Indian Dermatology Online Journal

IADVL - SIG PSORIASIS SYMPOSIUM
Year
: 2016  |  Volume : 7  |  Issue : 6  |  Page : 489--497

Biologics use in Indian psoriasis patients


Murlidhar Rajagopalan1, Asit Mital2,  
1 Department of Dermatology, Apollo Hospitals, Chennai, Tamil Nadu, India
2 Department of Dermatology, RNT Medical College, Udaipur, Rajasthan, India

Correspondence Address:
Murlidhar Rajagopalan
Department of Dermatology, Apollo Hospitals, Chennai, Tamil Nadu
India

Abstract

The biologics currently in use for psoriasis in India are etanercept, infliximab and recently introduced itolizumab and secukinumab. Biosimilars, expected to play a significant role in psoriasis management in future, have also been available for the last few years. Patients with psoriasis may be considered eligible to receive treatment with any of the licensed biologic interventions when they fulfill the eligibility criteria. The decision to proceed with treatment must be made in collaboration with the patient and include a careful assessment of the associated risks and benefits. Etanercept is indicated in moderate to severe psoriasis and moderate to severe psoriatic arthritis with a dose of 25 mg or 50 mg twice weekly. Methotrexate may be recommended as co-medication in certain clinical circumstances, e.g., where it is required for associated arthropathy, or to improve efficacy. Infliximab is indicated in severe psoriasis and moderate to severe psoriatic arthritis. Infliximab therapy should be initiated at a dose of 5 mg/kg at weeks 0, 2 and 6 and disease response assessed at 3 months.In patients who respond, subsequent infusions (5 mg/kg) should be given at 8-week intervals to maintain disease control although long-term data are available only up to 1 year.Interrupted therapy should be avoided given the associated increased risk of infusion reactions and poorer disease control. Itolizumab is indicated in moderate to severe plaque psoriasis. It is given in a dose of 1.6mg/kg iv infusions every 2 weeks for 12 weeks initially and then 1.6mg/kg every 4 weeks up to 24 weeks. Long term data are unavailable. Secukinumab is indicated in moderate to severe plaque psoriasis and psoriatic arthritis.An initial loading dosing regimen of 300 mg secukinumab should be given by subcutaneous injection at weeks 0, 1, 2 and 3 followed by maintenance dose of 300 mg every 4 weeks starting at week 4. To exclude tuberculosis (TB) before anti TNF alfa therapy and therapy with itolizumab, pretreatment chest X-ray and Mantoux skin test currently remain the preferred screening tests in patients not on immunosuppression. During treatment, and for 6 months following discontinuation, a high index of suspicion for TB should be maintained. The effect of secukinumab on TB reactivation is as yet poorly understood, hence, in the Indian scenario, it is better to follow the same guidelines for ruling out latent TB



How to cite this article:
Rajagopalan M, Mital A. Biologics use in Indian psoriasis patients.Indian Dermatol Online J 2016;7:489-497


How to cite this URL:
Rajagopalan M, Mital A. Biologics use in Indian psoriasis patients. Indian Dermatol Online J [serial online] 2016 [cited 2019 Jun 25 ];7:489-497
Available from: http://www.idoj.in/text.asp?2016/7/6/489/193915


Full Text

 Background



Psoriasis is a chronic relapsing disease, seen as a papulosquamous disorder, and affecting approximately 2–3% of the population. It is being increasingly recognized that psoriasis is a systemic disease and not merely confined to the skin alone. For example, approximately 25% of the cases are associated with inflammatory arthropathy. Metabolic syndrome is also being increasingly associated with the disease. Various therapeutic approaches are already in use for the disease. Most conventional modalities of therapy have end organ damage and are toxic in the long term. Therefore, one has to use the drugs with caution and keep in mind the disability induced by the disease in a working individual in India, which is a resource poor country.

