Rosacea Update

Judy Seraphine, Medical Editor, Maui Derm News

In this presentation, Dr Webster provides an update for the management of patients with rosacea.

There have been a number of theories about rosacea. In the past, clinicians believed that it had to do with blushing but that was never clear. Since then, newer observations have been made trying to explain the cause of rosacea.

Helicobacter pylori and Rosacea

Dermatologists should recognize that rosacea can improve during H. pylori therapy as H. pylori drugs may be active in rosacea independent of effects on the GI tract. It is important to understand that H. pylori is as common in rosacea as it is in normal controls and a blinded study showed no greater effect on the controls for H. pylori therapy. What was found that the therapy used to treat the GI effects of H. pylori, namely doxycycline, also tended to treat the rosacea.

Demodex in Rosacea

It is difficult to say what the role of Demodex is in rosacea. Demodex is present on both normal and rosacea skin, yet elevated demodex counts are seen in rosacea; however, demodex quantification is flawed, prone to error and difficult to do. Demodex is most increased in inflammatory rosacea. Follicles with demodex in normal skin tend to be inflamed. Dr Webster feels that an important study with regards to Demodex is that of it killing Lindane. The results were is ineffective.

B. oleronius in Rosacea

More recently, Dr Frank Powell and his colleagues discovered a Demodex-related bacteria that is more active in rosacea patients. They cultured mites and one mite grew a bacterium that was different from other skin flora, Bacillus oleronius. They found that ruptured activate mononuclear cells [16/23 (73%) rosacea patients versus 5/17 (29%) controls]. Rosacea patients seem to recognize a few antigens in western blots.

Dr Li and colleagues found an even greater reaction between B. oleronius and ocular rosacea. There are problems however, as in the first study only one mite out of 40 contained the bug. In addition to that and more importantly, PCR of many new Demodexs did not reveal the bug.. The cross-reactivity of the bug antigens with other more common bugs hasn’t been investigated. Many patients did not react and some normal patients did.  As of now, this information is on hold.

Etiology of Rosacea

What do we know about the etiology of rosacea? We know that there is excessive vascular reactivity and those who have rosacea tend to be “blushers and flushers.”  We know that the papules and postules, when cultured, are sterile and in some small genetic analyses, the skin does not show bacteria so we know that it is not some sort of infection. Rosacea does respond to anti-inflammatory drugs.  It is becoming clearer and clearer that the nerves are involved in skin “things” that we don’t quite understand, for example the sebaceous gland.  It is also pretty clear that there is a defect in control of the innate immune system. The inflammatory subunits are present in rosacea skin and if you purify them and inject them into mice, you can make rosacea-like inflammation in the back of the mouse.

Neuro-vascular Factors in Rosacea

The blush reflex to thermal stimuli is more easily triggered in rosacea patients than in normal patients. Also, plasma leakage from the blood vessels may incite inflammation. There are multiple flush/blush mechanisms, these include thermal, hormonal, nicotinamide, and autonomic and they are different among each patient.

Clinical Issues with Rosacea

The tried and true topical agents for the treatment of rosacea include:

  • Metronidazole (FDA approved)
    • 0.75 and 1%
  • Tacrolimus/pimecrolimus
    • “overlap” rosacea (e.g. eczema and rosacea)
  • BP/clindamycin
    • acne/rosacea
  • Azeleic acid (FDA approved)
  • Sodium sulfacetamide/sulfur
  • Tretinoin
    • Sun damage or rosacea? (data unclear)
Oral Flush Blockers

The flushing and the redness is the most difficult to treat.

  • Clonidine
    • Blocks carcinoid and menopause flush
    • No effect in chocolate, red wine, thermal flushing
  • Nadolol
    • No effect in rosacea thermal blush
  • Aspirin
    • Blocks Nicotinic acid flush

(Arch Derm 119:211, 1983; 118:109, 1983; Clin Pharm Ther 31:478, 1982; JAAD 20:202, 1989)

Topical Treatment of Erythema

Metronidazole and azelaic acid may diminish peri-lesional erythema. Oxymetazolone has also been shown to reduce erythema. A phase II study with topical brimonidine, which is an Alpha-2 inhibitor, has shown a clear benefit when reducing erythema.  Its effect has been very dramatic and produces 4-8 hours of reduced erythema.

