Biologics in dermatology: an integrated review.

The advent of biologics in dermatologic treatment armentarium has added refreshing dimensions, for it is a major breakthrough. Several agents are now available for use. It is therefore imperative to succinctly comprehend their pharmacokinetics for their apt use. A concerted endeavor has been made to delve on this subject. The major groups of biologics have been covered and include: Drugs acting against TNF-α, Alefacept, Ustekinumab, Rituximab, IVIG and Omalizumab. The relevant pharmacokinetic characteristics have been detailed. Their respective label (approved) and off-label (unapproved) indications have been defined, highlighting their dosage protocol, availability and mode of administration. The evidence level of each indication has also been discussed to apprise the clinician of their current and prospective uses. Individual anti-TNF drugs are not identical in their actions and often one is superior to the other in a particular disease. Hence, the section on anti-TNF agents mentions the literature on each drug separately, and not as a group. The limitations for their use have also been clearly brought out.

What was known?

Biologics have been used for various dermatological conditions with some good and some equivocal results. Their use in psoriasis spearheaded trials for use in other dermatoses. However, level of evidence for majority of these unapproved conditions is low.

Introduction

The term ‘biologic’ refers to agents synthesized from the products of living organism.[1] The target-specific mediators of inflammation have become an important and useful part of the dermatologists’ treatment armamentarium. They modulate the immune system through stimulatory or inhibitory actions, acting at only specific parts of the immune system; hence, their safety profile is generally considered to be more favorable than that of traditional systemic immuno-suppressive agents.[1] Nevertheless, they are not devoid of adverse reactions, a few of which are associated with significant morbidity. The initial over enthusiasm though has been replaced by a guarded and cautious approach now, with increasing years of experience with these drugs. The following account focuses attention to the biologics, which are/or may become useful in dermatological diseases. Broadly, these include agents acting against tumor necrosis factor-α (TNF-α), those acting on cell surface receptors, fuspion proteins and intravenous immunoglobulins (IVIG).

Biological Agents Acting Against Tumor Necrosis Factor-Alpha

Tumor Necrosis Factor-Alpha (TNF-α) is produced by multiple cell lines in the skin, including keratinocytes, langerhans cells and cutaneous mast cells.[2] It is released as a soluble cytokine (sTNF) following cleavage from its cell surface-bound precursor (tmTNF). Both sTNF and tmTNF are biologically active, and bind to either of two distinct receptors: TNF receptor 1 (TNFR1, p55) and TNF receptor 2 (TNFR2, p75).[3] This leads to NF-κB activation, promoting inflammation and/or cell apoptosis.[3] TNF receptors are primarily located on the surface of keratinocytes, neutrophils, endothelial cells and fibroblasts.[2] Soluble forms of the TNF receptors also exist and by binding and neutralizing sTNF may act as natural TNF antagonists.

TNF-α is involved in the recruitment of immune cells to the cutaneous micro-environment.[4] TNF also induces secretion of metalloproteinases and release of pro-inflammatory cytokines IL-1, IL-6, IL-8 and GM-CSF.[5] TNF-α also induces interferon γ, which in turn augments IL-12 secretion and ultimately causes a strong type 1 response. Thus, it plays a key role in the host response against inflammation, infection and tumor defense.[5]

TNF-α antagonists block its binding to the receptor, interrupting the subsequent signaling and inflammatory pathways. These are the most widely used biological agents and include infliximab, etanercept and adalimumab.

Infliximab (Remicade)

Infliximab is a 149 KDa chimeric antibody composed of murine variable (Fab) region and human constant (Fc) region which binds and neutralizes both sTNF and tmTNF. In addition, it can fix complement and cause cell apoptosis.[6] The second action of Infliximab probably explains its effect in granulomatous diseases. Infliximab binds TNF quickly and irreversibly. It was approved for the use in Crohn's disease in 1999, and a year later for rheumatoid arthritis.[7]

It is administered as an intravenous infusion in the doses of 5 mg/kg.[8] The commonly followed protocol is of administering at 0, 2 and 6 weeks, and subsequently every 8 weeks for maintenance. No systemic accumulation of Infliximab occurs upon continued repeated treatment.[9]

No major differences in clearance or volume of distribution occur with age, weight, gender, hepatic or renal function. A subgroup analysis of three randomized placebo-controlled trials showed that PASI-75 response rates at 10 weeks were similar regardless of body mass index (BMI).[10]

The pharmacokinerics are similar in the pediatric age group as well. Infliximab produces prompt effects in many responsive conditions.

Adalimumab (Humira)

Adalimumab is the first fully human monoclonal anti-TNF-α antibody. It is a highly specific TNF-α inhibitor. The drug exerts its pharmacological effect by binding to sTNF-α and preventing its interaction with TNFR1 and TNFR2 receptors.[11]

Adalimumab is administered subcutaneously. It is absorbed slowly, with peak serum concentrations being achieved in 5 days.[12] It is used in the doses of 80 mg subcutaneously initially, followed by 40 mg every other week (EOW), starting a minimum of 1 week after the first dose. Adalimumab is available as single-use pre-filled glass syringes, and also in vials as a sterile, preservative-free solution.[13]

Therapy should be reconsidered in case of no response within 16 weeks of treatment.[12] Safety and efficacy has not been established in children.