Biologic therapies for psoriasis utilize molecules that are designed to block specific molecular steps important in the pathogenesis of psoriasis and now comprise a number of well-established, licensed treatment options for patients with severe disease. There are several biologic drugs in use in India for various indications, both dermatologic and nondermatologic. In dermatology, we will address the use of these drugs in psoriasis. There are no existing guidelines in India as of now regarding the use of the biologics.

Purpose and scope

The overall objective of this manuscript is to provide update information on use of biologics in psoriasis in India.

Drugs included

The drugs covered will include those that are currently licensed for use in psoriasis in India; i.e., etanercept, infliximab, itolizumab, secukinumab, and biosimilars.

Drugs excluded

Drugs such as adalimumab, alefacept, ustekinumab, and some others are not available at present in India, and hence will not be covered in this manuscript.

Limitations

There are no controlled trials or case series on the use of biologics in India, though they are being used. Being a resource poor country and with no insurance coverage for the use of biologics, we find that while there is a need for guidelines, there is no sifficient Indian data to rely upon. The data for purpose of this manuscript have therefore been culled from the western literature, primary the UK, Europe, and the USA, where guidelines have been established and these drugs are being used with a larger reach. Itolizumab is a recently approved biologic by DCGI, specifically for use in India, however, experience with the drug is limited at present. Similarly, secukinumab has been very recently launched in India and the Indian experience with this drug is insignificant.

In the same vein, one must establish that guidelines are for reference only. Complying with guidelines does not absolve one of negligence and not complying with strictly does not constitute negligent practice. The use of therapy in dermatology has to be individualized for every patient.

 Indications for Biologic Therapy



Most patients with moderate-to-severe disease achieve good control, at least in the short term, with the currently used conventional drugs. The use of conventional systemic drugs over a prolonged period of time produces end organ damage and side effects that preclude re-administration of the drug. At present, the risks and benefits of biologic therapies relative to standard systemic therapy are largely unknown. Widespread use of these agents in uncomplicated moderate-to-severe psoriasis is inappropriate and is not supported by the licensed indications for these drugs.

Patients with psoriasis may be considered eligible to receive treatment with any of the licensed biologic interventions when they fulfill the eligibility criteria set out below. However, the decision to proceed with treatment must be made in collaboration with the patient and should include a careful assessment of the associated risks and benefits.[1]

Eligibility criteria

To be considered eligible for treatment, patients must have severe disease as defined in (A) and fulfill one of the clinical categories outlined in (B):

Severe disease defined as a psoriasis area severity index (PASI) score of 10 or more (or a body surface area (BSA) of 10% or greater where PASI is not applicable) AND a Dermatology Life Quality Index (DLQI) of >10. In exceptional circumstances (for example, disease affecting high-impact sites with associated significant functional or psychological morbidity such as acral psoriasis), patients with severe disease may fall outside this definition but should be considered for treatment (AND)Fulfil at least one of the following clinical categories

Where phototherapy* and alternative standard systemic therapy # are contraindicated or cannot be used due to the development of, or risk of developing, clinically important treatment related toxicity Are intolerant to standard systemic therapy #Are unresponsive to standard systemic therapy # Have significant, coexistent, unrelated comorbidity, which precludes the use of standard systemic therapy such as cyclosporine or methotrexate Have severe, unstable, life-threatening disease.

*Phototherapy may be inappropriate in patients

Who have exceeded safe exposure limits (150.200 treatments for PUVA, 350 treatments for narrowband UVB NB),Who are nonresponsive or relapse rapidly,Who have a history of skin cancer or repeated episodes of severe sunburn,Who are intolerant of UV exposure, especially if skin phototype I (sun.sensitive), orFor logistical reasons.

