Dermatology

A dermatoscope is a hand-held device for examining the appearance of the skin. Dermoscopy has become an increasingly used and valued tool in the assessment of various skin lesions, and more recently, inflammatory rashes. It is quick, cheap and when used correctly, dermoscopy is an essential tool in helping clinicians detect early stage skin cancer. Various national and international guidelines recommend routine use of dermoscopy in the assessment of pigmented lesions^1,2 because it enhances melanoma detection rates^3,4 and can help confirm the diagnosis of benign lesions such as haemangiomas and seborrhoeic keratoses. As with any skill, competency takes time to develop and a combination of various learning and assessment methods is best. The dermatology specialist training curriculum in the United Kingdom (UK) states that trainees should be competent in using a dermatoscope and interpreting findings, while recognizing the limitations of this tool⁵. Assessment of these clinical skill and behavioural competencies using direct observation of procedural skills (DOPS), case-based discussion (CBD), mini clinical examination (mini-CEX), and/or multisource feedback (MSF) is suggested. There is no specific guidance on what resources a trainee should use to achieve these competencies, nor on what is the minimum expected dermoscopy skillset at completion of specialist training.

The aim of this survey was to explore dermoscopy use amongst dermatology specialist trainee registrars in the UK including frequency of use, how it is being taught and whether trainees feel their dermoscopy training has been adequate.

An online survey was designed and distributed to dermatology trainees in the United Kingdom using an email link and hard copies were distributed at a national dermoscopy course. Respondents who did not identify themselves as dermatology trainees were removed from the analysis. Responses were collected anonymously, then collated and analysed using SurveyMonkey® computer software.

Twenty-five percent (59/238) of dermatology trainees completed the survey. On average, 92% (54/59) use dermoscopy more than once daily. Eighty-five percent (50/59) always use dermoscopy when assessing pigmented lesions while 34% (20/59) always and 59% (35/59) sometimes use it to assess non-pigmented lesions. When asked about specific tools used to learn dermoscopy, 41% (24/59) have been on a previous course, 42% (25/59) reported attendance at a lecture or seminar, 46% (27/59) have used a dermoscopy text book, 14% (8/59) have attended a conference, 19% (11/59) have used online resources. Seventeen percent (10/59) have never used any of the above learning methods. (Figure 1a). Amongst those who have attended a formal dermoscopy course (n=24), 92% (22/24) of these were ≤1 day in duration. When questioned about informal teaching in clinical practice, 12% (7/59) frequently, 56% (33/59) sometimes, 31% (18/59) rarely and 2% (1/59) never receive teaching from their supervising dermatology consultant. (Figure 1b). Fifty-four percent (32/59) feel they have received adequate training in dermoscopy while the remaining 46% (27/59) feel their dermoscopy training is inadequate for their training stage (Figure 1c). Seventy-three percent (43/59) have access to dermoscopic photography within their local dermatology department.

Fig 1a - Have you undertaken any formal study in dermoscopy? 49% of trainees have attended a lecture, 2% a seminar, 14% a conference, 41% a course, 19% have used an online resource, 46% have used a book, 17% have not used any resource.

Fig 1b- Do you receive dermoscopy training from your supervisor in clinic? 56% of trainees sometimes, 31% rarely, 12% frequently, and 2% have never received training from their seniors in clinic.

Fig 1c- Do you believe that you have received adequate training in the use of a dermoscopy for your training grade?

These results of this survey highlight the need for dermoscopy training to be reviewed within the UK national training curriculum for dermatology. Despite daily use by the vast majority, dermoscopy training is largely self-directed and highly variable amongst individual trainees. Of concern, a significant proportion of those who responded feel their dermoscopy skills are inadequate for their training stage. Of note, the 25% response rate means that the results of this survey may not be representative of dermatology trainees in the United Kingdom as a whole.

This is the first time that dermoscopy use has been explored through a national survey of dermatology trainees in the UK, to the best of our knowledge. A survey on dermoscopy use was carried out by The British Association of Dermatologists (BAD) in 2012⁶ but the majority of responses were from dermatology consultants. This confirmed that 98.5% of respondents regularly used dermoscopy, while 81% had received any training. The most frequent source of training was UK based courses, which 62% of respondents reported attending. Of note, 39% of all respondents lacked confidence when making a diagnosis based on their interpretation of dermoscopy findings. It is not clear how many of those lacking in confidence were consultants, trainees or specialty doctors. Although the situation may have improved since 2012, these results do suggest that dermoscopy training needs have not been met for a proportion of doctors across the dermatology community.

Dermoscopy training is an important issue to address for several reasons. The volume of cutaneous lesions being referred to dermatology is increasing, and skin cancer referrals and treatment now account for 50% of a UK dermatologists’ workload⁷. For every melanoma diagnosed, a dermatologist may expect to see 20–40 benign lesions referred from general practitioners (GPs)⁷. These facts highlight the importance of maximising diagnostic skills which frequently include using dermoscopy as part of clinial assessment. Lack of adequate training is a common self-reported reason for dermatologists not using dermoscopy⁸. Both trainees and their supervising bodies have a responsibility to maximize training opportunities and embed the use of dermoscopy in routine practice.

In conclusion, we feel UK dermatology trainees and indeed any clinician who utilizes this tool, would benefit from a more standardized and integrated approach to dermoscopy teaching to ensure safe practice of this skill and deliver high quality evidence-based patient care.

Introduction

Striae distensae, or stretch marks, are linear scars in the dermis which arise from rapid stretching of the skin over weakened connective tissue. It is a common skin condition that rarely causes any significant medical problems but is often a significant source of distress to those affected. Striae distensae were described as a clinical entity hundreds of years ago, and the first histological descriptions appeared in the medical literature in 1889.¹ With a high incidence and unsatisfactory treatments, stretch marks remain an important target of research for an optimum consensus of treatment. These appear initially as red, and later, as white lines on the skin, representing scars of the dermis, and are characterized by linear bundles of collagen lying parallel to the surface of the skin, as well as eventual loss of collagen and elastin. The estimated prevalence of striae distensae range from 50 to 80%.^2,3 The anatomical sites affected vary, with areas commonly affected including the abdomen, breasts, thighs and buttocks.⁴ The three maturation stages of striae include the acute stage (striae rubra) characterized by raised, erythematous striae, the sub-acute stage characterized by purpuric striae, and the chronic stage (striae alba), characterized by white or hypo-pigmented, atrophied striae.⁵ Although stretch marks are only harmful in extreme cases, even mild stretch marks can cause distress to the bearer⁶ (Table 1).

Table 1: Histological comparisons between striae rubrae and striae albae

Aetiology

Striae may result from a number of causes, including, but not limited to, rapid changes in weight, adolescent growth spurts, corticosteroid use or Cushing Syndrome, and generally appear on the buttocks, thighs, knees, calves, or lumbosacral area.⁷ In addition, approximately 90% of all pregnant women develop stretch marks either on their breasts and/or abdomen by the third trimester.⁸ Genetic predisposition is also presumed, since striae distensae have been reported in monozygotic twins.^9,10 There is decreased expression of collagen and fibronectin genes in affected tissue.¹¹ The role of genetic factors is further emphasised by the fact that they are common in inherited defects of connective tissue, as in Marfan’s syndrome.^12,13 Obesity and rapid increase or decrease in weight have been shown to be associated with the development of SD.¹⁴ Young male weight lifters develop striae on their shoulders.¹⁵ Striae distensae also occurs in cachetic states, such as tuberculosis, typhoid and after intense slimming diets.¹⁶ Rare etiologies include human immunodeficiency virus positive patients receiving the protease inhibitor indinavir and chronic liver disease.^13,15 A case of idiopathic striae was also reported.¹⁷

Rosenthal¹⁸ proposed four aetiological mechanisms of striae formation: insufficient development of tegument, including elastic properties deficiency; rapid stretching of the skin; endocrinal changes; and other causes, possibly toxic.

