Dermatologists should be aware that the global medical aesthetic market is expected to grow 10.8% per year between 2010 an 2015 and many other companies are joining the toxin “band-wagon”.
Products Under Development/Currently Approved in Other Countries
Medy-Tox – Neuronox (South American and Korea)
Siax – Neuronox (Colombia)
ChinaTox –Lanzhou Biological Products Institute, Nanfeng Medical Science and Tech co.
Lantox (South America)
Mentor is currently developing a product called PurTox, which is about one year away from filing with the FDA for approval. There are also several products currently available in Asia and South America. Dermatologist should recognize that in some instances where non-approved Botox formulations were used in the United States, patients required hospitalization due to paralysis and physicians were subject to major sanctions, fines, etc.
Summary
It is important that practitioners use branded products from legitimate companies that are either FDA approved in the US or CE marked in Europe, or received regulatory approvals in your country. There are various unbranded products available on the internet; however, clinicians should use caution with regard to the use of these products due to safety and efficacy issues.
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Botox, Dysport, and Xeomin are all FDA approved for glabellar lines. The products are also used for the forehead and crow’s feet.
Dangers
Dermatologists should be cautious of the dangers associated with delivering fillers and toxins simultaneously.
Dosing
Data suggest that higher botulinum toxin type A doses resulted in greater efficacy and longer duration of the effect. In 2008, experts developed a consensus with regards to how to best achieve an optimal, relaxed and natural outcome using botulinum toxin type A. This resulted in basically cutting the forehead doses in half.
Dermatologists should also understand gender differences that exist in upper face musculature. In a 1998 cadaver study by Dr Macdonald, et al, males were shown to have greater corrugator thickness at both the medial canthus and mid-pupil regions versus females. An understanding of these anatomic differences can facilitate proper injection technique.
Potency
Dr. Cohen indicates that he does not think physicians should be desperately trying to find the right conversion ratio between products. He feels that the reality is that each of these products is it’s own neuromodulator. As such, he indicates, that if we decide to use that specific neuromodulator, then we should know that neuromodulator independently—and thus how to specifically use that product.
Dueling
Patient satisfaction is a key aspect of facial aesthetics. Various studies have looked at patient reported outcomes among the products available; however, it is often difficult to compare the results.
Duration
Across the board, looking at the glabellar lines, the duration of botulinum toxin type A is about four months. Data has also demonstrated that patients tend to have a cumulative effect; in that, the efficacy is stretched out over a longer period of time.
Delivery
Drs. Richard Glogau, Fred Brandt and others have begun to research topically applied botulinum toxin type A for the treatment of primary axillary hyperhidrosis as well as lateral canthal rhytid studies. Results have shown that topically applied BTX-A appears to be safe and effective.
Revance, a California-based company, has developed a proprietary platform that enables transcutaneous flux. The Revance technology works by employing two complementary and distinct pathways that are both present in human skin:
The first pathway is energy independent and therefore can occur in non-living cells. like the stratum corneum. It could also occur in living cells. The second pathway is energy dependent and only occurs across living cells.
Devices
Myoscience is currently investigating a hand-held cryotherapy medical device for the treatment of facial wrinkles between the brow, forehead lines and crow’s feet. It has shown promising results in difficult patients, i.e., complete treatment of dynamic horizontal forehead lines, constant brow position, immediate onset, and it proves to be a potentially new option for toxin-averse patients. The device uses a 27-30-gauge needle placed near motor nerves that innervate frontalis muscle.
Summary
It is important that dermatologists convey the message that botulinum toxin type A has been studied and BTX injections can be beneficial for patients who want to delay the outward appearance of aging, for patients who believe their faces are not communicating their emotions properly and/or for patients who simply want to look their best.
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In this presentation, Dr Cohen reviews the use of botulinum toxins in clinical practice. He reviews the three Type A toxins such as Botox, Dysport, and Xeomin.
Science and Data To Be Considered
It is important that clinicians understand the molecular structure of Botulinum neurotoxin type A.
The core neurotoxin protein in all agents used clinically is 150kD BoNT/A. Botox and Dysport both have accessory proteins that surround the core neurotoxin, while Xeomin lacks accessory proteins.
Botulinum toxin Type A works via chemodenervation, in that the internalized toxin binds to the SNAP-25 target protein and then blocks the exocytosis of acetylcholine into the synaptic cleft following a neural impulse. This effectively denervates the segment of muscle supplied by the affected cholinergic nerve terminal.
Differentiating Botulinum Toxins
Regulatory agencies worldwide have recognized that these products are not interchangeable. The units of biologic activity in each available product cannot be compared or converted into the units of any of the other available products, nor can the doses or preparations be interchanged.
Immunogenicity
Dermatologists should be aware that botulinum toxin itself could be immunogenic. The protein added to stabilize the product also has immunogenic properties. If antibodies occur, the question is whether or not they are neutralizing “critical domain” antibodies or non-neutralizing “non-critical domain” antibodies. Antibody detection can measured through two tests. The Mouse Protection assay is the most widely used with the highest specificity. The patient’s serum is taken and given to a mouse. The mice are then given a lethal dose of BTX-A. If the mouse lives, the patient has antibody; in most cases the mouse would die. The rapid immunoassays (ELISA, W. BLOT) have a lower specificity and a lack of correlation between detected abs and clinical resistance.