One of the questions when using vasoconstrictors is “Do you get a rebound?”  In Dr Webster’s experience, he has only seen one rebound that lasted about one day.

Rosacea in Darker Skin

It is important to remember that rosacea is not a disease just of the fair skinned. Symptoms of rosacea in darker skinned patients include irritable skin, stinging, facial warmth, and a history of ocular rosacea. Darker skinned patients can be treated using the standard approaches.

Steroid Rosacea

When patients are applying steroids to their face, it becomes very irritable, There are lots of “homeopathic” products that have vasoconstrictor activity.  Rosacea under the nares is a tip-off.  Dermatologists should be aware that a “gentle withdrawal” does not work to treat this condition. TIMs and minocycline/doxycycline is the standard treatment.

Atopic/Seb Derm-Rosacea Overlap

Overlap is common among these patients and can also be very resistant to traditional rosacea treatment. It is important as dermatologists to remember to avoid irritants when managing these patients. Topical treatment includes tacrolimus/pimecrolimus and ciclopirox. Oral therapy includes the tetracyclines and cyclosporine followed by a topical treatment.

Defective Barrier in Rosacea

The fact that rosacea patients sting and burn is not just because they are blushy, but also because of the microscopic ruptures in their skin barrier, i.e., their stratum corneum is not in tact. There are areas that are extremely “leaky”. Sun damage can also affect the barrier. We also know that irritants can provoke rosacea by provoking inflammation and proteases. Moisturizing improves rosacea TEWL and the associated symptoms.

The graph below demonstrates barrier improvement as rosacea gets better with Metronidazole, which is designed to take the inflammation away.

Summary

What do we know about the pathogenesis and treatment of rosacea? We know that it is very complex. Improving the barrier,  can improve rosacea and it is important to remember that rosacea skin is extremely sensitive, such as that of atopic skin.

 

Combining Technology for Facial Rejuvenation

Suzanne L. Kilmer, MD

 Clinical Pearls: When Combining Devices with Injectables and Other Devices

In this presentation, Dr Kilmer reviews the techniques for combining the various technologies that are currently available for facial rejuvenation in order to obtain optimal cosmetic improvement for patients.

Dr Kilmer stresses the importance of remembering the 4 Rs:

  • Relax
  • Refill
  • Resurface
  • Redrape

During her initial consult with patients Dr Kilmer discusses the 4 Rs and how the various techniques that she uses in combination for facial rejuvenation can aide in maximizing the outcomes. It is also important, as dermatologists that full disclosure regarding outcomes is presented. Dr Kilmer informs her patients that she does not “have a magic wand or a crystal ball”; therefore, she can’t predict the outcomes of any given patient.

Relax

It is important to relax the skin with a botulinum toxin to keep both the muscles and the skin from moving as much as it otherwise would. If she is going to laser the skin, the results are improved when the skin/muscles are not moving. Dr Kilmer also uses fillers, in conjunction with the toxins and lasers to fill in lines, tighten up the skin and remove brown/red spots.

Clinical Pearl: Never use toxins, lasers, or any other device that can cause significant swelling on the same day. This can result in the toxin migrating to other places where you do not want it.

 Refill-Restore Volume Loss

When using dermal fillers, the objective is to restore volume based on a patient’s specific needs. Fillers can be placed in various areas locally such as the nasolabial folds, marionette lines, deep glabellar rhytids, tear troughs, and the nasal bridge. Fillers can also be used globally in the cheeks and temples.  It is important to remember that there may be a lag time resulting in delayed gratification.

It is very important to keep in mind that one can’t massage post poly-L-lactic acid (Sculptra) in areas where Botulinum toxin was placed.