A weight-dependent decrease of treatment efficacy has been reported in REVEAL, BELIEVE and CHAMPION trials.[14151617]

Etanercept (Enbrel)

Etanercept is a fusion protein consisting of the extracellular domain of the p75 TNF receptor and the Fc portion of human IgG1.[1819] It binds sTNF-α preventing its interaction with the receptor, and changes the cytokine pattern from type 1 to type 2.[20]

No formal pharmacokinetic studies have been conducted to examine the effects of renal or hepatic impairment on etanercept disposition.[21]

It is available as pre-filled syringes, and multiple use vials. In psoriasis, a starting dose of 50 mg. twice weekly is given for 3 months, followed by 50 mg once weekly.

For psoriatic arthritis, the dose is just 50 mg SC weekly.[21] For pediatric psoriasis a dose of 0.8 mg/kg, up to 50 mg weekly has been used, and is considered safe and effective.[22]

For etanercept as well, the effect of weight and BMI on therapeutic efficacy has been examined.[2324] In the study by Strobe et al. superior response (defined as PASI 90 response at 3 or more postbaseline visits) was achieved by 40.57% of normal-weight patients, and 28.57%, 18.29% and 15.25% of overweight, obese and extremely obese individuals, respectively. Sub-optimal response was noted in only 9.43% of normal-weight individuals, but noted in 20.73% and 27.12% of obese patients and extremely obese patients, respectively.[23]

Golimumab and certolizumab

Golimumab is a human monoclonal antibody to TNF-α, while certolizumab is a PEGylated Fab fragment of humanized monoclonal TNF-α antibody. Both of these were approved for RA in 2009. Efficacy has also been reported in psoriatic arthritis.[25]

Certolizumab differs from other TNF inhibitors in not having the Fc portion of the antibody and the PEGylation of the Fab fragment. This results in less immunogenicity and longer half life, respectively. It practically relates to less frequent dosing requirement. It is administered subcutaneously in a dose of 400 mg, which is repeated 2 and 4 weeks after the first dose and subsequently a maintenance dose of 400 mg every 4 weeks.[25]

The major advantage of Golimumab is the one monthly dosing schedule. It is administered in the dose of 50 mg subcutaneously.[25]

Ustekinumab (Stelara)

Ustekinumab is a human IgG1κ monoclonal antibody that specifically binds to the p40 protein subunit of the interleukins IL-12 and IL-23.[26]

It prevents IL-12 and IL-23 from binding to their IL-12Rβ1 receptor protein expressed on the surface of immune cells.[27] The two cytokines participate in the immune response by activation of natural killer (NK) cells and CD4+ T-cell differentiation. IL-12 induces differentiation towards a Th-1 type of response with expression of TNF-α, and interferon.[2829] IL-23, on the other hand, induces differentiation toward a T-helper 17 (Th17) phenotype, expression of IL-17, and an increase keratinocyte expression of inducible nitric oxide synthase, also implicated in the pathophysiology of psoriasis.[303132] In addition IL-20 and IL-22 are also released, which contribute to keratinocyte hyperproliferation in psoriasis.[3334]

It is available as 45 mg and 90 mg pre-filled syringes, and 45 mg vials.

It is administered subcutaneously, in the dose of 45 mg, in those weighing <100 kg, at weeks 0 and 4, and thereafter every 12 weeks. A dose of 90 mg is recommended in patients with a body weight greater than 100 kg.[27]

In case of an inadequate response, consideration may be given to treating every 8 weeks, and increasing dose to 90 mg, with the initial dosing regimen used was 45 mg.[2735] Should there be no response after 28 weeks,[26] it should be discontinued.

The apparent clearance of Ustekinumab is 55% higher for patients weighing more than 100 kg, compared with those 100 kg or less.[36] A decrease in serum Ustekinumab concentration with increasing weight was seen for both the 45 mg and the 90 mg doses in the PHOENIX 1 and PHOENIX 2 studies.[273537] Also, for patients weighing more than 100 kg, the PASI 75 response rate was about 20% higher in the 90-mg group than in the 45-mg group. By contrast, for lighter patients (≤100 kg), PASI 75 response rates were similar between the 90-mg and 45-mg groups.

Alefacept (Amevive)

Alefacept was the first biologic agent approved for the treatment of moderate to severe chronic plaque psoriasis (2003). It is a recombinant dimeric fusion protein that consists of the extra-cellular CD2-binding portion of the human leukocyte function antigen-3 (LFA-3) linked to the Fc portion of the human IgG[38] Activation of T lymphocytes involves interaction between LFA-3 on the antigen-presenting cells and CD2 on T lymphocytes. Alefacept binds to CD2 on lymphocytes, thereby inhibiting the LFA-3/CD2 interaction. Thus, it interferes with the activation and proliferation of memory T lymphocytes.[38] In addition, alefacept interacts with the immunoglobulin receptors FcγRIII on accessory cells, such as NK cells and macrophages, to induce selective CD45RO+ T-cell apoptosis. These effects produce a selective reduction in memory-effector T cells, the source of the clonal precursors that emigrate from the blood, and drive the disease in the skin, while having relatively no effect on naive T-cell populations.[29]