Various data and studies suggest that overall, few patients may develop antibodies; however, they if they do develop antibody, they seem to continue to respond to the products.
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Infliximab (initial response, with subsequent failure)
History of:
Hypertension
Hypercholesterolemia
Hypertriglyceridemia
Obese, 120 kg, BMI = 33
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There is concern for this patient because he is at a relatively high risk for cardiovascular disease. However, he has not responded to various treatments and needs therapy in order to function.
How do you discuss ustekinumab with this patient prior to initiation of therapy?
Discuss his risks of cardiovascular disease and conduct a benefit/risk assessment of ustekinumab prior to starting therapy
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[poll id=”4″]
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Case Study 2- Topical Therapy
42 year-old man
Psoriasis affecting 4% of BSA
Inverse pattern
Inguinal
Intergluteal and perianal
Refractory to alclometasone dipropionate cream
No psoriatic arthritis
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Case Study 3- Scalp Psoriasis
22 year-old woman
Severe scalp psoriasis, affects 50% of scalp surface area, failed:
OTC preparations (T-gel)
Fluocinolone acetonide topical scalp oil 0.01%
Clobetasol shampoo, solution and foam
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Case Study 4- Refractory Local Psoriasis in a Patient on Biologic Therapy
46 year-old man with > 20 years of severe psoriasis and psoriatic arthritis
Baseline: 20% BSA, PGA = 4
Currently managed effectively with:
TNF-inhibitor in combination with MTX 10 mg per week
BSA currently 4%, with residual disease on the elbows and lower extremities
Refractory to topical class 1 corticosteroids
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Case Study 5- Latent TB
52 year-old man with 40% BSA
Active psoriatic arthritis
Only treated with UV Phototherapy and topicals, neither of which is effective
PPD is positive to 12 mm induration
Chest X-ray shows no infiltrate and chest CT is normal
What if this patient had previous BCG vaccination?
Verify latent TB status with Quantiferon Gold test
What are your steps to starting therapy for this patient?
Quantiferon Gold test
If positive, treat with a full course of latent TB infection prophylaxis prior to initiation of immunosuppressive/immunomodulatory therapy. Therapy for psoriasis may be begun 1 month into treatment for latent TB.
Discuss various treatment options review the benefits/risks
How do you follow/monitor a patient with treated latent TB while on a TNF-inhibitor?
Be vigilant of signs and symptoms of TB
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Case Study 6- New Onset Psoriasis
53 year-old woman
Crohn’s disease on TNF-inhibiting antibody with gastrointestinal disease is well-controlled
Develops palmoplantar pustular dermatitis
Could the psoriasis have been induced by the TNF-inhibitor?
Written by: Judy Seraphine Based Upon a Presentation Delivered by Arthur Kavanaugh, MD at the 2012 Maui Derm
Introduction
B cells may play a prominent role in a number of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, pemphigus/pemphigoid, vasculitis, and many others. The mechanisms by which B cells may play a role in autoimmunity include autoantibody secretion, modulation of immune/inflammatory reactions via ctyokines and other mediators, antigen presentation / co-stimulation of T cells, and lymphoid organogenesis in target organs. The activity of B cells in autoimmunity represents a loss of immunologic tolerance. The targeting of B cells specifically is now possible; the first approved agent being the anti-CD20 monoclonal antibody, rituximab. Clinicians should be aware that B cells may be targeted in many other ways and the results on the efficacy and safety of these approaches are forthcoming. Safety issues related to targeting of B cells may be both agent-specific as well as target-specific and the major concerns include the potentially increased risk of infections.
B Cells – Autoimmunity: History
Paul Ehrlich, the “Grandfather” of autoimmunity, first studied B cells in autoimmunity via histologic staining and the identification of blood cells. More importantly, Dr Ehrlich came up with the side chain theory, i.e., a specific receptor for a counter-receptor on a type of cell. This really helped develop chemotherapy or the “magic bullet” theory, i.e., a single, very focused therapy would go straight to its target and not hurt the other tissue. However, scientists noted that this could go wrong and; therefore started what was known as “horror autotoxicus”, the idea that the body was attacking itself. In Rheumatology, the identification of autoantibodies, specifically rheumatoid factor (RF) and anti-nuclear antibodies (ANA) came about in the 1940s and really brought B cells into the forefront. In 1952, Bruton researched X-linked agammaglobulinemia, and the 1960s researchers began to the identify B cells. In the 1960s and 1970s, there was very important work done in autoimmunity, specifically, clonal deletion, clonal anergy and idiotypic network. In 1975, monoclonal antibodies were developed which really paved the way for modern immunology. In 1997, rituximab was approved for NHL. In 2006, rituximab received approval for RA and in 2011 it was approved for WG/MPA.
B cells are the source of all immunoglobulins and can be activated by antigen in conjunction with co-stimulatory signals provided by antigen-presenting cells (APCs) and T lymphocytes. If successfully stimulated, activated B cells differentiate into antibody-secreting plasma cells. Most plasma cells generated during the initial phase of clonal expansion are short-lived and tend to produce IgM antibody.