Pathogenesis

The pathogenesis of striae is unknown but probably relates to changes in the components of extracellular matrix, including fibrillin, elastin and collagen.¹⁹ There has been emphasis on the effects of skin stretching in the pathogenesis of striae because the lesions are perpendicular to the direction of skin tension.²⁰ A possible role of glucocorticoids in the pathogenesis of striae has been suggested because of an increase in the levels of steroid hormones and other metabolites found in patients exhibiting striae.²¹ There are studies suggesting the role of fibroblasts in the pathogenesis of striae. Compared to normal fibroblasts, expression of fibronectin and both type I and type III procollagen were found to be significantly reduced in fibroblasts from striae, suggesting that there exists a fundamental aberration of fibroblast metabolism in striae distensae.²²

Pathological aspects

The earliest pathological changes are subclinical to be detected by electron microscopy only. These changes include mast cell degranulation and the presence of activated macrophages in association with mid-dermal elastolysis.²³ When the lesions become become clinically visible, collagen bundles start showing structural alterations, fibroblasts become prominent, and mast cells are absent.²³ On light microscopic examination, Inflammatory changes are conspicuous in the early stage, with dermal oedema and perivascular lymphocytic cuffing.²⁴ In later stages, there is epidermal atrophy, loss of rete ridges and other appendages including hair follicles are absent.²⁵

Evaluation of striae distensae

Approaches to evaluating SD severity visually include the Davey ²⁶ and Atwal scores,²⁷ although these have not been validated specifically for SD. An objective evaluation of SD may be carried out using skin topography, imaging devices including three-dimensional (3D) cameras, reflectance confocal microscopy and epiluminescence colorimetry.^28,29,30

Table 2: Visual scoring systems for the assessment of striae distensae

Management

Striae distensae (striae alba) is a very challenging cosmetic problem for dermatologists to treat. Various modalities of treatment have been tried. Although therapeutic strategies are numerous, there is no treatment which consistently improves the appearance of striae and is safe for all skin types.³¹ Weight loss by diet alone or a combination of diet and exercise do not change the degree of striae distensae.³²

Topical treatments

Topical tretinoin (0.1%) ameliorates striae and the improvement may persist for almost a year after discontinuation of therapy.³³ More recently, tretinoin has been shown to improve the clinical appearance of stretch marks during the active stage (striae rubra), although with not much effect during the mature stage (striae alba).³⁴ Some of the studies have proven the inefficacy of the vitamin A derivative in the treatment of SD, but most of the patients included in these early studies presented with old lesions that had evolved into whitish atrophic scars.³⁵ A study comparing topical 20% glycolic acid and 0.05% tretinoin versus 20% glycolic acid and 10% L-ascorbic acid, found that both regimens improved the appearance of striae alba.³⁶

Hydrant Creams: 1) Trofolastin (a cream containing Centella asiatica extract, vitamin E, and collagen-elastin hydrolysates). The exact mechanism of action was identified as the stimulation of fibroblastic activity ³⁷ and an antagonistic effect against glucocorticoids.³⁸ 2) Verum (a cream containing vitamin E, panthenol, hyaluronic acid, elastin and menthol). The results suggest that the product may show the benefit of massage alone.³⁹ 3) Alphastria (a cream composed of hyaluronic acid, allantoin, vitamin A, vitamin E, and dexpanthenol). Only one study was conducted, which concluded that the product markedly lowered the incidence of stretch mark development after pregnancy.⁴⁰

Glycolic acid (GA): The exact mechanism of action of GA in the management of striae distensae is still unknown because, although GA is reported to stimulate collagen production by fibroblasts and to increase their proliferation in vivo and in vitro, which may be useful for the treatment of stretch marks.^41,42 A study comparing topical 20% glycolic acid and 0.05% tretinoin versus 20% glycolic acid and 10% L-ascorbic acid, found that both regimens improved the appearance of striae alba.⁴³

Trichloroacetic acid (TCA; 10–35%): It has been used for many years as a treatment option for striae distensae and is repeated at monthly intervals with reported improvement in texture and color of marks.⁴⁴

Other topical products: Several oils have been used in the prevention of SD. A non-randomized, comparative study investigated the effect of almond oil in the prevention of SD in which they noted significant differences in the frequency of SD between the groups (almond oil and massage 20%, almond oil alone 38.8%, control 41.2%).⁴⁵

Overall, there is limited evidence for the efficacy of topical therapy for the treatment of SD.

Microdermabrasion

Microdermabrasion may improve many skin problems including acne scars, skin texture irregularities, mottled pigmentation and fine wrinkles. Karimipour et al reported that microdermabrasion induces epidermal signal transduction pathways associated with remodelling of the dermal matrix.⁴⁶ However, studies documenting the efficacy of rnicrodermabrasion in treatment of striae are lacking. Published in 1999, a book on microdermasion written by a French dermatologist, Francois Mahuzier, and translated to English, has a chapter "Microdermabrasion of stretch marks^”.⁴⁷ The author states that 10-20 sessions of microdermabrasion at an interval of not less than 1 month, each session resulting in bleeding points, provide satisfactory results. The author concludes that, "microdermabrasion is the only effective treatment of stretch marks today."

Lasers

Lasers have recently become a popular therapeutic alternative to ameliorate and improve the appearance of stretch marks. Most commonly used lasers used include pulsed-dye laser (PDL), short- pulse carbon dioxide and erbium-substituted yttrium aluminium garnet (YAG), neodymium- doped YAG (Nd:YAG), diode, and Fraxel.

Pulsed dye laser: The dilated blood vessels render the striae rubrae a good candidate for PDL.⁴⁸ The 585- nm pulsed dye laser has a moderate beneficial effect in the treatment of striae rubra.⁴⁹ To evaluate the effectiveness of the 585-nm flashlamp-pumped pulse dye laser in treating cutaneous striae, 39 striae were treated with four treatment protocols.⁵⁰ Subjectively, striae appeared to return toward the appearance of normal skin with all protocols. Objectively, shadow profilometry revealed that all treatment protocols reduced skin shadowing in striae. Laser treatment of SD should be avoided or used with great caution in darker skin types (IV–VI), because of the possibility of pigmentary alterations after treatment.⁵¹

Excimer laser: Studies have shown temporary repigmentation and improvement of leukoderma in SD with excimer laser, although it failed to show any improvement in skin atrophy.^52,53 To evaluate the true efficacy of the 308-nm excimer laser for darkening striae alba, 10 subjects were treated using the excimer laser on the white lines of striae, while the normal skin near to and between the lines was covered with zinc oxide cream. The results of this study showed the weakly positive effect of the 308-nm excimer laser in the repigmentation of striae alba.⁵⁴

Copper Bromide laser: copper-bromide laser (577-511 nm) has been used for stretch marks. A clinical study was conducted in 15 Italian women with stretch marks, treated with the CuBr laser (577-511 nm) and followed-up for 2 years.⁵⁵ The results of the study concluded that the copper-bromide laser was effective in decreasing the size of the SD and there were some pathogenic considerations that justified the use of this laser.

1,450-nm Diode Laser: The non-ablative 1,450-nm diode laser has been shown to improve atrophic scars and may be expected to improve striae. To evaluate the efficacy of the 1,450-nm diode laser in the treatment of striae rubra and striae alba in Asian patients with skin types 4-6, striae on one half of the body in 11 patients were treated with the 1,450-nm diode laser with cryogen cooling spray with the other half serving as a control.⁵⁶ None of the patients showed any noticeable improvement in the striae on the treated side compared to baseline and to the control areas. The study concluded that the non-ablative 1,450-nm diode laser is not useful in the treatment of striae in patients with skin types 4, 5, and 6.

1,064-nm Nd:YAG Laser: A study was aimed to verify the efficacy of this laser in the treatment of immature striae in which 20 patients with striae rubra were treated using the 1,064-nm long-pulsed Nd:YAG laser.⁵⁷ A higher number of patients (55%) considered the results excellent when compared to the same assessment made by the doctor (40%).

Intense Pulsed Light: In order to assess the efficacy of IPL in the treatment of striae distensae, a prospective study was carried out in 15 women, all of them having late stage striae distensae of the abdomen.⁵⁸ All the study subjects showed clinical and microscopical improvement after IPL. It seems to be a promising method of treatment for this common problem with minimal side-effects, a wide safety margin and no downtime.

Fractional Photothermolysis: To determine the efficacy of fractional photothermolysis in striae distensae, 22 women with striae distensae were treated with two sessions each of fractional photothermolysis at a pulse energy of 30 mJ, a density level of 6, and eight passes at intervals of 4 weeks and response to treatment was assessed by comparing pre- and post-treatment clinical photography and skin biopsy samples.⁵⁹ Six of the 22 patients (27%) showed good to excellent clinical improvement from baseline, whereas the other 16 (63%) showed various degrees of improvement. This study concluded that Fractional photothermolysis may be effective in treating striae distensae, without significant side effects.

Ablative 10,600-nm carbon dioxide fractitional laser: Ablative 10,600-nm carbon dioxide fractional laser systems (CO₂ FS) have been used successfully for the treatment of various types of scars. To assess the therapeutic efficacy of CO₂ FS for the treatment of striae distensae, 27 women with striae distensae were treated in a single session with a CO₂ FS and clinical improvement was assessed by comparing pre- and post-treatment clinical photographs and participant satisfaction rates.⁶⁰ The evaluation of clinical results 3 months after treatment showed that two of the 27 participants (7.4%) had grade clinical 4 improvement, 14 (51.9%) had grade 3 improvement, nine (33.3%) had grade 2 improvement, and two (7.4%) had grade 1 improvement. None of the participants showed worsening of their striae distensae.To assess and compare the efficacy and safety of nonablative fractional photothermolysis and ablative CO(2) fractional laser resurfacing in the treatment of striae distensae, 24 ethnic South Korean patients with varying degrees of atrophic striae alba in the abdomen were enrolled in a randomized blind split study and were treated with 1,550 nm fractional Er:Glass laser and ablative fractional CO(2) laser resurfacing.⁶¹ These results of the study support the use of nonablative fractional laser and ablative CO(2) fractional laser as effective and safe treatment modalities for striae distensae of Asian skin with neither treatment showing any greater clinical improvement than the other treatment.