Alefacept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system and possesses a molecular weight of 91.4 kilodaltons.[3940]

The standard treatment course consists of twelve 15 mg weekly injections.[38] Repeat courses are considered for patients only after a 12-week drug holiday provided that CD4+ T lymphocyte counts are within the normal range.[38] Various modifications of this regimen have been tried including using a higher doses in the initial or later part of the course or extended duration of treatment extending to 16 to 24 weeks.[41] Although it has the distinct advantage of safety, yet one of the longest durations of therapeutic effect. It is the least used biologic due to its erratic efficacy and slow onset of action, maximal efficacy is seen approximately 6 weeks following a full 12-week course of the medication. However, it has been reported in a small pilot study that, whether a systemic course would achieve a satisfactory response or not, may be assessed by the response achieved with a single intralesional injection into a target plaque.[42] But, further studies are required to confirm these findings.

Efalizumab (Raptiva)

Efalizumab is a recombinant, humanized, monoclonal immunoglobulin G1 antibody that binds to CD11a, the α-subunit of the T-cell marker leukocyte function-associated antigen (LFA)-1, preventing LFA-1 from binding to intercellular adhesion molecule 1.[4344] As a result, multiple LFA-1-mediated T-cell interactions that are critical to the pathogenesis of psoriasis and the maintenance of psoriatic plaques are inhibited.[43]

Multiple placebo-controlled Phase III clinical studies have assessed the safety and efficacy of efalizumab therapy in patients with moderate to severe chronic plaque psoriasis.[45464748495051]

However, following reports of development of progressive, multifocal, leukoencephalopathy (PML) during treatment it has been pulled from the market by European and Canadian regulatory agencies. Later, the manufacturer voluntarily withdrew efalizumab from the United States market.[52]

Rituximab (Rituxan)

Rituximab is a chimeric murine-human monoclonal antibody to CD20 which induces depletion of B cells in vivo.[53] CD20 is a B-cell-specific antigen expressed on the surface of B lymphocytes throughout differentiation from the pre-B-cell to the mature B-cell stage, but not on plasma cells or stem cells.[5354] Because plasma cells and hematopoetic precursors are spared, immunoglobulin levels do not fall dramatically and B cells typically begin to return to the circulation within 6 months of therapy.[5556] The Fab regions of Rituximab binds to the CD20 antigen on B lymphocytes, while the Fc domain recruits antibodies and complements to mediate cell lysis.[57] Thus, Rituximab's cytotoxicity is mediated by three mechanisms including antibody-dependent cellular cytotoxicity, complement-mediated lysis, and direct disruption of signaling pathways and triggering of apoptosis. The contribution of each mechanism in vivo remains unclear, and different mechanisms may predominate in the treatment of different diseases.[585960]

It has a half life of 8 hours and is most likely removed from the system by opsonization via the reticuloendothelial system when bound to B lymphocytes, or by human antimurine antibody production.[57]

The initial approved dosing regiment was four weekly infusions of 375 mg/m2.[61] However, modifications of this have been used in many studies.

Intravenous immunoglobulin (IVIG)

It is composed of human plasma derived from pools of 1000 to 15,000 donors.[62] It is derived from healthy human plasma via Cohn fractionation. The purification processes to remove pathogenic organisms include cold alcohol fractionation, polyethylene glycol precipitation, and ion exchange chromatography.[63] Caprylate and nanofiltration may also remove prions.[64] Newer viral inactivation techniques include incubation at pH 4 and solvent detergent treatment.[65] The purified immunoglobulin is stabilized with glucose, maltose, sucrose, mannitol, sorbitol, glycine, or albumin.

IVIG is made up of more than 90% IgG and small amounts of IgM and IgA. IgG subclasses are represented as approximately 70.3% IgG1, 24.7% IgG2, 3.1% IgG3, and 1.9% IgG4.[63] The total amount of immunoglobulins that are infused with a 2-g/kg dose is enormous leading to approximately five-fold increase in serum IgG concentrations.[66]

It has varied mechanisms by which it acts in different group of disorders. In the dermatologic setting, the major mechanisms include: Reducing levels of deleterious antibodies, via the contained anti-idiotypic antibodies[6768] accelerating the catabolism of pathogenic IgG by saturating FcRn receptors with exogenous IgG,[6970] anti cytokine effect[71] inhibiting T-cell activation,[7273] inhibiting complement-mediated damage,[74] interfering with the production, release, and function of inflammatory cytokines, including interleukins 2, 3, 4, 5, 6, and 10, tumor necrosis factor-alpha, and granulocyte-macrophage colony-stimulating factor,[7576777879] inhibiting the differentiation and maturation of dendritic cells,[80] inhibition of thromboxane A2 and endothelin, and increased prostacyclin secretion.[81]

The most commonly used dosing schedule in dermatological disorders is 2 g/kg/cycle, with cycles being repeated every 3-4 weeks. The interval between cycles may be prolonged as the disease comes under control.[82]

Omalizumab (Xolair)

Omalizumab is a humanized recombinant monoclonal antibody that blocks the high-affinity.

