**9.4.4 Biologics**

An increasing number of "biologics" have been developed in the last decade. They counteract extremely potent immunological targets such as tumor necrosis factor-α (TNF-α), T cells, B cells, various cytokines, some immunoglobulins and key enzymes. A variety of them has been used in psoriasis, often with astonishing success (Lawry, 2007). Also nail psoriasis was the object of some studies. This chapter is, however, not suited to discuss all as this will be discussed in the psoriasis treatment chapters.

#### **9.4.4.1 TNF- inhibitors**

TNF- promotes cytokine secretion, such as interleukin (IL)-1, IL-6, IL-8, by macrophages and other inflammatory cells, activates T cells and induces adhesion molecule expression by vascular endothelial cells which in turn promote angiogenesis and keratinocyte proliferation, both key events in the pathogenesis of psoriasis (Smolen and Emery, 2011).


Table 5. Application, dosage and indications of the commonly used TNF- antagonists

**Infliximab** (Remicade®) is an inhibitor of TNF-, which is a proinflammatory cytokine in psoriasis, psoriatic arthritis, ankylosing spondylitis, Reiter's disease and several more chronic inflammatory diseases. Given as an intravenous infusion of 5 mg/kg at weeks 0, 2, 6, and then every 8 weeks, infliximab, a chimeric monoclonal antibody, is effective in psoriasis, psoriatic nail lesions (Reich et al, 2005), psoriatic arthritis and Reiter's disease including its nail changes (Gaylis, 2003). Many reports have described the dramatic infliximab-induced improvement of both psoriatic skin and nail lesions (Antoni et al, 2005a, 2005b, Rich et al, 2008, Hussain et al, 2008, Reich, 2009). Another study showed a reduction of the mean NAPSI of 55.8 at baseline to 29.8 at week 14 and 3.3 at 38 (Rigopoulos et al, 2008). In the evaluation mentioned above, NAPSI improvement after 12,

Nimesulide is a non-steroidal anti-inflammatory agent. After first positive experience (Piraccini e al 1994) it was given to 13 patients with pustular nail psoriasis of whom 4 responded well to twice daily 100 mg. All these 4 responders relapsed after withdrawal of

An increasing number of "biologics" have been developed in the last decade. They counteract extremely potent immunological targets such as tumor necrosis factor-α (TNF-α), T cells, B cells, various cytokines, some immunoglobulins and key enzymes. A variety of them has been used in psoriasis, often with astonishing success (Lawry, 2007). Also nail psoriasis was the object of some studies. This chapter is, however, not suited to discuss all

TNF- promotes cytokine secretion, such as interleukin (IL)-1, IL-6, IL-8, by macrophages and other inflammatory cells, activates T cells and induces adhesion molecule expression by vascular endothelial cells which in turn promote angiogenesis and keratinocyte proliferation,

> **Adalimumab**  Humira®

Loading dose: week 0 2x40 mg, week 1 40 mg, then 40 mg every

Psoriasis, psoriatic

antibody

2 weeks

arthritis

**Infliximab** (Remicade®) is an inhibitor of TNF-, which is a proinflammatory cytokine in psoriasis, psoriatic arthritis, ankylosing spondylitis, Reiter's disease and several more chronic inflammatory diseases. Given as an intravenous infusion of 5 mg/kg at weeks 0, 2, 6, and then every 8 weeks, infliximab, a chimeric monoclonal antibody, is effective in psoriasis, psoriatic nail lesions (Reich et al, 2005), psoriatic arthritis and Reiter's disease including its nail changes (Gaylis, 2003). Many reports have described the dramatic infliximab-induced improvement of both psoriatic skin and nail lesions (Antoni et al, 2005a, 2005b, Rich et al, 2008, Hussain et al, 2008, Reich, 2009). Another study showed a reduction of the mean NAPSI of 55.8 at baseline to 29.8 at week 14 and 3.3 at 38 (Rigopoulos et al, 2008). In the evaluation mentioned above, NAPSI improvement after 12,

Table 5. Application, dosage and indications of the commonly used TNF- antagonists

Application Intravenous infusion Subcutaneous Subcutaneous

**Etanercept**  Enbrel®

Human fusion protein

50 mg/week, or 2x50mg/week for 12

Psoriasis, psoriatic

weeks

arthritis

the drug (Piraccini et al 2001). It was judged as not being superior to other drugs.

as this will be discussed in the psoriasis treatment chapters.