UVB/UVA1 Combined Therapy: Besides lasers, light sources emitting ultraviolet B (UVB) irradiation have been shown to repigment striae distensae. A study was conducted on 9 patients with mature striae alba who received 10 treatment sessions, and biopsies were taken at the baseline and end of the study.⁶² At the end of the study, all patients reported some form of hyperpigmentation that was transient and did not affect any surrounding tissues. No changes were seen on biopsy to indicate an effective remodelling collagen effect of the device, although it needs further assessment. Another study was conducted to analyse the histologic and ultrastuctural changes seen after UVB laser- or light source-induced repigmentation of striae distensae in which analyses of biopsied skin after treatment with both the UVB laser and light source showed increased melanin content, hypertrophy of melanocytes, and an increase in the number of melanocytes in all patients.⁶³

Radiofrequency devices: RF devices are based on the principle of heat generation that occurs in response to poor electrical conductance according to Ohm’s law (heat generation is directly correlated with tissue resistance). The heat that is generated is sufficient to cause thermal damage to the surrounding connective tissue,⁶⁴ which is responsible for the partial denaturation of pre-existing elastic fibers and collagen bundles.⁶⁵ Initial collagen denaturation within thermally modified deep tissue is thought to represent the mechanism for immediate tissue contraction; subsequent neocollagenesis further tightens the dermal tissue and reduces striae.⁶⁶ The efficacy and safety of combination therapy with fractionated microneedle radiofrequency (RF) and fractional carbon dioxide (CO2) laser in the treatment of striae distensae has been evaluated revealing that this combination therapy is a safe treatment protocol with a positive therapeutic effect on striae distensae.⁶⁷ A recent study evaluating the effectiveness of a RF device in combination with PDL subjected 37 Asian patients with darker skin tone with SD to a baseline treatment with a RF device and PDL.⁶⁸ All histological evaluations demonstrated an increase in the amount of collagen fibers, and six of the nine specimens showed an increase in the number of elastic fibers.TriPollar RF device appears to be a promising alternative for the treatment of striae distensae in skin phototypes IV-V.⁶⁹

Needling therapy:

To evaluate the effectiveness and safety of a disk microneedle therapy system (DTS) in the treatment of striae distensae, 16 Korean volunteers with striae distensae alba or rubra were enrolled which received three treatments using a DTS at 4-week intervals.⁷⁰ Marked to excellent improvement was noted in seven (43.8%) patients, with minimal to moderate improvement in the remaining nine. This study revealed that Disk microneedle therapy system (DTS) can be effectively and safely used in the treatment of striae distensae without any significant side effects. Another study assessed and compared the efficacy and safety of needling therapy versus CO2 fractional laser in treatment of striae and the results supported the use of microneedle therapy over CO2 lasers for striae treatment.⁷¹

Platelet-rich plasma:

Platelet-rich plasma has these wound-healing properties, affecting endothelial cells, erythrocytes, and collagen,⁷² which potentially aids in the healing of the localized chronic inflammation believed to be a factor in the aetiology of striae distensae. Platelet-rich plasma is well tolerated by the patients and is a safe and cost effective treatment option for striae distensae.

Platelet-rich plasma alone is more effective than microdermabrasion alone in the treatment of striae distensae, but it is better to use the combination of both for more and rapid efficacy.⁷³

The plasma fractional radiofrequency and transepidermal delivery of platelet-rich plasma using ultrasound has also been found to be useful in the treatment of striae distensae.⁷⁴

Since thermal damage from intradermal RF has characteristics similar to those of many wounds, combination treatment with intradermal RF and autologous PRP would eventuate in enhanced localized collagen neogenesis and redistribution. In one of the studies, three sessions of intradermal RF were used combined with autologous PRP administered once every four weeks.⁷⁵ All of the participants showed satisfactory changes and no patient was reported to show no improvement.

Transepidermal retinoic acid:

Transepidermal retinoic acid delivery using ablative fractional radiofrequency associated with acoustic pressure ultrasound has also been used for the treatment of stretch marks.⁷⁶

Conclusion

Striae distensae are an extremely common, therapeutically challenging form of dermal scarring. Adequate scientific knowledge and the evidence behind both preventative and therapeutic agents are vital in order to understand striae and to offer patients the best therapeutic options. The treatment of this cosmetically distressing condition has been disappointing and there is no widely accepted surgical procedure for improving the appearance of stretch marks. Laser therapy has been advocated as a treatment for striae distensae.

Introduction

Dermatomyositis (DM) is a rare autoimmune process with not yet fully understood aetiology. It is characterised by a combination of striated muscle inflammation and cutaneous changes. The pathogenesis of the cutaneous manifestations of DM is not well understood either. DM occurs in all age groups. Therefore, two clinical subgroups of DM are described: adult and juvenile. The adult form is predominant among female patients with a clinical presentation which includes a Heliotrope rash (Fig. 1), Gottron’s papules (Fig. 2), nail fold telangiectasia and other various cutaneous manifestations in association with inflammatory myopathy.¹ In addition to the previous mentioned symptoms, juvenile patients also commonly suffer from ulcerative skin and recurrent abdominal pain due to vasculitis. An increased occurrence of oncological processes in combination with adult DM has been observed with a slight predominance for the female gender.² These patients carry a higher risk for comorbid cancers. The most common ones include malignant processes of the ovary, lung, pancreas, stomach, urinary bladder and haematopoietic system.³ The significance of these observations is that the development of DM should raise suspicion with regard to a possible parallel oncological process.

Figure 1

Figure 2

Materials and Methods

A retrospective consecutive case series was performed on a group of 12 patients that were hospitalised at the Department of Dermatology, Venereology and Allergology at the Medical University of Gdansk between 1996 and 2013. The diagnostic criteria for DM included: hallmark cutaneous lesions of DM, clinically significant muscle weakness evaluated by electromyography (EMG), indicative laboratory findings - muscle enzymes, muscle biopsy, autoantibodies. All 12 cases had muscle biopsy, serum studies and EMG performed. The retrospective study analysed the age and sex of the patients, course of the disease, accompanying diseases, clinical picture and treatment. The patients with malignancies were analysed by the primary organs of origin, and the period between the diagnosis of DM and that of malignancy (Table 1).

Table 1. Patient characteristics

No. = number (patient), DM = dermatomyositis, F = female, M = male, CK = creatine phosphokinase, ANA = antinuclear antibodies, LDH = lactate dehydrogenase, AST = aspartate transaminase, ALT = alanine transaminase, N = negative, P = positive, USG = ultrasonography, EMG = electromyography, CT = computerised tomography

Limitations

The small sample size is a significant limitation in this retrospective analysis. DM is a rare disease with a prevalence of 1:1000. Increasing sample size, by combining cases from multiple institutions, and implementing control would further strengthen the presented material.

Results

The average age of onset of the disease was 48 years. All 12 subjects were female. Previous medical history included chronic eosinophilic leukaemia, diabetes mellitus type II, hypertension, leiomyomas, hypo- and hyper- thyroid disease, chronic obstructive pulmonary disease, peptic ulcer disease, autoimmune hepatitis and osteopenia. The two most common are diabetes mellitus type II and hypertension. The clinical picture of each case was similar in that all of the patients presented with some form of muscle weakness. In addition, typical features of DM with Gottron’s papules, periorbital oedema, facial oedema and erythema were noted in five patients. Antinuclear Antibodies (ANA) Hep-2 of values >1:160 were identified in nine patients. Additional laboratory markers such as creatine kinase (CK), lactate dehydrogenase (LDH), aspartate transaminase (AST) and alanine transaminase (ALT) were elevated in five patients. Two patients had muscle biopsies performed. The immunohistopathology picture consisted of Immunglobulin G (IgG), fibrinogen, C1q, and C3 deposition around the perimysium and granular deposits of Immunoglobulin M (IgM) in the dermal epidermal junction. Of the 12 patients, four had neoplasms in addition to the diagnosed DM. The primary cancers were originating from the cervix, breast, stomach and ovary. Of these four patients, all had the diagnosis of DM prior to the diagnosis of a malignancy.

Discussion

The diagnosis of DM is made by combining the clinical picture with the results of various laboratory findings: skin and muscle biopsies, EMG, serum enzymes and ANAs.