If all of these procedures are being done in one patient, Dr Kilmer typically tries to slow down the movement and relax the muscles. Discussions with patients regarding the overall procedures that could be performed are very important. Considerations for patients include money, down time, and fear factor, i.e., what are they willing to go through? In these consultations, Dr Kilmer and her patients decide on the best approach based upon their issues and the issues that she sees.

 Combination Treatments

  • Best order
    • Start with toxins to stop movement and relax muscles.
      • Relax frown, smile and lip lines when doing facial rejuvenation
      • Relax DAOs and neck bands when doing fillers, tightening or resurfacing
        • May need less filler and patients are happy sooner with tightening devices
        • Then filler or laser depending on a patient’s specific needs (and ability for downtime)
          • Never do toxins and lasers that cause swelling at the same time because toxins can migrate.
          • Typically end with filler if still needed after toxins and laser
            • Sometimes the combination will diminish the need for filler
            • If able to tell that will need volume, can do before or at same time as laser

Caveats of Combining Treatments

  • Toxin with Filler
    • Can’t massage post poly-L-lactic acid (Sculptra) in areas where Botulinum toxin was placed
    • Toxin with Laser
      • Can’t do toxin same day as Fractional lasers – swelling can lead to migration
      • Can do botulinum toxin with PDL, IPL, CoolTouch, SmoothBeam, Thermage, Titan
      • Filler with Laser
        • Can do filler same day but do first if doing fractional as swelling can mask need for filler.
        • Fractional with nonablative RF tightening
          • Same day – do Thermage 1st because need intact skin but when you do the fractional laser the skin may still be sensitive. (wait an hour or two because the sensation will decrease with time)

Combining Fractional with other Devices

  • Fractional laser with other lasers/txs
    • Lentigines – pre-tx QS lasers, KTPs, etc
    • AKs – LN2
    • Sebaceous hyperplasia, nevi – 1450 nm
    • Vascular lesions – PDL, KTP, Alex
    • Downtime from other treatment is simultaneous and shortened
    • Fractional resurfacing with ablative resurfacing
      • Almost always do fully ablative to upper eyelids
        • More tightening/more predictable – do inner canthi
  • Can ablate/sculpt edges of scars, upper lip lines and elevated lesions
  • Ablative fractional and nonablative fractional resurfacing
    • Nonablative fractional to face, ablative to neck for more tightening /crepiness – useful for those with hx ablative resurfacing/chemical peels/dermabrasion

Other Combination Therapy

Other combination therapy includes fat loss and tissue tightening (CoolSculpting + RF tissue tightening, lipo/laser lipo + tissue tightening); Fractionated RF ((ePRime) + QS/KTP/PDL); and Fractionated US ((Ulthera) + QS/KTP/PDL).

Now that the 4Rs have been implemented, dermatologists need to be particularly aware of reassessing. Combination treatments may minimize the need for other treatments; therefore, increasing the interval for maintenance. For example, one can decrease the need for the amount and frequency of dermal fillers and one can conduct fewer fractional treatments when lentigines are specifically targeted. There may also be the possibility of foregoing vascular laser treatment if the fractional laser used to treat facial vessels was sufficient. Patient concerns should be addressed, i.e., were his/her expectations met? Is there anything new on the patient that has become noticeable since the initial treatment needs have been performed and met? Normally, with time, additional needs will become apparent.

 Summary

In summary, botulinum toxins, fillers and lasers can be used synergistically to minimize the signs and sun damage and aging. To produce the optimal results, expertise in the techniques are required, one should use the best possible modalities and watching and treating for any possible complications is imperative. Combining these modalities may obviate the need for more invasive procedures.

Managing Pemphigus and Pemphigoid: How to Avoid Getting Sued

John J. Zone, MD

In general, Dermatologists see very few blistering diseases. Therefore, managing these autoimmune conditions can often be a challenge in practice.  Dr Zone, an expert in the field of autoimmune blistering diseases, discusses these conditions and optimal strategies for managing these patients from his perspective.