#Standard systemic therapy includes cyclosporine (2.5 mg/kg daily; up to 5 mg/kg daily), and in men, and women not at risk of pregnancy, methotrexate [single dose (oral, subcutaneous, intramuscular) of 15 mg weekly; max 25 mg weekly] and acitretin (25–50 mg daily).[2]

Eligibility criteria for patients with skin and joint disease

Patients with active psoriatic arthritis and skin disease that fulfil defined British Society for Rheumatology (BSR) and BAD guideline criteria, respectivelyPatients with severe skin psoriasis and psoriatic arthritis who have failed or cannot use methotrexate.

 Definition of Disease Response



Adequate response to treatment is defined as EITHER

A 50% or greater reduction in baseline PASI (PASI 50 response) (or % BSA where the PASI is not applicable) and a 5-point or greater improvement in DLQI (OR)A 75% reduction in PASI score compared with baseline (PASI 75 response)With newer biologics like secukinumab in market, we are moving towards defining adequate response rate as PASI 90 or even 100 as this drug has shown the ability to do so.[3]

 Tumor Necrosis Factor Alpha Blockers in India



TNF plays a central role in the pathogenesis of psoriasis, psoriatic arthritis, and a number of other disease states. TNF is released from cells as a soluble cytokine (sTNF) following cleavage from its cell surface-bound precursor (transmembrane TNF, tmTNF). Both sTNF and tmTNF are biologically active, and bind to either of the two distinct receptors: TNF receptor 1 (TNFR1, p55) and TNF receptor 2(TNFR2, p75). This leads to NF-kB activation (which promotes inflammation) and ⁄ or cell apoptosis.[2] In addition, tmTNF can itself act as a ligand (via a process of reverse signaling) to induce cell activation, cytokine suppression, or apoptosis of the tmTNF bearing cell. Soluble forms of the TNF receptors also exist, and by binding and neutralizing sTNF, may act as natural TNF antagonists. There are currently two approved groups of biologic agents that target TNF: anti-TNF monoclonal antibodies (adalimumab and infliximab), and sTNF receptors (etanercept). Adalimumab is not currently available in India. Infliximab is a chimeric human–murine monoclonal antibody (~25% mouse-derived protein) Etanercept is a genetically engineered fusion protein composed of a dimer of extracellular portions of human TNFR2 (p75) fused to the Fc domain of human IgG1.

Anti-CD6 antibody in India

Itolizumab is a “ first in class” humanized IgG1 monoclonal antibody. It selectively targets CD6, a pan T cell marker involved in co-stimulation, adhesion, and maturation of T cells. Itolizumab, by binding to CD6, downregulates T cell activation, causes reduction in synthesis of pro-inflammatory cytokines, and possibly plays an important role by reducing T cell infiltration at the sites of inflammation.[4]

Anti-interleulin 17A antibody in India

Secukinumab is a recombinant, high-affinity, fully human immunoglobulin G1k antibody that selectively binds and neutralizes interleukin (IL) 17-A. IL-17A is the primary effector of type 17 helper T (Th17) cells, however, it is also produced by other cell types in psoriatic lesions, including γδ T cells, neutrophils, and possibly mast cells. It stimulates keratinocytes to secrete chemokines and other pro-inflammatory mediators that recruit additional inflammatory cells, including neutrophils, Th17 cells, dendritic cells, and innate lymphoid cells. Thus, IL-17A potentially acts as a master cytokine in the pathogenesis of psoriasis. Although there are no published studies from India on secukinumab, the efficacy of the drug in moderate-to-severe plaque psoriasis has been established in a phase 3 trial over a period of 52 weeks.[5] In clinical trials, secukinumab was more effective than placebo, etanercept, and ustekinumab at improving both psoriasis symptoms (with high skin clearance) and health-related quality of life.