Fc receptor of immunoglobulin E (IgE) reduces serum levels of IgE and blocks the attachment of IgE to mast cells, and other immune cells, thereby preventing IgE-mediated inflammatory changes. Dosing is based on weight and pretreatment serum IgE levels and is administered via subcutaneous injection every 2 to 4 weeks.

Indications and Uses

Biologics have been used in many dermatological conditions. However, indications approved by various drug authorities are only a few.

The sections beneath first list the approved uses of these drugs followed by brief descriptions and available evidence for the off label uses.

TNF-alpha inhibitors amongst dermatological diseases, Infliximab, Adalimumab and Etanercept are all approved by the US-FDA for the treatment of moderate to severe plaque psoriasis and psoriatic arthritis.

Off-label dermatologic uses of anti-TNF-a therapies

Pyoderma gangrenosum

The efficacy of Infliximab has been demonstrated in a randomized controlled trial and many case series and case reports (LOE1B).[83848586] The reports include patients both with/without underlying inflammatory bowel disease. In the trial by Brooklyn et al., there was no difference in the response to Infliximab with or without coexistence of IBD.[85]

Case reports of a good response to Adalimumab are also reported in the literature (LOE5).[878889] Hubbard et al.[90] published a case, who responded well to but had a severe systemic reaction to Infliximab at the second dose. The disease did not respond to etanercept given subsequently. However, with treatment with Adalimumab, initially in combination with prednisone 20 mg, the PG resolved within 5 months.

On the other hand, Etanercept has also been shown to be beneficial in PG in few case reports and small patient series (LOE4).[91929394]

Autoimmune bullous diseases

A case of aggressive IgA pemphigus of the subcorneal pustular dermatosis (SCPD) subtype treated with Adalimumab, 40 mg subcutaneously eow, and myco-phenolate mophetil (1 g daily) gives direction to the use of TNF inhibitors in this group of disorders (LOE5).[95]

There are three reports[969798] of efficacy of Infliximab in subcorneal pustular dermatoses, one of which reports a patient with concomitant SLE (LOE5). However, the response was found to be only transient.[98] Etanercept[99100] has also been successfully tried in SCPD on two occasions (LOE5).

There are two case reports of efficacy of Infliximab, and one report of its failure in the management of pemphigus vulgaris. Hence, further studies to validate the role in pemphigus are warranted.[101102103] Adalimumab has been used with success, in a patient of pemphigus vulgaris who developed severe side effects with combined immunosuppressive therapy.[104] Etanercept has been used in pemphigus vulgaris, vegetans and foliaceus in occasional reports.[105106107] However, there is also a report[108] of induction of pemphigus vulgaris with etanercept, which was used for psoriasis in this case. Hence, so far the level of evidence for all these three drugs is low.

There is one report[109] of concomitant bullous pemphigoid and psoriasis treated with etanercept, which allowed successful tapering of the systemic steroids without inducing a flare (LOE5). Four treatment refractory patients of mucous membrane pemphigoid have been treated with etanercept and achieved clinical remission (LOE5).[110111]

Though these drugs may prove useful in a few recalcitrant cases, further data is needed to confirm their benefits. But, the reports of induction of autoimmune bullous disorders (pemphigus vulgaris/foliaceus and bullous pemphigoid) with TNF-α inhibitors raise a grave safety concern in the use in TNF-α inhibitor[112] in these conditions.

Hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a recurrent suppurative disease with a prolonged and indolent course. None of the available therapies are wholly satisfactory or uniformly effective.[113]

Infliximab has been assessed in HS in a few prospective observational studies, retrospective analyses, case series and case reports (LOE4).[114115116117118119120121] Although a significant benefit has been shown in most, confounding factors in terms of concomitant medications and diseases (Crohns) are present in many.

Adalimumab

Satisfactory evidence for this drug comes from a double-blind placebo-controlled randomized trial (LOE1B).[122] Twenty-one patients were included, of whom 15 received Adalimumab and 6 received placebo. A significant reduction was seen in Sartorius score after 6 weeks and an almost significant reduction after 12 weeks of active treatment when compared with placebo. However, no long-term curative effect was uniformly seen.

Another parallel randomized, placebo controlled, blinded trial[123] involving 154 patients across 26 centers compared treatment with weekly Adalimumab injections, EOW injections and placebo. At week 16, 3.9% of placebo patients, 9.6% of EOW patients, and 17.6% of weekly patients, achieved clinical response.[123] Significantly, greater improvements in patient-reported outcomes and pain were seen in the weekly dosing group than in the placebo group. A decrease in response was seen after the switch from weekly to EOW dosing.

Etanercept

Open-label trials and case report[124125126] related to use of etanercept in HS are available (LOE4). Some have reported good efficacy, while others have achieved minimal to no response.

Efalizumab[127] has been tried in five patients, only two of whom completed the study and none showed improvement in disease severity (LOE4).

Connective Issue Disorders

Although TNF-α is proposed to have a pathogenetic role in connective tissue disorders, the utility of TNF-α inhibitors is marred by the reports of development of anti-nuclear antibodies with the use of these agents.

Scleroderma

There are occasional report[128] of treatment of scleroderma with etanercept. It has been shown, in a mouse model of bleomycin-induced scleroderma, to significantly reduce the dermal sclerosis, collagen accumulation and the number of infiltrating myofibroblastic cells.