The clinical picture varies. The typical dermatological presentation consists of a erythematous and oedematous periorbital rash - the Heliotrope rash (Fig. 1). Symmetrical redness and flaking can be observed on the elbows and dorsal sides of the phalanges, especially over the distal metacarpal joints - Gottron’s papules (Fig. 2). Erythematous lesions can also be found on other locations such as the face, upper chest and knees.⁴ The dermatitis heals with atrophy, leaving behind areas that resemble radiation-damaged skin. The striated muscle inflammation most often involves the shoulder and hip area, leading to muscle weakness and atrophy. The intercostal muscles and the diaphragm may be involved causing alarm with regards to respiratory compromise. Dysphagia can be present due to inflammation of the smooth and skeletal muscles of the oesophagus. These inflammatory processes often lead to muscle calcification.⁵ The sum of all these changes clinically is seen most often as weakness, weight loss and subfebrile temperatures. All patients in our study had co-existing muscle and cutaneous symptoms, with variation in severity and localisation. Five patients had the classical picture of shoulder and hip area weakness. The rest of the patients had a more general muscle weakness. Two patients had atypical complaints of hand paraesthesia and extremity pain respectively.

Subtypes of DM exist for the purpose of epidemiological research and sometimes prognosis. They are categorised by the clinical presentation and presence or absence of specific laboratory findings. These subtypes are as follows: Classic DM, Amyopathic DM, Hypo-amyopathic DM and Clinically Amyopathic DM. These subtypes have little impact on routine diagnosis. Common laboratory findings in DM are enzymatic elevation of CK, AST, ALT and LDH; these mainly reflect the muscle involvement. Amyopathic DM lacks both abnormal muscle enzymes and weakness.⁶ Enzymatic elevation may sometimes precede the clinical symptoms of muscle involvement. Hence, an enzymatic raise in a patient with a history of DM, should raise suspicion of recurrence. Positive ANA findings are frequent in DM but not necessary for diagnosis. More myositis-specific antibodies include anti-Mi 2 and anti-Jo 1. A typical histopathological examination shows: myofiber necrosis, perifascicular atrophy, patchy endomysial infiltrate of lymphocytes and occasionally the capillaries may contain membrane attack complexes.⁷

Cutaneous changes and muscular complaints can correspond to: 1. Systemic scleroderma which often has a positive ANA; 2. Trichinosis, in which periorbital swelling and myositis occurs, but there is a prominent eosinophilia and a history of consuming undercooked swine or bear meat; 3. Psoriasis with joint involvement which may give a clinically similar picture to DM. However, the skin changes in psoriasis have a more flaking pattern. In doubtful cases, a skin and muscle biopsy together with an electromyography will set the diagnoses apart. A facial rash may also be observed in systemic lupus erythematosus together with nail fold telangiectasia. They are usually distinguished by a clinical picture with more organ system involvement in systemic lupus and by serological studies. A drug-induced picture of DM exists and is particularly associated with statins and hydroxyurea.⁸

It is estimated that around 25% of DM cases are associated with a neoplastic process that can occur prior, during or after the episode of DM. The risk of developing a malignancy is highest in the first year of DM and remains elevated for years after diagnosis. ^{9, 10, 11} This was the case with patient number 1, 2 and 4 in our study, where the malignant process appeared in the first year following onset of DM. Risk factors seen in DM patients include male gender, advanced age and symptoms of dysphagia.¹² The age range of the four patients in our study with malignancy was between 43 and 66. Symptoms that clinically raised suspicion of a malignant process included weight loss, lack of appetite and dysphagia. All neoplasms were discovered within one year after the diagnosis of DM was made. One patient had a previous history of cervical cancer, six years prior to the onset of DM.

The most common neoplasms seen in patients with DM vary in the world. In Europe the malignancies are located mainly in the ovaries, lungs, and stomach. The cancer types associated with the DM correlate with common cancers seen in the same area. For instance, in Asia, nasopharyngeal carcinoma (which is a rare malignancy in Europe) is a frequent occurrence in DM.^{1, 3} The location of neoplasms seen in our study varied from gastric, breast, ovary and pulmonary. The screening in regards to malignancies in patients with DM is individualised and should be based on risk factors such as previous malignancies, alarming symptoms such as weight loss or dysphagia, or abnormal findings on physical exam. This was the case with patient number 10 in our study who had a previous history of cancer, and patient number 2 who had symptoms of weight loss and decreased appetite. Initial screening was negative for patient number 1 and 2, where the malignancy developed first after the onset of DM. Age-appropriate screening with mammography, faecal-occult blood test and Papanicolaou smear should be considered. Additional investigations with chest films, computerised tomography (CT) scanning of chest, abdomen or pelvis; colonoscopy, cancer antigens; and gynaecological ultrasonography should be done when indicated.

The main objective of treatment in DM is to improve muscle strength and obtain remission, or at least clinical stabilisation. No specific protocol exists with regard to treatment of DM. Treatment is individualised and adapted to the specific condition of the patient. High-dose corticosteroids are the basis of treatment. However, randomised placebo clinical trials failed to show their efficacy. Clinical efficacy of corticosteroid therapy demonstrates itself and hence is the initial treatment of choice. Doses start at around 1 mg/kg/day depending on the corticosteroid of preference. This dosing is maintained for approximately two months until clinical regression is achieved, followed by approximately 10 mg decrease in dose for the coming three months. A maintenance dose of approximately 5-10 mg should be achieved. The exact parameters are patient-specific. In the case of a severe flare of dermatomyositis, 1 g per day for three days of methylprednisolone intravenous pulses can be administered. The systemic effects of long term therapy with corticosteroids have to be kept in mind. Hence, yearly dual-energy X-ray absorptiometry bone scans can be administered to monitor the development of osteopenia.

Further treatment options are offered in situations where the initial disease presentation is severe, involves internal organs, if relapse occurs during steroid dose reduction, and steroid side-effects. It has been proposed that combination therapy is a better method of approach due to lower reported relapse rates and lower need to use high-dose corticosteroids. Methotrexate is second-line therapy when steroids fail alone. Methotrexate is used with a maximum dose of 25 mg per week plus folate supplementation. The limitations of Methotrexate are immunosuppression and pulmonary fibrosis. Methotrexate is considered preferable to Azathioprine because the latter has a longer onset of efficacy. Azathioprine is administered at doses ranging from 1.5 - 3 mg/kg/day and has a side-effect profile is similar to that of other immunosuppressants. Cyclosporin A is a T-cell cytokine moderator that has a similar efficacy profile to Methotrexate. Side-effects include renal impairment, gingival hyperplasia, and hypertrichosis. Dosing of Cyclosporin A ranges from 2 - 3 mg/kg/day.

An expensive but effective and rather low side-effect alternative is intravenous immunoglobulins. The dosage of this medication has not been officially established in the treatment of DM, but options are: 2 g/kg given either in 1 g/kg/day for two days every four weeks; or 0.4 mg/kg/day for five days initially, and then for three days monthly for three to six months. Other alternatives include Mycophenolate Mofetil, Cyclophosphamide, Chlorambucil, Fludarabine, Eculizumab, Rituximab.⁹ Further options might be treatment targeted toward malignancy when associated with DM. This was observed in our patient number 10, where full remission of DM was obtained first after lobectomy and chemotherapy for the mammary carcinoma.

Conclusion

DM mainly affects women and all 12 cases presented in our study were female. One third of our cases had malignancies associated with their course of DM. We conclude that it is reasonable to screen these patients, especially in those with already established cancer risk factor. Age-appropriate screening and beyond is indicated by high risk factors or clinical presentation. High suspicion should be raised in patients with a previous history of oncological treatment since DM can be the first clinical sign of cancer recurrence.

Case Report

Blue discolouration of the skin can have a multitude of causes, including Mongolian spots, blue naevi, the naevi of Ito and Ota and metallic discolouration¹ or the use of drugs such as minocycline. Here we report the case of a 61 year old gentleman who developed blue macular skin lesions that were not attributable to any obvious cause and may be the result of an unidentified occupational exposure.

A 61 year old Caucasian gentleman developed blue macular skin lesions over a 14 year period. The very first lesion appeared in the middle phalanx of the right middle finger (figure 1). It was light blue and pinpoint, eventually darkening and increasing in size to approximately 1mm x 1mm, at which point becoming permanent and non-evolving. The lesion had no notable associated features and the patient was in otherwise good health.

Figure 1: The first blue macular lesion on the middle phalanx of the right middle finger.

Figure 2: A blue macular lesion on the terminal phalanx of the left middle finger.

Figure 3: A lesion on the anterior abdomen from which a punch biopsy was taken.

