controlled trials conducted in pregnant women. Hence, this drug should be used in pregnancy only after judging the risk-benefit ratio. TNF-α inhibitors can be used with caution for severe, recalcitrant disease, but it remains uncertain whether routine use during pregnancy is advisable.
There is little data from clinical studies which suggests that adalimumab is secreted in breast milk, but it is not likely to be absorbed in the infant gastrointestinal system. Case reports of the use of adalimumab during lactation have shown no adverse effects in the infant. Hence, adalimumab may be used in lactation with caution.
In this age group, the safety and efficacy of adalimumab has been studied only in juvenile idiopathic arthritis patients. Postmarketing cases of lymphoma including hepatosplenic T-cell lymphoma have been reported in children and young adults. However, it has not been studied in patients under the age of 4 years and <15 kg.
The incidence of serious infections and malignancies was higher in patients above the age of 65 years. Therefore, adalimumab must be used carefully in geriatric age group.
| Conclusion|| |
TNF-α is an important mediator for initiation and maintenance of the inflammatory cascade in psoriasis and psoriatic arthritis. Adalimumab, which is an anti-TNF-α antibody, is a well-tolerated biological agent and has shown excellent efficacy in the treatment of psoriasis and psoriatic arthritis. However, considering its spectrum of side effects, judicious patient selection is the most important step toward helping patients with moderate to severe psoriasis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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