In a trial[129] of 10 patients of systemic sclerosis, treated with etanercept (LOE4) for 6 months, 4 had improvement of skin scores and 3 of 4 patients with digital ulcers reported improvement. Other measures like pulmonary function tests, oral aperture and hand extension remained stable.[129]

In a retrospective trial[130] of 18 patients with joint involvement, treated with etanercept, it was found that 15 of 18 patients experienced a significant decrease in signs of inflammation and synovitis. There was no worsening of skin involvement during the treatment.

However, there are two reports[131132] of development of multifocal and localized morphea with the use of etanercept for psoriasis vulgaris and rheumatoid arthritis, respectively.

An open-label trial[133] reported 16 cases of diffuse cutaneous systemic sclerosis who received five infusions of Infliximab. Although there was no clear benefit at 26 weeks but clinical stabilization and a fall in two laboratory markers of collagen synthesis was observed (LOE4).

Another report[134] mentions the efficacy of Infliximab treatment in a patient with lung fibrosis and pulmonary hypertension associated with advanced systemic sclerosis, refractory to conventional therapies. The patient was treated with Infliximab, 5 mg/kg, and methotrexate 10 mg/week for 1 year, with which there was improvement in patient's quality of life and laboratory and radiological parameters remained stable. The condition worsened on stopping Infliximab.[134]

However, there are reports[135136] of severe adverse effects like pancytopenia and pulmonary actinomycosis in patients of scleroderma treated with Infliximab.

Also, there is a case reported,[137] of development of scleredema-like skin induration after treatment with Infliximab skin induration occurred within a few weeks of initiation of Infliximab, resolved with discontinuation of the drug, and recurred with rechallenge with the drug, implicating Infliximab as the offending agent. Interestingly, it did not recur with the use of etanercept.[137]

Dermatomyositis

There are conflicting results on the use of Infliximab in dermatomyositis (DM), with few reports demonstrating benefit while others demonstrate a failure (LOE5).[138139140141142] The treatment has been beneficial in some patients, whether treatment resistant or naive, but it is difficult to predict which patients would respond. A report of development of non-Hodgkin lymphoma 4 months after Infliximab infusions raises concern in the use of TNF blockers in syndromes known to have paraneoplastic associations (like DM).[143]

There is a single report of successful treatment of recalcitrant dermatomyositis with efalizumab.[144]

Systemic lupus erythematosus (SLE)

TNF-α is implicated as a key player in the SLE disease process. However, its treatment with TNF inhibitors remains controversial. There are numerous reports of increased production of autoantibodies and of drug-induced lupus with this group of drugs.[145] Most of these reports are of patients with rheumatoid arthritis and Crohn's disease.[145]

However, there are also reports of beneficial outcomes (LOE5). Improvement of arthritis and proteinuria has been reported in six patients treated with Infliximab.[146] Aringer et al.[147] reported improvement in lupus nephritis in patients receiving Infliximab along with immunosuppressive therapy.

Report[148149] of improvement of subacute Cutaneous LE treated with etanercept can also be found in the literature (LOE5).

Sweet's syndrome

There are two reports of improvement in Sweet's syndrome with etanercept, wherein two of the patients (Yamauchi et al.) had co-existing rheumatoid arthritis (LOE5).[150151]

There are two reports of Crohn's-associated Sweet's syndrome, and one of polychondritis associated disease responding to Infliximab infusions (LOE5).[152153154]

Another report[155] mentions successful treatment of highly refractory Sweet's syndrome with underlying myelodysplastic disorder, with Infliximab, which was subsequently changed to Adalimumab for sustained remission. The disease did not recur with this therapy.

Sarcoidosis

Among the biologic agents which inhibit TNF, Infliximab (LOE1B) has been studied[156157158] most extensively in sarcoidosis with fewer reports available for Adalimumab and etanercept.

Infliximab has been used with success in cutaneous, ocular, neuro, pulmonary and musculoskeletal manifestations.[159160161162163] Rosen et al.[163] have reported long-term control (>3 years) with 8-10 weekly maintenance infusions.

However, there are also concerns of development of sarcoidosis, mainly pulmonary and lymph node involvement with TNF inhibitors.[164]

Granuloma annulare

Granuloma annulare (GA) generally resolves itself within 2 years in 50% of cases, but there is a 40% recurrence rate.[145]

There are a few case reports[165166] of success of Infliximab therapy in disseminated GA (LOE5). The response was maintained even after stopping the drug. There is also a report[167] of beneficial response with efalizumab in a patient of disseminated GA, who also had plaque psoriasis.

However, there are also numerous cases of GA, mostly generalized induced by TNF inhibitors (Infliximab, Adalimumab and etanercept) in patients of rheumatoid arthritis treated with these drugs.[168]

Toxic epidermal necrolysis (TEN)

The role of TNF α in TEN is well known, hence the enthusiasm of using anti-TNF agents in this disease. There are many reports[169170171172173174] of successful use of Infliximab, and a few of etanercept (LOE5). It has been used alone, as well as in combination with IVIG and steroids, producing rapid response. However, the risk of infection is a major limiting factor.