Figure 4: Haematoxylin and Eosin stained slide at 10x magnification. Abdominal skin biopsy showing dermal interstitial and perivascular distribution of black coloured pigment deposits

At present, he has approximately thirteen blue macular lesions in total, all of which have developed in the same manner. They are distributed predominantly on his hands with one on his left forearm and one on the right abdominal flank. New spots still continue to arise on his hands (figure 2).

A punch biopsy of the abdominal lesion (figure 3) was carried out. The histological findings were those of skin with normal intact epidermis and the presence of black coloured pigment granular deposits, located largely within the papillary dermis and occasional smaller deposits in the superficial reticular dermis (figure 4). The deep reticular dermis and subcutaneous fat were normal.  The pigment had a perivascular distribution and in dendritic histiocytic cells, with close association to fibroblasts. Histiocytic cells form part of the mononuclear phagocyte system and these cells are abducted mainly for phagocytosis removal or storing material². Apart from the pigment, the remaining skin was normal. The use of light microscopy alone does not identify all substances on examination of a Haematoxylin and Eosin (H&E) stained section of tissue. Applying polarisation light microscopy enables the identification of numerous structures, for example crystals, pigments, bone and amyloid³. However, the black coloured material here was non polarisable (no refractile foreign material could be identified).  These appearances as seen on light microscopy alone are most frequently seen where there is a history of tattoo artistry, but tattoo pigment is typically identified as showing reflective properties using polarisation⁴. Interestingly, the patient had no clinical history of deliberate tattooing and other causes were considered.

Discussion

The discovery of black coloured deposits in the dermis excludes the diagnoses of Mongolian spots or blue naevi and the naevi of Ito and Ota, all of which are disorders of dermal melanocytes. Another important differential is malignant melanoma, but it is not the diagnosis as the histopathological findings did not find any evidence of dysplasia or malignancy.

In a disorder known as anthracosis, similar findings of black coloured deposits can be seen in other organs such as within the lung and draining lymph nodes. It is often found in smokers and urban populations and reflects the deposition of carbon which is the most commonly identified exogenous mineral substance within tissue sections. The skin is not a site where such carbon pigment is typically seen and therefore, this is not a credible diagnosis in this case.

Agyria is a condition that occurs as a result of silver particle impregnation of skin leading to blue-grey skin discolouration. Silver exposure may be due to occupational or surgical exposure (by use of silver sutures) or medication with silver salts. On interview, the patient denied any occupational exposure to silver and the use of silver salts. Although the patient had had previous shoulder surgery, silver sutures are no longer used in modern day surgical practice and therefore this cannot be the cause of his skin discolouration.

Unfortunately, histological examination of paraffin embedded tissue sections can only confirm the presence and distribution of an exogenous substance and it is not possible to precisely differentiate the exact type of material which is present. The use of an electron probe micro analyser may have been useful in identifying the substance, however, such equipment is not currently available and was not used in this case.

Interestingly, in tattoo artistry, carbon black may be used to give blue tattoos their colour⁵ and this is also a component of tyres and industrial rubber products⁶. This provided us with a link to occupational exposure, given that this gentleman is a tyre worker and has been involved in both the manufacture and assembly of tyres for 34 years. Carbon can cause discoloration of the skin, depending on the extent of deposition.

It is notable that in his 34 years of working with tyres, this gentleman did not routinely use gloves or protective uniform until only 10 years ago. This was as workplace safety precautions were not as strongly enforced in previous times. He admitted to have been in direct contact with the materials involved in tyre building and also suffered accidental superficial cuts on his hands whilst working, which may be a route by which carbon may have been introduced into the dermis. This is supported by the observation that the majority of the blue macular lesions were on the hands. Adding credibility to this theory is the identification of a colleague of this gentleman’s (who did not wish to be identified), whose job also involved the manufacture and assembly of tyres, who also has a similar single blue macular lesion on his hand.

In addition to this we have identified a forum on the internet⁷ that reports other similar cases of blue pin-point macular lesions appearing on the skin of tyre factory workers – some of whom worked for the same tyre company that this gentleman did. This may suggest that there is an association between exposure to a chemical, possibly carbon black, involved in the manufacture of tyres, and the appearance of these blue macular lesions.

In this case report, the identity of the material deposited and the route by which it accumulated in the dermis is unclear, but may have been related to an occupational exposure – this was in keeping with the general consensus upon presentation of this case at the West Midlands Dermatology Conference at New Cross Hospital Wolverhampton. We welcome any new case reports or literature that may be able to shed further light on this subject.

INTRODUCTION

The US Food and Drug Administration (USFDA) considers the following as biologics: any therapeutic serum, toxin, antitoxin, vaccine, virus, blood, blood component or derivative, allergenic product, analogous product, or derivatives applicable to the prevention, treatment, or cure of injuries or disease of man¹. However, generally, biologics refer to protein molecules therapeutically used in various diseases so as to target specific points in the inflammatory cascade of these disorders ². Hope for an improved tolerability, convenience in usage and lasting remissions, combined with increased knowledge of immune-pathogenesis of various cutaneous diseases has lead to the introduction of biologics as alternative immune-modulating agents in the field of dermatology.

CLASSIFICATION

Biologics are generally divided into three major groups ³:

a) Monoclonal antibodies

b) Fusion antibody proteins

c) Recombinant human cytokines and growth factors

The main groups and the principal agents in each group are summarised in Box 1 and described below.

A) MONOCLONAL ANTIBODIES

Monoclonal antibodies target specific cell-surface receptors. In the early days of biologic therapy, purely murine monoclonal antibodies were used. However, due to the development of antimurine antibodies, which blocked their action, these could be given only for very short periods. The monoclonal antibodies used now have different amounts of murine sequences in the variable region. They may be categorised into three classes:

(a) chimeric antibodies comprising of 30% murine genes fused with human antibodies

(b) humanised antibodies, which have 10% murine sequences, and

(c) human antibodies, which are solely derived from human immunoglobulin genes ⁴.

Principal monoclonal antibodies with therapeutic relevance in Dermatology

The principal monoclonal antibodies known till date are enumerated in Box 1 and described briefly below.

1. Infliximab

Infliximab (trade name Remicade) is a human-mouse monoclonal antibody that binds to and inhibits the activity of TNF-α, and also causes lysis of TNF-α producing cells⁵.

Important uses of Infliximab

Psoriasis: Infliximab is approved for the treatment of psoriatic arthritis and plaque psoriasis by FDA^{6, 7}. Infliximab may also be of value in recalcitrant or unstable disease and in generalised pustular psoriasis. It is given as an IV (intravenous) infusion in doses of 5 or 10 mg/kg, over a period of 2 hours at weeks 0, 2, 6 and may be followed by repeat single infusions at 8-12 week intervals ⁸. In various controlled trials, improvement at 10 weeks has been noted in 87% of patients ^{7, 9}.

Atopic dermatitis: Infliximab has also been evaluated in a study of atopic dermatitis ¹⁰. At 2 weeks, there was significant improvement in all patients. At 10, 14, and 30 weeks, variable response was seen.

Hidradenitis suppurativa: Long-term efficacy has also been evaluated in hidradenitis suppurativa. In one study, some patients had no evidence of recurrence after 2 years, while others relapsed within a mean of 8.5 months¹¹.

2. Adalimumab

Adalimumab (Humira®) is a human IgG1 monoclonal antibody directed against TNF-α. Adalimumab is given in a dose of 40 mg subcutaneously (SC) every other week as self-injection ^{5, 12}.

Important uses of Adalimumab

Psoriasis: Adalimumab rapidly reverses the decrease in epidermal Langerhans cell density in psoriatic plaques ¹³. In a trial, patients with psoriatic arthritis received adalimumab every other week for 24 week¹⁴. It was well-tolerated and helped improve joint and skin manifestations significantly.

Hidradenitis suppurativa: An increasing number of reports in refractory hidradenitis supprativa have shown successful control with adalimumab ^{15, 16, 17}.

3. Basiliximab

Successful treatment for severe psoriasis and generalised pustular psoriasis has been reported with basiliximab, an interleukin-2 receptor (IL-2R; CD25) chimeric monoclonal antibody ^{18, 19}.

4. Daclizumab

Daclizumab is a humanised monoclonal antibody thatbinds to the CD25 subunit of the IL-2 receptor onT-cells, thus blocking T-cell proliferation. It has been tried in recalcitrant psoriasis and HIV-associated psoriatic erythroderma with a mean reduction in PASI of 30% ^{20, 21 22}.

5. Siplizumab

Siplizumab (Medi-507) is a humanisedmonoclonal antibody directed against CD2. It is designed to block stimulationby inhibiting the CD2–LFA-3 interaction. In earlyphase studies in psoriasis, significant response to therapy has been noted²³.

6. Efalizumab

Efalizumab is a recombinant humanised monoclonal IgG1 antibody that binds to CD11a, a subunit of leukocyte function-associated antigen 1 (LFA-1) ²⁴. It destabilises and decreases the trafficking of T-cells into dermal and epidermal tissues.