Structure Chimaeric antibody Human monoclonal

both key events in the pathogenesis of psoriasis (Smolen and Emery, 2011).

**9.4.3 Nimesulide** 

**9.4.4 Biologics** 

**9.4.4.1 TNF- inhibitors** 

**Infliximab**  Remicade®

Dosage 5 mg/kg at weeks 0,

weeks

Indications Psoriasis, psoriatic arthritis

2, 6, then every 8

24 and 48 weeks was 50%, 81%, and 92%, respectively (Sánchez-Regaña et al 2011). There appears to be general agreement that infliximab is the most potent antipsoriatic biologic (Noiles and Vender, 2009).

**Adalimumab** (Humira®) is a human antibody. In an open study, significant NAPSI reductions were obtained for finger and toe nails both in patients with cutaneous psoriasis as well as with psoriatic arthritis (Rigopoulos et al, 2010). In a large cohort of 442 patients with psoriatic arthritis, the mean NAPSI was reduced by 44% (Van den Bosch et al, 2010). Nail psoriasis response may be rapid (Irla and Yawalkar, 2009) although some authors found skin lesions to respond less than articular inflammation (Otten et al, 2011). In a group of ankylosing spondylitis and psoriatic arthritis patients, the NAPSI score was demonstrated to be reduced by 6 points (Rudwaleit et al, 2010). Adalimumab-induced improvement in nail psoriasis correlated with a good response in palmar plantar psoriasis (Langley et al, 2011). In the Spanish study, NAPSI improvement after 12, 24 and 48 weeks was 37%, 73%, 84%, respectively. Adalimumab was also beneficial for nail psoriasis after etanercept treatment (Puig et al, 2010).

**Etanercept**, a fully human TNF-α receptor fusion protein, binds TNF-α with greater affinity than natural receptors. The bound TNF-α is biologically inactive and many of the proinflammatory pathways responsible for initiation, maintenance, and recurrence of skin lesions in psoriasis are inhibited (Weinberg, 2003). The starting dose is twice weekly 50 mg subcutaneously, which may be reduced to once weekly 50 mg or twice weekly 25 mg. In a comparison of systemic nail psoriasis treatments, NAPSI improvement after 12, 24 and 48 weeks was 24%, 68%, and 87%, respectively (Sánchez-Regaña et al, 2011). The commonest adverse effect is an irritation reaction at the injection site. Infections and reactivations may occur as in infliximab treatment though probably less commonly. It should not be combined with systemic corticosteroids (Sanchez et al, 2006, Scheinfeld, 2004). There are some otherwise rare skin diseases that have been observed during etanercept treatment, such as lupus erythematosus, vasculitis, eosinophilic cellulitis like inflammation and interstitial granulomatous dermatitis (Scheinfeld, 2004, Winfield et al, 2006, Deng et al, 2006).

**Golimumab** (Simponi®) is a new human monoclonal antibody against TNF- binding with high affinity and specificity to soluble and transmembrane TNF-. It was studied once in psoriasis and nail psoriasis and showed an improvement in the NAPSI score of 25% and 43% after 14 weeks and 33% and 54% after 24 weeks in a dose of 50mg or 100 mg subcutaneously, respectively, at weeks 0, 4, 8, 12, 16, and 20 (Kavanaugh et al, 2009).