Pityriasis rubra pilaris

Anti-TNF agents, primarily Infliximab and etanercept, have been used in adult and juvenile forms of Pityriasis rubra pilaris (PRP) (types 1, II and III) with good responses (LOE5). In a report of seven patients, only one patient, who had type II PRP, developed disease in the 12 month post treatment discontinuation period. Muller et al. also reported a persistent response following Infliximab in their patient.[175176177]

A recent systematic literature review[178] concluded that a complete response occurs in 80% of patients with a mean time to maximal response being 5 months.

Behcet's disease

A large number of publications suggest that inhibition of TNF, mainly using Infliximab, is a promising therapeutic approach for this disease. However, the current evidence of therapeutic efficacy is low grade, and there is only one randomized trial available, which assessed the effects of the soluble TNF receptor etanercept in muco-cutaneous manifestations and found it to be very effective (LOEIB).[179180]

There are numerous reports[181182183184185186187188189] of rapid and marked response with Infliximab in refractory disease, either alone or in combination with other immunosuppressives. Case series and case reports suggest that patients with severe mucocutaneous lesions exhibit rapid and good responses to 5mg/kg or 3mg/kg of Infliximab (LOE4). Some patients with orogenital ulcers being unresponsive[183] and/or intolerant[186] to conventional treatments remained disease-free for the first time in years. Almost all patients were resistant to conventional treatments and were treated with Infliximab alone[181183] or as an add-on therapy.[184185187188]

In addition, Infliximab has been extensively studied in ocular Behcets with rapid and gratifying results.[190]

Cases of efficacy in gastro-intestinal,[191] vascular[192] and neurological[193] manifestations are also reported.

Etanercept has been evaluated in a double-blind, placebo-controlled study[194] of 40 male patients with Behcet's disease (LOE2B). Etanercept 25 mg twice a week for 4 weeks was effective in suppressing most muco-cutaneous lesions. The drug had a clear effect on oral ulcers, and nodular lesions, and the response was evident as early as the 1st week.[194] Almost half of the patients receiving etanercept were free of oral ulcers at the end of the study, compared with 5% of the placebo group, whereas the absence of nodular lesions was evident in 85% and 25% of patients receiving the drug and placebo, respectively.[194] Although the drug decreased the number of genital ulcers and arthritis episodes during the treatment period, the difference was not significant. Recurrences developed in some patients 3 months after etanercept was discontinued.[194]

In other report[195196197] rapid resolution of severe mucocutaneous manifestations and arthritis[196] were noted following etanercept treatment, while another patient who failed to respond to etanercept, responded dramatically to Infliximab treatment with rapid resolution of orogenital ulcers and erythema nodosum and marked improvement in arthralgia and iritis.[198] Etanercept was also given to two children with BD-associated uveitis. A favorable response was noted in the first, but not in the second patient. The latter patient achieved a moderate response following subsequent treatment with Infliximab.[199]

Adalimumab has also been tried in a few reports (LOE5). In a retrospective analysis of 19 patients treated with Adalimumab, 17 achieved clinical improvements of note, ocular manifestations panuveitis and retinal vasculitis responded rapidly in all cases.[200]

Calvo Catalá et al.[201] also reported their experience of using Adalimumab in six cases with a good clinical response in all patients. Good disease control was achieved after a mean follow-up of 26.8 months with no adverse effects. Olivieri et al.[202] reported response to Adalimumab in patients who had failed Infliximab previously (LOE5).

Synovitis Acne Pustulosis Hyperostosis Osteitis Syndrome (SAPHO)

Cases of response with Infliximab have been reported. Iqbal et al.[203] used Infliximab in a patient with the SAPHO syndrome with acne fulminans. Ten months after initiating therapy with Infliximab, the area of the patient's ulcerative lesions was reduced by 70%. In another two cases,[204] only four infusions of Infliximab achieved remission of both skin and bone involvement, which was maintained over a period of 18 months (LOE5). However, in the report by Massara et al.[205] although the osteoarticular complaints improved, palmoplantar pustulosis relapsed in two of four patients.

Necrobiosis lipoidica diabeticorum

A few cases of the use of Infliximab and etanercept in ulcerated (and one in pre-ulcerative stage) can be found in the literature with reported good efficacy (LOE5).[206207208209]

There is one report of intralesional Infliximab (three cycles of weekly injections of intralesional Infliximab for 3 weeks followed by a 1-week treatment interruption) which produced complete remission for up to 18 months in two of the three patients treated.[210]

Others

Anecdotal reports of efficacy of TNF inhibitors in multicentric reticulohistiocytosis, atopic dermatitis, erythema annulare centrifugum, cutaneous vasculitis, erosive oral lichen planus and alopecia areata can also be found in the literature.[211212213214215216217

Omalizumab

Omalizumab has been used off label in the management of severe atopic dermatitis (one prospective stud; case series and reports), (LOE2B) and chronic urticaria (case series and reports) (LOE4).[218219220221222]

Rituximab

Rituximab is approved for the treatment of B-lymphocyte malignancies and rheumatoid arthritis.[223]

Although there have been only occasional randomized trials of Rituximab in dermatologic diseases, case reports describe its use in treatment of pemphigus vulgaris (PV), paraneoplastic pemphigus (PNP), epidermolysis bullosa acquisita, cutaneous B-cell lymphoma, DM, and Graft-versus-host disease (GVHD).