Important uses of Efalizumab

Psoriasis: Efalizumab was approved by the US FDA in October 2003 for the treatment of psoriasis⁵. It is currently the only biologic agent approved for continuous administration to adult patients²⁴. The licensed dose of efalizumab is 1 mg/kg weekly as a subcutaneous self- administered injection for 12 weeks, following a first conditioning dose of 0.7 mg/kg ²⁴.

Lichen planus: There is one case report of 3 months duration of treatment with efalizumab for lichen planus with resolution of skin lesions and pruritis ²⁵.

7. Rituximab

Rituximab is a monoclonal humanised antibody directed again in the B cell-specific antigen CD20.

Important uses of Rituximab

Lymphoma: It has been used in patients with CD20-positive non-Hodgkin's lymphoma in a dosage of 375 mg/m² for four infusions²⁶.

SLE: In systemic lupus, dose escalation studies revealed no differences with respect to clinical outcome in patients who received either a single infusion of 100 mg/m², a single infusion of 375 mg/m², or four weekly infusions of 375 mg/m^{2 27}.

Blistering diseases: For patients with blistering diseases, most patients receive the lymphoma dosage schedule. However, serious side effects were considerably higher.

There are reports of refractory pemphigus patients who received infusions of rituximab and had rapid resolution of lesions and a long lasting clinical remission ^{28, 29, 30}.

8. Galiximab

Galiximab a humanised monoclonal antibody directedagainst CD80 and blocks its interaction with CD28 on the T cell, for T-cell stimulation ³¹. Clinicaldata for this drug are just beginning to emerge with 40% of patients achieving at least 50% reduction in PASI after receiving4 biweekly doses in a trial^{32, 33}.

9. Ustekinumab

It is a fully human monoclonal antibody targeting IL-12 and IL-23, presently undergoing clinical trials for psoriasis and psoriatic arthropathy^{2, 34}. In placebo-controlled studies, (PHOENIX 1) and (PHOENIX 2) have shown that ustekinumab could control plaque psoriasis with only four injections a year resulting in greater ease of use and more sustained relief ^{35, 36}.

10. Certolizumab pegol

Certolizumab is the recombinant antibody Fab' fragment of a humanised TNF inhibitor monoclonal antibody. A study in chronic plaque psoriasis showed that certolizumab pegol, given subcutaneously every two weeks, over a period of 12 weeks shows significant improvement ³⁷.

11. Golimumab

Golimumab, a fully human monoclonal antibody is at present undergoing Phase III clinical trials in psoriatic arthropathy ³⁸.

12. Orthoclone or OkT4a

It is a humanised antihuman CD4 IgG4 monoclonal antibody preventing the recognition of the MHC-bound antigen by an appropriate T-cell receptor, hence T cells do not get activated ³⁹. Several studies have found orthoclone to be effective in moderate to severe psoriasis ^{40, 41}.

13. ABX-IL8

ABX-IL8 is a fully human monoclonalantibody designed to bind free IL-8, a key chemokine in psoriasis and deactivate it in theskin^{42, 43}. In early trials, the drug has demonstrated good clinical responsein psoriasis ^{44, 45}.

14. Omalizumab

Omalizumab is a recombinant, humanised, monoclonal antibody against immunoglobulin IgE. This agent acts as a neutralising antibody by binding IgE at the same site on IgE as its high-affinity receptor, FcεR _I, thus inhibiting the biological effects before the generation of allergic symptoms ⁴⁶. There are reports of the efficacy of omalizumab in chronic urticaria ⁴⁷, cold urticaria ⁴⁸ and atopic dermatitis ⁴⁹.

15. Mepolizumab

Mepolizumab is a humanised monoclonal IgG antibody to the IL-5 molecule, which is essential for eosinophil growth and differentiation. Two weekly infusions showed significant clinical improvement in atopic dermatitisand clinical trials are underway for hyper-eosinophillic disorders ^{50, 51}.

16. SMART Anti–IFN-γ

SMART anti–IFN- γ,a humanised monoclonal antibody, binds and inactivates IFN- γ, an important Th1 cytokinein psoriasis. Early phase studies are being performed at this time ⁵².

B) FUSION ANTIBODY PROTEINS

Fusion proteins, also known as chimeric proteins, are proteins which are created by the fusion of the receptor domain of a human protein with the constant region of human IgG. The resultant fusion protein binds specifically to a ligand or co-receptor ⁵³. The most commonly used fusion proteins in dermatology are briefly described below and enumerated in Box 1.

1. Alefacept

Alefacept is a bivalent recombinant fusion protein composed of the first extracellular domain lymphocyte function antigen 3 (LFA-3), fused to the hinge domain of human IgG1. The LFA-3 portion of alefacept binds to CD2 receptors on T-cells, thereby blocking their natural interaction with LFA-3 on antigen presenting cells (APCs). The IgG1 portion of alefacept binds to FcγR receptor on natural killer cells to induce T-cell apoptosis ⁵⁴.

Important uses of Alefacept

Psoriasis: The US FDA approved alefacept in January 2003 for treatment in adult patients with moderate to severe chronic plaque psoriasis. It is given by intramuscular or intravenous route with a dose of 10-15 mg IM weekly or 7.5 mg IV weekly and a 12 week course is recommended ^{5, 54}. Two 12-week courses showed a75% or greater reduction in the PASI ⁵⁵.

Alopecia areata: Case reports have shown that alefacept may be effective in the treatmentof AA^{56, 57}.

Pyoderma gangrenosum: Alefacept has been used for pyoderma gangrenosum and improvement was shown in 25% of these patients ⁵⁸.

Other Indications

Some of the off-label conditions where alefacept has been used with success are graft-versus-host disease (GVHD), lichen planus, alopecia areata, atopic dermatitis, mycosis fungoides,alopecia universalis, erosive lichen planus,Hailey-Hailey diseaseand hand dermatitis ^{58, 59, 60, 61, 62, 63}.

2. Denileukin diftitox

Denileukin diftitox is a novel recombinant fusion protein consisting of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptors. It was tried in patients with recalcitrant psoriasis and the rate of improvement for treated patients was found to be significant ⁶⁴.

3. Abatacept (Ctla4ig)

It is a fusion protein composed of the extracellular domain of CTLA4 and the Fc region of IgG4. It interferes with T-cell activation by competitively binding the B7.1 and B7.2 molecules on the surface of APC ⁶⁵. In a study, patients with stable psoriasis vulgaris showed good improvement with IV infusion of abatacept ³³. A second generation CTLA4Ig, Belatacept, is currently under Phase II clinical trial for allograft diseases ⁶⁶.

4. Etanercept

Etanercept is a recombinant fully human dimeric fusion protein comprising of the human TNF-α p75 receptor and the Fc portion of human IgG1 molecule. It functions as a TNF inhibitor, thereby preventing interaction with its cell surface receptors on target cells and blocking its pro-inflammatory effects.

Important uses of Etanercept

Psoriasis: Etanercept (Enbrel®) is FDA approved for use as subcutaneous monotherapy in psoriasis. Several clinical trials have shown that it is effective^{67, 68, 69, 70}. The adult dose is 50 mg/week, given subcutaneously for three months ⁵. The drug is also indicated for treatment of psoriatic arthritis ^{71, 72}.

Hidradenitis supprivata:There is a study of etanercept in patients with severe hidradenitis with more than 50% score improvement¹².

5. Onercept

Onercept is a recombinant human soluble p55 tumour necrosis factor binding protein under development for the potential treatment of psoriasis and psoriatic arthritis⁷³.
C) RECOMBINANT HUMAN CYTOKINES AND GROWTH FACTORS

Cytokines are non-immunoglobulin proteins and glycoproteins produced by a wide variety of cells in the human body and released in response to any immune stimulus ^{74, 75}. Recombinant cytokines or cytokine antagonists have been used as immunomodulators ⁷⁶. The principal recombinant cytokines used in dermatology, enumerated in Box 1, are described below.

1. Interferons (IFNs)

IFNs, a family of related proteins, are produced by virus-infected leucocytes. They exhibit anti-proliferative, immune-modulatory and anti-neoplastic functions ⁷⁷.

· Interferon α

Recombinant IFNα is given as a subcutaneous or intramuscular injection to treat verruca vulgaris ⁷⁸ , condyloma acuminatum ⁷⁹, cutaneous T cell lymphoma ⁸⁰, Kaposi's sarcoma (AIDS related) ⁸¹, melanoma ⁸², basal cell carcinoma ⁸³, squamous cell carcinoma ⁸⁴, actinic keratosis ⁸⁵, Behçet's disease ⁸⁶, hemangiomas ⁸⁷ and keloids ⁸⁸.