 Biosimilars in India



Biosimilars are copies of innovator biologics agents and represents important advances in the field of biologics therapeutics. They have similar safety and efficacy profile as their reference product and are generally used to treat the same conditions. Unlike chemical generics, biosimilars are only similar to and not an exact replica of the original drug. Manufacturing of biologics and biosimilars is very complex with many steps. Biosimilars have the potential to induce antibodies. Therefore, an effective pharmacovigilance program is important in identifying rare side effects. In India, comprehensive regulatory guidelines governing the approval were announced in June, 2012. The regulatory body is responsible for similar biologics in India are Department of Biotechnology (Under the Ministry of Science and Technology). As patents for biologicals used to treat psoriasis expire, biosimilars are becoming and will become more and more important. At present, biosimilars for infliximab, etanercept, and adalimumab are available in India [Table 1].{Table 1}

General recommendations for all patients who will be treated with biologics at baseline

Obtain an age appropriate history along with an updated medication list (for psoriasis as well as any other comorbidities) Complete dermatologic and systemic examination including documentation of psoriasis activity Baseline laboratory studies, blood chemistry, and especially a TB screen that will allow the clinician to detect and be aware of any underlying infections, and other medical conditions or risk factors Use all approaches to prevent infection, including vaccines. Before starting a biologic, it is preferable to vaccinate the patient. In general, it takes 2 weeks for vaccines to be effective. While biologics may not completely prevent the activation of the vaccine, some degree of attenuation does occur if the biologic is started too early. In most countries including India, it is therefore worthwhile to follow the regimen of vaccines being followed for solid organ transplants, where guidelines have already been established.[1] It is not recommended to give live vaccines after starting the biological agent Treatment is contraindicated in patients with active serious infection Use of biologics in children has not been properly evaluated.

During biologic therapy

Patients need to be periodically reevaluated for infections or malignancy by history, physical examination, and laboratory investigations.

Recommendations specific to tumor necrosis factor inhibitors

TNF inhibitors should not be used in patients with multiple sclerosis (MS) or other demyelinating diseases; first-degree relatives of patients with MS have an increased risk of developing MS, with a sibling relative risk of between 18 and 36; evidence strongly suggests that TNF inhibitors should not be used in first-degree relatives of patients with MS Caution should be used when considering TNF inhibitor use in patients with congestive heart failure (CHF) on account of reports of new onset and worsening of CHF in patients treated with TNF inhibitors. It is recommended that patients with New York Heart Association class III or IV CHF avoid all use of TNF inhibitors. Patients with class I or II CHF should undergo echocardiogram testing; if the ejection fraction of these patients is <50%, then TNF inhibitor treatment should potentially be avoided Hepatitis B reactivation after treatment with TNF inhibitors has been reported; in the appropriate clinical setting, patients should be screened for hepatitis B infection.[2]

Recommendations for etanercept

Indications: Moderate-to-severe psoriasis, moderate-to-severe psoriatic arthritis, adult and juvenile rheumatoid arthritis (as young as 4 years), and ankylosing spondylitis Dosing: 50 mg twice/week given subcutaneously for 3 months followed by 50 mg once/week. The choice of which dose to use will depend on the clinical need, disease severity, body weight and, in the UK, the dose that will be funded. Patients established on etanercept 25 mg twice weekly may wish to consider switching to etanercept 50 mg twice weekly because these two dosing regimens are almost equivalent in terms of efficacy Short-term results: 49% of patients given 50 mg twice/week achieved a PASI-75 at 12 weeks; 34% of the patients given 25 mg twice/week achieved a PASI-75 at 12 weeks Step-down results: 54% of the patients whose dose was decreased from 50 mg twice/week to 25 mg twice/week achieved a PASI-75 at 24 weeks; 45% of patients whose dose remained at 25 mg twice/week achieved a PASI-75 at 24 weeks In patients who respond, treatment may be continued according to the clinical need, although long-term data on efficacy are limited to 2 years. Treatment may be discontinued without the risk of disease rebound, although there may be a lower response rate on restarting therapy. Methotrexate may be recommended as co-medication in certain clinical circumstances, e.g., where it is required for associated arthropathy or to improve efficacy Toxicities: Mildly pruritic injection site reactions may occur Rare cases of serious infections (i.e., TB) and malignancies There are also rare cases of drug-induced, reversible side effects including lupus without renal or CNS complications, cytopenia, MS, and exacerbation and new onset of CHF Baseline monitoring: Purified protein derivative (PPD) is required (see below for British recommendations on PPD and IGRA which are relevant in the Indian scenario) LFT and CBC Ongoing monitoring Periodic history and physical examination are recommended while on treatment Consider yearly PPD, and periodic CBC and LFT Pregnancy category B Contraindications: Sepsis Pregnancy test both at the baseline and during ongoing monitoring These recommendations have been arrived at by the American academy of dermatology. They do not reflect the picture of screening for TB in India and the modified suggestion comes later. (from the British Thoracic Society).