**Certulizumab** (Cimzia®) has not been used in nail psoriasis (Gartlehner et al, 2009).

All TNF- inhibitors were reported to have induced psoriasis or psoriasiform skin and nail lesions (Sfikakis et al, 2005, Wollina et al, 2010). The spectrum of conditions induced by TNF- is very wide and it apparently does not depend on the specific disease treated nor on the anti-TNF- agent used (Pine et al, 2010, Conrad et al, 2011; Lee et al 2011). In more than half of the cases, the TNF- induced skin lesions were successfully suppressed despite continuation of the drug. It is speculated that as TNF- blockade is one of the strongest inducers of interferon- production an unabated IFN- production by plasmocytoid dendritic cells might result in these paradoxical psoriasis flares under anti-TNF- treatment (Conrad et al, 2011).

Nail Psoriasis 177

marked improvement of his nail signs was noted after 4 weeks. A complete cure was

**Tocilizumab** (Actemra®) is an IL-6 receptor inhibitor. No reports on nail psoriasis treatment

**Abatacept** (Orencia®) is a soluble chimeric protein consisting of the extracellular domain of human CD152 linked to the modified Fc portion of human IgG1. By binding to B7-1 (CD80) and B7-2 (CD86) molecules on antigen presenting cells, CTLA4Ig blocks the CD28-mediated costimulatory signal for T cell activation. Success with abatacept has been noted in psoriasis. Abatacept was administered to two patients with refractory psoriasis and psoriatic arthritis after the patients had failed all conventional treatment methods. Both patients experienced

**Rituximab,** a B cell depleting chimeric antibody has no place in the treatment of nail

In clinical routine, different treatments are often combined as one is either insufficient or too slow. The combination should always consist of drugs with different mechanisms of action. In contrast to skin psoriasis, there are almost no studies on the effect of combination therapy on nail psoriasis (Jiaravuthisan et al 2007). A single-blinded study on 54 patients with nail psoriasis examined the effects of cyclosporine monotherapy versus cyclosporine systemically plus calcipotiriol cream topically (Feliciani et al 2004). The cyclosporine dose was 3.5 to 4.5 mg/d, calcipotriol was applied twice daily. After 3 months, the combined treatment showed significant improvement of pitting, subungual hyperkeratosis and onycholysis in 79%, whereas the cyclosporine monotherapy group showed 48% marked improvement. Six months after treatment, the cyclosporine monotherapy group showed a relapse rate of 52.9% (9/17), whereas only 37% (10/27) of patients in the combined therapy

Nail psoriasis is frequent in psoriatic subjects with about 50% of psoriasis patients presenting with nail changes at any time and a life-time prevalence of up to 90%. Nail psoriasis has a strong genetic background and a frequent association with psoriatic arthritis. The most frequent signs of nail matrix involvement are pitting, leukonychia, crumbling and red spots in the lunula, whereas salmon or oil spots, subungual hyperkeratosis, onycholysis and splinter haemorrages represent changes of nail bed involvement. Understanding the mechanism of psoriatic nail sign development requires some basic knowledge of the nail organ, its specific reaction patterns and of nail histopathology. Nail psoriasis has a serious impact on the quality of life interfering particularly with manual work but also being cosmetically embarrassing. Treatment of nail psoriasis is difficult as the matrix pathology is hidden by the proximal nail fold and the nail bed changes are protected against treatment by the overlying nail plate and nail bed hyperkeratosis. Progress has been made with the new biologic drugs, which are

however, usually only administered for skin plus nail involvement.

achieved 4 weeks later after the second injection (Rallis et al, 2010).

very brief improvement in disease (Altmeyer et al, 2011).

have been published hitherto.

**9.5 Combined treatments** 

group had any signs of recurrence.

**10. Conclusion** 

**T cell inhibitors** 

psoriasis.

Serious adverse events of all TNF- inhibitors include the development of viral, bacterial, mycobacterial, and fungal infections (Lowther et al, 2007), reactivation of tuberculosis, hepatitis B and C, allergic infusion reactions, malignancies, autoantibody formation with lupus erythematosus, pancytopenia and aplastic anaemia, neurological disorders and worsening of congestive heart failure (Smolen and Emery, 2011). Experience in pregnancy is lacking. Further, infliximab comes with an information what to look for before starting a treatment. Paradoxical sarcoidosis while on anti-TNF- treatment was also reported (Pine et al, 2010)