The injections are usually given thrice weekly and the dose (depending on the condition being treated) varies from low-dose therapy for condyloma acuminatum to high-dose therapy for melanoma ^{89, 90}. Of late, pegylated IFNα is being used for convenience, because it has a longer half-life and hence can be given once weekly ⁸⁰.

· Interferon-γ

It is FDA approved for the treatment of chronic granulomatous disease ⁹¹ and has also been used in atopic dermatitis ⁹² and cutaneous T cell lymphoma ⁹⁰.

2. Interleukin 1 receptor antagonist (IL1Ra, Anakinra)

Anakinra is the non-glycosylated form of human IL-1Ra and acts by blocking the functions of the naturally occurring IL-1⁹³. Good results have also been reported in Schnitzler's syndrome⁹⁴, familial cold auto-inflammatory syndrome ⁹⁵ and psoriatic arthropathy⁹⁶. It is given by subcutaneous injection 100 mg once a day.

3. Interleukin 2

Recombinant IL-2 is an antitumour cytokine that has been used in cutaneous T cell lymphoma (CTCL) and metastatic melanoma ⁹⁷. When given intravenously in high doses of 600,000-720,000 IU/kg in melanoma, IL-2 has produced a 15-20% overall response, with complete cure in 4-6% ⁹⁸.

4. Interleukin 4 (rhIL-4)

In a dose-escalation study (0.5 to 5mg/kg given by subcutaneous injection thrice a week), IL-4 has been shown to cause improvement in psoriasis by inducing Th2 differentiation in human CD4 ⁺ T cells ⁹⁹.

5. Interleukin 11 (rhIL-11, Oprelvekin)

It has also shown reasonably good results in the treatment of psoriasis at doses of 2.5 or 5mg/ kg, by subcutaneous injection ¹⁰⁰.

6. Granulocyte macrophage colony stimulating factor (GM-CSF)

GM-CSF acts by stimulating stem cells to produce granulocytes, monocytes and macrophages ¹⁰¹. Recombinant human GM-CSF has been used to promote wound healing in ulcerated skin for example leg ulcers ^{102, 103}, and for the treatment of melanoma ¹⁰⁴ and Sezary syndrome ¹⁰⁵.

7. Platelet derived growth factor (PDGF)

PDGF is a dimeric glycoprotein which regulates and promotes granulation tissue formation, re-epithelialisation and wound angiogenesis ¹⁰⁶. Recombinant PDGF-BB topical gel (100ìg/g), applied once daily, has been approved by FDA for the treatment of diabetic foot ulcers ^{107, 108}.

8. Recombinant Human IL-10

Recombinant Human IL-10 (Tenovil)can be given in subcutaneousinjections. Early phase clinical trials have shown thatrecombinant human IL-10 three times a week improved psoriasis ^{109, 110}.

SIDE EFFECTS OF BIOLOGICS ^{5, 111, 112, 113}

Some of the adverse effects of biologics are described below:

• Allergic reaction and antibody formation: Mostly seen with TNF-α blockers.
• Mild transient injection site reactions: Comprising of erythema, oedema and bruising, noted with etanercept in 10-20% of cases in the first month of therapy. Antibodies to etanercept may develop in 6% of patients.
• Infusion reaction: Occurs during or within 1-2 hours of treatment and may affect up to 20% of all the patients treated with infliximab, rarely anaphylactic shock may occur.
• Acute flu-like symptoms: Headache, chills, fever, nausea and myalgia may occur within 48 hours after administration of the first two doses of efalizumab and Interferon α.
• Infections: Reactivation of tuberculosis may occur on treatment with anti-TNF-α agents and sepsis secondary to Listeria monocytogenes and Histoplasma capsulatum have been reported ¹¹³.
• Malignancy: Patients previously treated with PUVA represent an at-risk group.
• Demyelinating disease: Worsening of multiple sclerosis and demyelination reported with infliximab.
• Thrombocytopenia: Occurs with efalizumab and warrants discontinuation of therapy.
• Autoimmune haemolytic anemia: Occurs 4-6 months after the start of treatment with efalizumab.
• Congestive cardiac failure: Worsening of congestive cardiac failure with TNF-α blockers is reported to occur.
• Antinuclear antibodies and lupus-like syndrome: May develop during therapy with anti-TNF-α agents, but not associated with symptoms and signs of lupus in the majority.
• Hepatitis: Reported following infliximab therapy, occurring from 2 weeks to more than a year after initiation of treatment. Treatment should be stopped in the event of jaundice and/ or marked elevations (>5 times the upper limit of normal) in liver enzymes.

PATIENT SCREENING FOR BIOLOGIC THERAPY ^{113, 114}

All patients to be put on biologics should undergo a thorough evaluation including detailed clinical history, physical examination and relevant investigations with particular reference to known toxicity profile of the agent being considered. The investigations generally advised are¹¹³: full blood count, liver and renal function tests, screening for hepatitis and HIV infection, anti-nuclear antibodies, anti-ds DNA, urine analysis, chest X-ray and Tuberculin skin testing.

For efalizumab, haemogram (including platelet count) is recommended monthly for the first 3 months and then every 3 months. For TNF blockers, it is done at 3 months initially and repeated every 6 months.

Liver and renal function tests, serum electrolytes and urine analysis are done at 3 months initially and then every 6 months.

EXCLUSION CRITERIA/ CONTRAINDICATIONS

There are various contraindications for use of biologics, warranting their exclusion and precautions are to be exercised because of their immune-modulator properties. The main exclusion criteria are: active tuberculosis, severe congestive heart failure, patients having >200 treatments of PUVA (because of a risk of developing malignancies with anti- TNF agents), history of demyelinating disease or optic neuritis, hepatitis B and C positivity, HIV positivity, premalignant states, active infections and high risk states such as chronic leg ulcers, persistent or recurrent chest infections and indwelling urinary catheter infections, pregnancy and breast-feeding.

ASSESSMENT OF THE RESPONSE TO BIOLOGICS

Many scoring systems for assessing the severity of various dermatological diseases exist. These scoring systems and other indices can be used for assessment of response to the use of biologics. For example, for evaluation of improvement in psoriasis, PASI (psoriasis area and severity index) and DLQI (dermatology life quality index) are recommended at 3 months initially and then every 6 months ¹¹³. Reduction in baseline PASI score of >75% is the standard used by FDA to assess the efficacy of a new psoriasis agent ¹¹⁵. Similarly in atopic eczemas, improvement is monitored based on the Eczema Area and Severity Index, Pruritus Severity Assessment and DLQI. Reduction of the Eczema Area and Severity Index score by 50% is considered excellent, 30-49% moderate and <29% non-significant.

SUMMARY

To summarise, biologics represent the future of therapeutics, not only in dermatology but also in other fields of medicine. Among the various dermatological disorders where they are used, biologics have been most evaluated in psoriasis ¹¹⁶. However, the possibility of serious infections and the oncogenic potential combined with the high cost of the drugs limit their routine use at the present stage ¹¹⁷. Regular re-evaluation of efficacy and safety is essential if these agents are to be used to the maximum benefit of patients¹¹⁸.

Introduction

Atopic dermatitis (AD), also known as atopic eczema is a chronic, relapsing, inflammatory skin disease that can cause significant physical, psychological and social stress for patients and their families.¹ This article focuses primarily on AD in adults. It is the most frequent inflammatory skin disease in the western world and is often characterized by chronic inflammation and pruritus interrupted by acute flares and bacterial infection.^2,3 The majority of the care of AD is provided in primary care, with a minority of patients being referred to secondary care. There are currently extensive cost implications to the National Health Service (NHS) for both treating patients and for lost working days.⁴ AD can be a therapeutic challenge, especially in primary care, and there appears to be a great potential for improving the outcome and cost effectiveness of treatment in the community setting.4

Epidemiology and pathogenesis

AD typically begins in young infants or early childhood and subsides spontaneously by adolescence in approximately 90% of patients although it can persist into adulthood in about 10% of patients.⁵ The incidence of AD is generally considered to be increasing worldwide.⁶ AD affects both sexes equally, and in the United kingdom (UK) approximately 15-20% of school-aged children and 2-10% of adults will be affected by the condition at some stage.⁷

AD appears to result from a complex interplay between defects in skin barrier function, environmental agents, modified immune responses of the immune system to exogenous and endogenous factors, IgE-mediated mechanisms and other factors. However, the pathogenesis leading to the precise manifestation of AD is not completely understood.^3,8

Diagnosis

There are no laboratory or diagnostic tests for AD. The diagnosis is based on visual assessment and clinical history. The UK diagnostic criteria (Table1) has been shown to be the most extensively validated for AD in comparison to the Hanifin and Rajka criteria, Schulz-Larsen criteria, Diepgen criteria, and Kang and Tian diagnostic criteria. Although several different diagnostic criteria have been developed they should mainly be used for research purposes as opposed to daily clinical management.⁴

Skin tests and laboratory investigations (specific IgE) may be helpful in the investigation of provocative factors such as food or environmental allergens. It is important to note that laboratory investigations should be interpreted in the context of the patient’s history.⁹

It is often difficult to differentiate AD from other skin conditions (e.g. seborrhoeic dermatitis, contact dermatitis, psoriasis, scabies). However, a family history of atopy and the clinical distribution of the lesions are helpful in making the diagnosis. Other conditions that need to be considered in the differential diagnosis of AD are metabolic and nutritional deficiencies, malignancies and immunodeficiency syndromes that present with skin manifestations.⁸

Table 1 – UK Working Party Diagnostic Criteria⁴

Management

The management of AD should involve a combination that includes short-term treatment of flares and a long-term maintenance approach to prevent flares. For patients with mild to moderate AD, topical therapy may be sufficient to control the condition. Patients with more severe disease may require advanced therapy such phototherapy or systemic therapy.