Recommendations for infliximab

Indications: Severe psoriasis, moderate-to-severe psoriatic arthritis, adult rheumatoid arthritis, ankylosing spondylitis, ulcerative colitis, and Crohn's disease Dosing: Infliximab therapy should be initiated at a dose of 5 mg/kg at weeks 0, 2, and 6 and disease response assessed at 3 months In patients who respond, subsequent infusions (5 mg/kg should be given at 8-week intervals to maintain disease control, although long-term data are available only up to 1 year. Interrupted therapy should be avoided given the associated increased risk of infusion reactions and poor disease control term response: 80% of the patients achieved a PASI-75 at week 10, 50% PASI improvement noted by week 2 Long-term response: 61% of patients achieved a PASI-75 at week 50 Methotrexate may be recommended as a co-medication in certain clinical circumstances, e.g., where it is required for associated arthropathy to improve efficacy or to reduce the development of antibodies to infliximab Pregnancy test both at the baseline and during ongoing monitoring Toxicities: Infusion reactions and serum sickness can occur more commonly in patients who have developed antibodies. The incidence of infusion reactions may be reduced by concurrent administration of methotrexate Rare cases of serious infections (i.e., TB) and malignancies including hepatosplenic T-cell lymphoma (in children); there are rare reports of drug-induced, reversible side effects including lupus without renal, or CNS complications Cytopenia, MS, and exacerbation of and new onset of CHF Baseline monitoring: PPD is required. Consider incorporating the British association of dermatologists guideline of combining mantoux with quantiferon TB test LFT, CBC, and hepatitis profile Ongoing monitoring: Periodic history and physical examination are recommended while on treatment Consider a yearly PPD, as well as periodic CBC and LFT Pregnancy category B Contraindications: Infliximab at doses >5 mg/kg should not be given to patients with New York Heart Association functional class III or IV CHF.

Recommendations for itolizumab

Indications: Moderate-to-severe plaque psoriasis Dosing: Recommended dose of itolizumab for the treatment of plaque psoriasis is 1.6 mg/kg given as intravenous infusion once every 2 weeks for 12 weeks, followed by 1.6 mg/kg every 4 weeks up to 24 weeks Toxicities: Infusion reactions, infections and rarely exfoliative dermatitis, erythrodermic psoriasis, adjustment disorder with anxiety, bacterial arthritis Contraindications: The drug is not to be used in inflammatory diseases and systemic autoimmunity (other than psoriasis); psoriatic erythroderma, psoriatic crisis; and if there is evidence of active or latent tuberculosis (TB) Baseline monitoring: PPD testing is required LFT, CBC, and hepatitis profile should be obtained. Ongoing monitoring: Periodic history and physical examination are recommended while on treatment Consider yearly PPD, as well as periodic CBC and LFT.