In pemphigus (LOE4), two dosing regimens[226] for Rituximab have been used-the lymphoma protocol, consisting of four weekly infusions of 375 mg/m2, and the rheumatoid arthritis (RA) protocol consisting of two infusions of 1000 mg each 15 days apart.

A recent review[224] on the use of Rituximab in pemphigus vulgaris stated that a complete remission occurred in 66.66% of patients in the lymphoma protocol and 75% in the RA protocol.

The authors also noted that the use of the lymphoma protocol produces a lower response rate, a lower rate of recurrences and serious infections, but a higher mortality rate,[224] whereas patients treated by the RA protocol had higher response rates, a larger number of infections, but a lower mortality rate.[224] This could be partly due to the fact that more patients were on corticosteroids and immunosuppressive agents as concomitant therapy in the lymphoma protocol, thus adding to the degree and duration of prolonged immune suppression. Of significant interest is the fact that there were no non-responders in patients treated with the RA protocol compared to 3.9% in the lymphoma protocol (LOE4).[224]

Studies[225] have shown that patients with severe disease often have high levels of anti-dsg3 IgG-producing B cells in the peripheral blood, which may explain the therapeutic effect of Rituximab.

Rituximab has also been tried in bullous pemphigoid with 69% patients showing a complete response, 6% having a partial response, and another 6% showing no response. 14 of the 16 patients were treated with the lymphoma protocol, and two with RA protocol.[226]

Paraneoplastic pemphigus (PNP)

Case reports[227228229] of both success and failure of Rituximab included regimens, for PNP associated with B-cell lymphoma, can be found in the literature (LOE5).

Ishigami et al.[230] have suggested that since almost all patients with NHL and PNP succumb within 3 months to 2 years after diagnosis, except for a couple of individual reports of long-time survivors by classical immunosuppressive treatments, the regime including Rituximab may be more effective for PNP than the classical treatments.

Rituximab has also shown efficacy in epidermolysis bullosa acquisita (EBA) in a few case reports[231232] either alone or with other modalities (LOE5).

There are also a few reports and case series[233] of efficacy in mucous membrane pemphigoid (LOE4). Recently, a critical analysis was published,[234] where in 20 of 28 patients had a complete response, 3 had a partial response, 2 were nonresponders, and 1 had stabilization of disease. However, they noted that long-term follow-up data after Rituximab therapy is lacking.

Rituximab has been evaluated in DM in a randomized trial, a prospective multicenter study and case reports (LOE1B).[235236237238] It has been reported to reduce steroid requirement, and allow for tapering of steroid doses and avoid use of other imnunosuppressives. In the study by Bader-Meunier et al.[236] complete clinical response was achieved in three patients treated with Rituximab for muscle involvement. In these responders steroid therapy was stopped or tapered to <15% of the baseline dosage, with no relapse, with a follow up ranging from 1.3 to 3 years. But, calcinosis did not improve in the six affected patients.[236] Rituximab has also been used in systemic lupus erythematosus and lupus nephritis. Systematic review and meta-analysis by Lan et al.[239240241] noted that the observational studies indicate that Rituximab is effective in severe and refractory SLE patients, with decreased Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group Index (BILAG), urine protein levels, prednisolone dosage and also complete or partial remission in some lupus nephritis patients. But, a randomized controlled trial did not achieve primary and second endpoints, which makes the true effect attributed to Rituximab questionable.

Other conditions[242243244245] where Rituximab has been tried with variable success include Graft-versus-host disease (GvHD), atopic dermatitis and vasculitis (LOE5).

Intravenous Immunoglobulin (IVIG)

Approved indications for IVIG include hypogammaglobulinemia, chronic lymphocytic leukemia, HIV in children, allogeneic bone-marrow transplantation, idiopathic thrombocytopenic purpura, and Kawasaki syndrome.[82] However, it has been used in numerous dermatological disorders, mainly autoimmune bullous disorders, connective tissue diseases, toxic epidermal necrolysis, vasculitides, urticarias, pyoderma gangrenosum (PG), scleromyxedema, pretibial myxedema, nephrogenic fibrosing dermopathy, Kaposi's sarcoma, mixed connective tissue disease, anticonvulsant syndrome and Polymorphous light eruption.[82246] Here, we shall be reviewing the literature on most important of these disorders.

Autoimmune bullous disorders

IVIG has been shown to have good efficacy in a variety of autoimmune bullous disorders especially pemphigus (LOE1B). It can rapidly lower serum levels of auto-antibodies in patients with pemphigus. Coadministration of a cytotoxic drug[247] may improve its efficacy.