Education

For optimal disease management, patients and/or their carers should be educated about the nature of AD, the need for continued adherence to prescribed treatment and about the appropriate use of topical therapies. Time spent educating patients and carers have been shown to have a positive effect on disease outcomes. Patients may also benefit from written information to reinforce learning.⁸

Emollients

Emollients soften the skin, aid in restoring the impaired barrier function, reduce itching, prevent moisture from leaving the skin and increase the efficacy of topical corticosteroids (TCS). They also replace the natural surface oils that are essential to preventing irritant materials, infection and allergy-inducing substances from entering the skin.⁴

Healthcare professionals should offer a range of emollients, and prescriptions should be reviewed frequently. To optimise adherence to emollient therapy, creams, lotions, and ointments, or a combination can be used depending on patient preference. Continued use of emollients during periods of disease quiescence can reduce the likelihood for exacerbations.¹⁰

When the treatment regimen involves both an emollient and TCS, there is no evidence on which to base the order of application. Patients should be advised to apply emollients liberally and frequently (at least 2-4 times a day). It is especially important to use emollients during or after bathing. The emollient should be applied in the general direction of growth of body hair in order to prevent accumulation at hair bases which might predispose to folliculitis. Emollients can become contaminated with bacteria and the use of pump dispensers minimises this risk. If the emollient is in a pot it should be removed with a clean spoon or spatula.⁴

Topical corticosteroid therapy (TCS)

TCS is considered first-line therapy for AD flares. Available preparations include ointments, creams, gels, lotions, liquids, and foams. Ointments and creams are generally the most effective in treating AD as they tend to be more moisturising.¹⁰ The least potent preparation required to control AD, particularly in sensitive areas, should be utilised. When possible the TCS should be stopped for short periods to reduce the risk of adverse events.⁸

TCS is categorised into four groups according to potency: mild, moderately potent, potent and very potent. The choice of TCS potency should be tailored to the age of the patient, the body region being treated, and the severity of inflammation. Patients should be advised to apply TCS once daily. If there is an inadequate response to once daily application, the frequency should be increased to twice daily.⁴ Once control has been achieved, twice weekly maintenance therapy with a TCS should be considered in patients with moderate to severe AD experiencing frequent relapses. The local adverse effects of TCS usage include skin thinning, bruising, perioral dermatitis, folliculitis, pruritus, allergic contact dermatitis and the spread of fungal infection. Patients being treated with intermittent courses of TCS should be reviewed regularly (depending on TCS potency and site of application) to determine response to therapy and assess skin for potentially reversible atrophic changes.⁴

Table 2 - The ‘fingertip unit’ (FTU) is a method of determining the amount of TCS to apply. It is described as “the amount of ointment expressed from a tube with a 5 mm diameter nozzle, applied from the distal skin crease to the tip of the palmar aspect of the index finger.” The following table is a guide to the use of FTU in adults.⁴

Topical calcineurin inhibitors (TCIs)

TCIs are non-steroidal immunomodulating agents licensed for the treatment of AD.⁴ TCIs work by inhibiting the phosphatase activity of calcineurin to block expression of cytokines and are thought to represent a more targeted way to limit inflammation and avoid many of the adverse effects of TCS. TCIs may be used either as monotherapy, as a combination or as sequential therapy. TCS are generally less expensive and more effective than TCIs although individual clinical situations will arise in which TCIs are preferred.¹⁰

Two TCIs are available: tacrolimus (0.03% and 0.1% ointments) and 1% pimecrolimus cream. The tacrolimus 0.03% and 0.1% ointments are both licensed for moderate to severe eczema and the 0.03% ointment is licensed for use in children aged two years and over. The 1% pimecrolimus cream is licensed for mild to moderate eczema in patients aged two years and over. The use of tacrolimus should be limited to doctors with a specialist interest and experience in treating AD.⁴

TCIs should not be used as first line treatment unless there is a specific reason to avoid the use of TCS.⁴ Given the high cost of TCIs, and the fact that their long-term safety is not fully known, they are generally reserved for patients with persistent disease or frequent flares that would require continuous TCS treatment. They are also of use in patients with severe disease in sensitive skin areas (e.g. around the eyes, face, neck and genitals) where systemic absorption and the risk of skin atrophy with TCS are of concern. Considering the possibility that the normal immunological response to infection may be suppressed, TCIs should not be applied to skin which appears actively infected.^{4, 8}

Dressings and wet wrap treatment

Patients with non-infected moderate to severe AD can be advised to cover affected areas with dry wrap dressings to provide a physical barrier to scratching and improve the retention of emollients. Wet wrapping generally consists of two layers of bandage applied over topical preparations. The bottom layer is soaked in warm water, squeezed out and then put onto the skin over the topical preparation. The top layer is dry. Wet wraps can be worn under nightwear or ordinary clothes and used during the day or night. They are available in bandage form or as garments.⁴ Disadvantages include a high cost, inconvenience, a need for specialised training, and an increased potential for adverse effects from occluded corticosteroids (such as systemic absorption, atrophy, striae), and increased incidence of skin infection.¹⁰ There is currently insufficient consistent evidence on which to base a recommendation for wet wrap use in the primary care setting.⁴

Antimicrobial measures

Skin lesions of around 90% of patients with AD are colonised compared to less than 5% of individuals with healthy skin. Staphylococci are the main organisms isolated although other organisms such as streptococci may also cause infection. The routine swabbing of skin is not indicated although swabs of potential Staphylococcus aureus carriage sites should be considered in patients with recurrent infection. Oral antibiotics are not recommended in the routine treatment of non-infected AD but patients with clinically infected AD can be prescribed short term oral antibiotic treatment based on local/regional antibiotic sensitivities. However, first- or second-generation cephalosporins or penicillins for 7 to 10 days are usually effective in managing bacterial infection. Macrolides are less useful alternatives due to resistant patterns in patients with AD. Patients with AD are also prone to recurrent viral infections. Eczema herpeticum is a severe disseminated herpes infection that is a serious risk in patients with widespread AD and may be misdiagnosed as a bacterial infection. Patients with eczema herpeticum normally require systemic antiviral treatment^{4, 10}.

Antihistamines

Although first-generation antihistamines do not directly affect the itching associated with AD, the sedative effects have been found to help improve sleep. Therefore, short-term bedtime use of sedating antihistamines should be considered in patients with AD where there is debilitating sleep disturbance. Daytime use of first generation antihistamines should be avoided given their sedative effects. Non-sedating antihistamines appear to have limited value in patients with AD but they may provide some benefit in patients with allergic triggers.^{4, 8}

Dietary interventions

Although there is an association between IgE mediated food allergy and AD severity in infants, it is unclear whether hypersensitivity to food is a major factor in causing and maintaining AD. Dietary exclusion is not recommended for managing AD in patients without confirmed food allergy. The exclusion of foods during pregnancy and breast feeding to prevent the development of AD in infants is not recommended. Breast feeding for three months or more may help prevent the development of infant eczema where there is a family history of atopy. However, current UK guidelines state that weaning should start at six months.⁴

Table 3 - Guidance on when to refer to secondary care⁴

Other therapies

Systemic corticosteroids are usually reserved for the acute treatment of severe AD exacerbations. Prolonged use of oral steroids is associated with potentially serious adverse effects and their long-term use should be avoided. Furthermore, relapses are common following discontinuation of oral corticosteroid therapy.⁸

Ultraviolet (UV) phototherapy may also be beneficial for the treatment of AD in adults. In addition, systemic therapies are available and may be broadly classified into traditional medications (e.g. cyclosporine, azathrioprine, methotrexate) and biologic agents (targeted monoclonal antibodies). These options are available for severe, refractory AD. These therapeutic options should generally be reserved for unique situations and require consultation with a dermatologist. These therapeutic options are beyond the scope of this article.⁸