In the second phase of clonal expansion, high-affinity (germinal center) B cells give rise to long-lived plasma cells and extremely long-lived memory B cells. When memory B cells re-encounter antigen, they rapidly differentiate into plasma cells and proliferate into more memory B cells. The plasma cells themselves are “terminally differentiated” and are no longer able to divide in response to antigen.
Reference: Ahmed R, Lanier JG, Pamer E. Immunological Memory and Infection. In: Kaufman SH, Sher A, Ahmed R, eds. Immunology of Infectious Diseases. ASM Press; 2002:175–189.
What do B Cells do in Autoimmune Disease?
Production of autoantibodies
Co-stimulation/antigen presentation
Immunomodulation/cytokine secretion
Lymphoid organogenesis
In rheumatoid arthritis, the efficacy and safety of rituximab has been demonstrated in several studies. With the use of rituximab also comes B cell depletion; however, only about 60% of patients respond; therefore, there is no correlation with clinical response. So what is the mechanism of depleting B cells? Is it bone marrow B cells? Is it synovial B cells? Scientists are still not sure what the specific target is. We’re not always sure why they work. A related issue in rheumatoid arthritis is a biomarker and the idea of personalized medicine. The patients who were positive for RF or ANA, tended to do better with rituximab.
Many open studies showed that perhaps B cell therapy would work in SLE.
Why did the EXPLORER study fail?
There was no statistical significance between rituximab and placebo and there were no differences by AUC of total activity, landmark analyses, or flares in “responders”.
The study demonstrated that rituximab significantly depleted CD19+ B cells and there were significant reductions in adsDNA, ACL Abs; memory CD8+ T cells. In summary, high dose steroids with prolonged taper may have blunted the effects of rituximab, and longer term follow-up may have shown beneficial effect but open-label extension was cancelled due to PML concerns. Healthcare providers should also be aware that BILAG is a difficult instrument to use and/or adjudicate.
There is another line of thought that is dedicated to the differential effects of rituximab on serum autoantibody levels, i.e., some diseases are rituximab-sensitive; some are partially rituximab-sensitive and some are rituximab-resistant.
We are now thinking of our targets based on the types of B cells that we may be eliminating or modulating with different types of therapies.
Targeting B Cells
Anti-CD20:
Rituximab
Ofatumumab (HuMax CD20):
Ocrelizumab
Trubion synthetic anti CD20
B-cell growth factors
BR3-Fc
Atacicept [TACI-Ig
Belimumab (anti-sBLyS)
Anti-CD22
Epratuzumab
Anti-CD40L (CD154)
Studies halted
BLyS/BAFF: Ensuring B Cell Survival
BLyS/BAGG is potentially expressed by multiple immune cells, specifically neutrophils, monocytes, B cells, activated T cells, plasma cell, and dendritic cells. It exists in membrane-bound and soluble forms. Three molecules bind together to form the trimeric soluble protein; soluble BLyS is considered to be the active form. BLyS is important in ensuring that new B cells mature, survive, and differentiate themselves. BlyS (BAFF) levels are elevated in patients with SLE.
Belimumab
Belimumab received FDA approval in May of 2011. The only prior FDA approved drugs for SLE were aspirin, prednisone, and HCQ. Belimumab is considered to be relatively safe, but its efficacy is modest (cutaneous outcomes; only significant for rash, not alopecia, oral ulcers: improved BILAG rash seen in placebo – 30% / 1 mg – 42% / 10mg – 44%). There is a question as to its utility as a steroid-sparing agent in milder lupus. The long-term efficacy, safety and cost of belimumab are yet to be determined.
Epratuzumab, the anti-CD22 mAb, is currently under study in SLE.
What about using B cell therapy in the ANCA-associated vasculitides? In the RAVE study (RTX vs CTX), rituximab demonstrated increased efficacy (63.6% v 51.1%). Looking at long-term efficacy, a single course of rituximab is as effective as 18 months of standard therapy with cyclophosphamide and azathioprine.
Clinicians should also note that rituximab has also had a dramatic effect in patients with MS.
Safety Issues with B Cell Targeted Therapies
There are a number of safety issues with the use of biologic DMARDs in RA, including serious infections, opportunistic infections such as tuberculosis (TB), malignancies, demyelination, hematologic abnormalities, administration reactions, congestive heart failure, and autoantibodies and lupus.
Target Related
•Impaired humoral immunity / B cell costimulatory function
•Infections / serious infections
•Impaired vaccine responses
Agent Related
•Infusion / administration reactions:
•RTX: mostly on 1st infusion; mild (common) à severe (rare)
•RTX: lesser frequency / severity, RA vs NHL
•Immunogenicity: antibodies to treating agent
•RTX: HACA ~ 1% NHL studies; ~ 4%-12% RA studies
•? Clinical relevance ?
Conclusions
There is a lot of promise with targeting B cells. There are lots of potential mechanisms that may have varying efficacy and different safety concerns. There is a lot of excitement in the future for B cell directed autoimmune diseases.