Recommendations for secukinumab

Indications: Secukinumab has been approved by the US Food and Drug Administration (FDA) for the treatment of adults with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis Dosage: For moderate-to-severe plaque psoriasis, 300 mg by subcutaneous injection with initial dosing at weeks 0, 1, 2, and 3 followed by 300 mg every 4 weeks starting at week 4. For some patients, a dose of 150 mg may be acceptable For psoriatic arthritis: Patients with coexistent moderate-to-severe plaque psoriasis, use the dosage and administration for plaque psoriasis. For other psoriatic arthritis patients, administer with or without a loading dosage. The recommended dosage: With a loading dosage, it is 150 mg at weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter Without a loading dosage, it is 150 mg every 4 weeks. If a patient continues to have active psoriatic arthritis, consider a dosage of 300 mg Toxicities: Most common adverse reactions (>1%) are nasopharyngitis, diarrhea, and upper respiratory tract infection Serious infections have occurred. Caution should be exercised when considering the use of secukinumab in patients with a chronic infection or a history of recurrent infection Cases of inflammatory bowel disease were observed in clinical trials A small, incremental risk in Candida infections (limited to nonserious, localized mucosal, or cutaneous candidiasis) has been noted No reactivation of TB or viral hepatitis was observed in any psoriasis trial Incidence rates for the adverse events of interest for an immunomodulatory biologic including serious infections, autoimmune disorders, major adverse cardiovascular events, and malignancies were similar to rates on etanercept and placebo Monitoring: Evaluation of TB is required prior to initiation of secukinumab [Table 2] Pregnancy category B.{Table 2}

Adalimumab biosimilar usage in India

We have discussed the use and indications of conventional biologics in India. These have included etanercept, infliximab, itolizumab, and secukinumab. Adalimumab (Humira) is also a TNF-α antagonist. It is not yet available in its originator molecule form in India. However, as the patent has run out on this molecule, Indian companies among others have been making biosimilars of the drug. A biosimilar may not have the exact molecular structure as the originator molecule, however, bioequivalence and molecular fingerprinting of the active part of the molecule have shown biosimilarity to the originator adalimumab.

The drug is used just like the originator molecule. It can be used when a TNF-α blocker is needed. Zydus Cadilla has made a biosimilar adalimumab, which has undergone trials comparing it to the originator Humira and has shown biocomparability (Exemptia). However, immunogenicity data are not available. The prebiologic screening and monitoring and posology for this biosimilar is the same as for Humira or any TNF-α blocker. There are other biosimilars available in the country for adalimumab, however, studies comparing them to the originator molecule have not been published.

The Indian drug controller (DCGI) has allowed the use of exemptia in rheumatoid arthritis, psoriasis, and psoriatic arthropathy with a rider to maintain strict pharmacovigilance after usage.

 General Safety Issues



TNF blockers have been in use for more than 10 years and more than 1.5 million patients have received them. Their use in psoriasis is recent, but has rapidly gained acceptance. However, unlike other diseases, most patients with psoriasis have been treated with monotherapy biologic.