IVIG is usually employed when conventional therapy fails, causes side effects or is contraindicated. Beneficial clinical effects have been demonstrated in the treatment of pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane pemphigoid and epidermolysis bullosa acquisita.[248]

A ‘Consensus Statement’ on the use of IVIG in these diseases recommended a dose of 2 g/kg/cycle, given monthly until clinical control, with a progressive increase of the intervals between the cycles thereafter.[249] The last cycle is given after a 16-week interval and is considered as the end point of therapy.[249]

156 patients treated with IVIG using this protocol demonstrated successful clinical outcomes.[250] In these patients IVIGg could be used as monotherapy, once concomitant prednisone and immunosuppressive agents were gradually discontinued.[250] These included 42 patients with pemphigus vulgaris, 26 with pemphigus foliaceus, 32 with bullous pemphigoid, 68 with mucous membrane pemphigoid and 9 with epidermolysis bullosa acquisita.[250] IVIG produced long-term, sustained remission for at least 2 years of follow-up, after discontinuation. The patients were in serological remission, and enjoyed a high quality of life.[250]

Pyoderma gangrenosum

Evidence for efficacy comes from case reports and small case series (LOE4). Patients treated include those with and without other underlying disorders, like inflammatory bowel disease RA, and myelodysplastic syndromes.[251252253254255]

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)

The evidence for and against IVIG in the treatment of SJS and TEN consists of a few prospective, retrospective studies, case series and case reports (LOE2B).

In a retrospective multicenter-study, 48 patients treated with IVIG had a survival rate of 88%, much higher than expected.[256]

In a review of published literature by Mydlarski et al., 11 out of 14 studies demonstrated IVIG's effectiveness.[257] European Dermatology Forum Guidelines Subcommitte, recommends starting IVIG treatment early after confirmation of TEN diagnosis (LOE IIIb).[258]

However, there is evidence pointing to lack of efficacy also, with 2 prospective studies with 3[259] and 16 patients[260] and showing no benefit.

Although a high dose of >2 g/kg is generally recommended, a few reports[261262] have reported shown efficacy with much lower doses, thus bringing down the cost significantly.

Connective tissue disorders

Dermatomyositis

IVIG is generally not the first-line therapy for DM/polymyositis (PM), but is used in conjunction with other drugs. The beneficial effect of IVIG in refractory, flared-up, rapidly progressive, or severe PM/DM has been documented in many open-label trials and reports (LOE2).[263264265]

In a recent systematic literature review, Wang et al. evaluated the literature on the use of IVIG in DM/PM from 1985 to 2011, which included two randomized controlled trials, nine prospective open studies, and three retrospective studies with a total of 308 adult patients.[266] They concluded that IVIG has been used successfully in the treatment of PM/DM (LOE1B). The standard dose is 2 g/kg,[266] its course is usually 3 to 6 months. In some patients, IVIG can lower the corticosteroid dose required for maintenance, demonstrating the most effective steroid-sparing effect.[266]

Another retrospective study, on the long-term effects of IVIG, concluded that patients on drug combinations, which included IVIG, had lesser muscular and cutaneous involvement, as well as lower percentages of muscular relapses. The total number of muscular relapses was inversely associated with the number of pulses of IVIG.[267]

Lupus erythematosus

Many reports and open label trials had documented the efficacy of IVIG in treatment of cutaneous manifestations of lupus erythematosus (LE), including facial rash, photo-sensitivity, vasculitis, urticaria, discoid lesions and subacute cutaneous LE lesions.[268269270271] However, there are also reports of failure/limited response.[272]

IVIG has shown efficacy in experimental murine models of bleomycin (BLM)-induced scleroderma. It has been tried in systemic sclerosis, with success being assessed by improvement in skin scores and joint involvement (LOE4).[273274275]

There are three reports[276277278] of the beneficial effect of IVIG in mixed connective tissue disease (MCTD), especially with severe cutaneous involvement (LOE5).

IVIG has also shown efficacy in different forms of cutaneous vasculitis, Behçet's disease, leukocytoclastic vasculitis, livedoid vasculitis and cutaneous polyarteritis nodosa.[279280281282]

Contemporary Prospective Innovations

Interleukin-17A (IL-17 or IL-17A) has now emerged as a major factor in the pathogenesis of psoriasis vulgaris.[283284] It is produced by Th17 cells, a class of T helper cells that act outside the established Th1/Th2 paradigm for regulation of innate and adaptive immunity. Hence, drugs targeting this cytokine are being widely researched. Currently, there are three different IL-17 antagonists under clinical evaluation for psoriasis. The monoclonal antibodies ixekizumab and secukinumab both target IL-17A, while brodalumab blocks the IL-17 receptor IL-17RA.1. All three drugs have completed phase 2 trials and have entered into phase 3.[285286287]

In phase 2 trials with ixekizumab, at 12 weeks, the percentage of patients with a reduction in the PASI score by at least 75% was significantly greater with ixekizumab-with 82.1% participants in the 150 mg group, 82.8% in the 75 mg group, and 76.7% in the 25 mg group achieving this figure.[285]

With Brodalumab, 77% patients receiving 140 mg dose and 82% patients receiving 210 mg dose achieved PASI 75 after 12 weeks of treatment. PASI 90 was achieved by 72% in the first group and 75% in the second group.[286]

Similar results have also been reported with secukinumab with 82% patients achieving PASI 75 at 12 weeks.[287]

However, the safety profile of these drugs is not well known so far, and hence it will be some time before they get incorporated into routine practice.

What is new?

Newer molecules and newer indications of older molecules are emerging in the field of biological drugs. Drugs against IL-17 cytokine are the latest to join this ever enlarging group. Longer experience with the older drugs has paved the way for their judicious and safer use.