All of the TNF inhibitors carry the potential for an increased risk of infection, with upper respiratory tract infections being the most common. Serious infections are uncommon, with patients with underlying predisposing medical conditions being more at risk. Rare opportunistic infections, including histoplasmosis, listeriosis, coccidioidomycosis, cryptococcosis, aspergillosis, candidiasis, and pneumocystis have been reported more often in patients treated with anti-TNF antibodies such as infliximab or adalimumab than in those treated with fusion protein receptor drugs such as etanercept. Many of these patients were also treated with other immunosuppressive agents such as methotrexate and systemic corticosteroids. One must exercise great caution when considering anti-TNF therapy in patients with concomitant chronic its hepatitis B infection. Given the lack of prospective randomized controlled trials using TNF-α antagonists in patients with hepatitis B infection, screening patients for hepatitis B before treatment with anti-TNF therapy should be considered in the appropriate clinical setting TB is of particular interest in India, where the risk of contracting it is very high, and the risk of reactivating latent TB is high when on biologics or any immunosuppressive, including the conventional immunosuppressive. TNF-α plays an important role in the host response against TB. In addition to several case reports of TB reactivation in patients on anti-TNF therapy, registry data from patients with rheumatoid arthritis and post-marketing reports to the FDA have identified numerous cases of TB reactivation associated with all three TNF inhibitors. There is an increased incidence of extrapulmonary or disseminated cases of TB occurring in patients on anti-TNF therapy. A separate section on screening has been included Both peripheral and central demyelinating disorders, including MS, have been reported to not only develop but also worsen in patients taking TNF-α antagonists. These medications should be avoided in the setting of a personal history of demyelinating conditions. First-degree relatives of patients with MS have an increased risk of MS, with a sibling relative risk of between 18 and 36, strongly suggesting that TNF inhibitors should not be used in first-degree relatives of patients with MS Heart disease: This issue is somewhat controversial. Several studies have been conducted on heart disease and concomitant usage of TNF-α blockers. The results were inconclusive. It is recommended that TNF inhibitors be avoided in patients with severe CHF (New York Heart Association class III or IV) and those with milder CHF should have their TNF inhibitors withdrawn at the onset of new symptoms or worsening of pre-existing CHF Drug-induced lupus-like syndromes: The development of or an increase in the levels of circulating antinuclear antibodies may occur in patients taking any of the three anti-TNF agents. This condition may be reversible on cessation of the drug. It is not necessary to evaluate patients for antinuclear antibodies or to conduct other serologic tests before ordering anti-TNF therapy unless clinical symptoms warrant Hepatic diseases: Fulminant hepatic disease has been seen with infliximab but not the other TNF blockers. The possibility that concomitant or previous hepatotoxic drug administration could have a role to play has not been discounted. In 2004, the FDA issued a warning that hepatic disease, including severe hepatic failure, might complicate infliximab therapy Lymphoma: This is also a debatable issue. While a consensus panel of experts reviewing the clinical trial evidence concluded that the overall risk of malignancies including lymphoma was not increased over baseline levels in patients with rheumatoid arthritis being treated with TNF inhibitors, clinical trials are underpowered to evaluate the risk of rare events such as cancer. There have been numerous anecdotal cases of lymphomas reported in patients being treated with TNF inhibitors, with many of these being resolved after discontinuation of the drug Melanoma and nonmelanoma skin cancer: There are several case reports to this effect and a trend toward an increased risk of melanoma. Importantly, this large observational study also demonstrated no increased risk of any other type of solid cancers. These findings are in contrast with the results of a meta-analysis of rheumatoid arthritis patients treated with adalimumab and infliximab, which revealed an increased risk of solid cancers Pregnancy: All of the TNF inhibitors are pregnancy category B.[3]

 Specific Issues for Individual Agents



Etanercept

Injection site skin reactions occur in up to 37% of patients treated with etanercept, which are mild-to-moderate and generally do not require drug discontinuation.

Infliximab

Infusion-related reactions occur in 16% of patients treated with infliximab compared with 6% of patients treated with placebo. The majority of the infusion reactions are mild consisting of pruritus or urticaria. Some patients have moderate reactions consisting of chest pain, hypertension, and shortness of breath, and only rarely severe reactions with hypotension and anaphylaxis occur. Infusion reaction risk tends to correlate with the development of human antichimeric antibodies and can usually be managed by slowing the rate of infusion or stopping the treatment entirely. Concurrent treatment with methotrexate can reduce this reaction and antibody formation.

Itolizumab

Infusion-related reactions are seen in 20% of patients. Rarely exfoliative dermatitis, erythrodermic psoriasis, adjustment disorder with anxiety, and bacterial arthritis can be noted.

Secukinumab

Incidence of infective adverse events need continued vigilance particularly, with respect to potential for candida infection.

Recommendations of biologic therapy in children

Etanercept is recommended for the treatment of severe psoriasis in children from the age of 8 years who fulfil the stated disease severity criteria. Etanercept therapy should be initiated at a dose of 50 mg weekly and disease response assessed at 3–4 months.

Recommendations on use of biologic therapy in the perioperative period for elective surgery

TNF antagonists should be discontinued at least four half-lives prior to major surgery (two weeks for etanercept, 6–8 weeks for adalimumab, 4–6 weeks for infliximab) Biologic therapy can be restarted postoperatively if there is no evidence of infection and wound healing is satisfactory.

Pretreatment assessments and monitoring

Full clinical history Physical examination Specifically rule out CNS disease, malignancy in the last five years, severe, or ongoing infection Rule out preexisting cardiac disease Look for latent infections, especially hepatitis B and hepatitis C Look for latent TB.

Assessment for risk of TB in patients considered for tumor necrosis factor antagonist therapy

This is the recommendation from the British thoracic society [Figure 1]. It takes into account previous exposure to BCG and immunosuppressives that may have been used for psoriasis prior to initiation of therapy.{Figure 1}

A pretreatment chest X-ray and Mantoux skin test currently remain the preferred screening tests in patients not on immunosuppression. Tuberculin testing is not valid in patients already established on immunosuppressive therapy (e.g., methotrexate). IGRA tests may have a role in this group and can be used, if practicable, although the positive and negative predictive values are unknown The T-SPOT.TB test may be more sensitive in patients on immunosuppressive drugs. Patients with signs to suggest TB or a history of previous treatment for TB should be referred to a TB physician. Patients with test (s) to support latent TB should be stratified for risk and considered for prophylactic antituberculous therapy; further advice should be sought from a TB physician when necessary. When antituberculous therapy is indicated, patients should complete 2 months of treatment before commencing biologic therapy with either isoniazid (total treatment course 6 months), or rifampicin plus isoniazid (total treatment course 3 months), or rifampicin alone (total treatment course at least 4 months) During treatment and for 6 months following discontinuation, a high index of suspicion for TB should be maintained, especially in those at high risk. For patients on biologic therapies longer than 1 year who have negative screening tests for TB on initiation of therapy, annual assessment for TB may be considered in high-risk patients using whichever IGRA is locally available.

Indications for stopping therapy

Patients fail to achieve an adequate response following treatment initiation or when treatment response is not maintained A serious adverse event. Serious adverse events which may justify the withdrawal of treatment include malignancy (excluding NMSC), severe drug-related toxicity, and severe intercurrent infection (temporary withdrawal) Pregnancy (temporary withdrawal) Elective surgical procedures.

Effectiveness of biologic therapies in erythrodermic and pustular psoriasis

Biologic therapies cannot at present be recommended for palmoplantar pustulosis TNF antagonists may be considered for patients with severe, disabling acropustulosis (acrodermatitis continua) of Hallopeau, which has failed to respond to standard systemic agents. TNF antagonists may be considered for patients with generalized pustular psoriasis. TNF antagonists (infliximab and etanercept) may be considered for patients with erythrodermic psoriasis.

Summary: Instructions for use of biologics

Pretreatment: Objective assessment of the disease (such as PASI/BSA/PGA; arthritis) Health-related quality of life (HRQoL) (such as DLQI/Skindex-29 or 17) History and clinical examination should focus on prior exposure to treatments, malignancies, infection, congestive heart failure, and neurological symptoms Recommended measures include:

Check for skin cancerCheck for lymphadenopathyLaboratory parametersUrine analysisChest X-rayMantoux test and/or QuantiFERON®-TB Gold test® testIn case of doubt, contact a specialistPregnancy testContraception During treatment Objective assessment of the disease (such as PASI/BSA/PGA; arthritis) HRQoL such as (DLQI/Skindex-29 or 17) Clinical examination should focus on malignancies, risk factors for serious infections, congestive heart failure, and neurological symptoms Recommended measures include:

Check for skin cancerCheck for lymphadenopathyLaboratory parametersUrine analysisContraceptionPosttreatmentAfter discontinuation of biologics, patients should be followed up with medical history and physical examinationPhysicians are encouraged to enroll their patients in a registry (if available).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

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