Dr Zone came upon this topic because over the years he has managed a large number of people with both pemphigus and pemphigoid. He always asks himself “what would I do if I was sitting here?”

Virtually, all medications for the treatment of pemphigus and pemphigoid are used off’-label.

 

Case Study 1

In this first case, we can see a lot of acnatholysis and one would assume that it looks like pemphigus.

The above picture shows the direct immunoflourescence, the epidermis is at the top and is totally black.

This case was actually Hailey Hailey disease; therefore, histology alone does not make a diagnosis. According to Dr Zone, treating people on the basis of histology alone is a mistake.

Pemphigus- How do I biopsy people?

Biopsy of the wrong location for direct immunofluorescence is the single greatest problem that is seen in the specimens that are received. Dr Zone would not biopsy in the crusty area; he would biopsy the clinically normal appearing skin (see circle above) near the lesion. That is where one would find the classical cell surface antibody of pemphigus.


Dr Zone also sees a lot of mucosal pemphigus and pemphigoid. Again, it is important to biopsy the normal appearing mucous membrane immediately adjacent to the lesion. There is antibody all around the lesion so there is no need to get involved in in areas with intense inflammation that disrupt the antibody deposition pattern.


Ocular and Esophageal Pemphigoid

In the case of ocular pemphigoid (above), it is important to biopsy the reddish area NOT the bands of scar tissue called symblepharon that are usually negative on immunofluorescence. This should be done by an ophthalmologist.

Clinical Pearl- Dr Zone believes that rituximab should be used as initial therapy for ocular pemphigoid. Dr Zone has seen seven patients who have gone blind from this disease. Dermatologists should biopsy for direct Immunofluorescence if considering immunobullous disease. It is imperative that the biopsy is performed on clinically normal appearing skin adjacent to a lesion. 

 Pemphigus Antigens

Pemphigus foliaceus  (PF) and pemphigus vulgaris (PV) have different desmoglein antigens. The PF antigen is Dsg 1 and the PV antigen is Dsg 3, both of which are calcium-dependent adherence molecules. Desmoglein causes epithelial cells to stick one to another. Dr Zone finds that these antibody levels correlate extremely well with disease activity.  (see figure below)

In this case, Dr Zone treated this patient with azathioprine; however, he wasn’t fully responding.  The  “dip” in antibody levels reflects plasmapheresis. From there, he stopped the azathioprine and the patient was started on CellCept and the levels went up. Dr Zone, remembering that azathioprine induces thiopurine methyl transferase and patients become resistant to the drug, went back to azathioprine at very large doses, to the point of leucopenia, and eventually the patient went into remission.

These levels allow Dr Zone to predict how the patient is responding to therapy.

This (above) case represents a case where the antibodies were presumably against non-pathogenic epitopes.  Dr. Zone used plasmapheresis at the beginning of her clinical presentation (seen in the antibody titer drop)  In this particular case the high titer antibodies were likely against non pathogenic epitopes, and the patient went into remission without a corresponding decrease in antibody levels.

Indirect Immunofluorescence (IIF). Dr. Zone commented that the pemphigus antibody titers on IIF were found to correlate roughly with disease activity however the correlation with clinical activity was not as good as we now see with the ELISA technique. IIF has low accuracy and reproducibility .

Clinical Pearl- Dermatologists should biopsy for direct Immunofluorescence if  they are considering immunobullous disease. Biopsy clinically normal appearing skin adjacent to a lesion. It is important to monitor response with serial antibody level.

Pemphigoid

For antigen identification it is important testing using salt-split skin or ELISA.  This allows identification of specific antibodies that can then be used as an index of response to therapy. BP180(BPAg2) is the most common antigen and can be quantified using ELISA.

This patient’s BP180 antibody levels correlated very well with her disease activity.

Several studies have shown the correlation of disease activity with these antibodies.

Why is this important to test for antibodies?

Research has suggested that ant-epiligrin (laminin 332)  usually found in mucous membrane pemphigoid has a strong association with cancer. In a study of 35 patients with laminin V (332) mucous membrane pemphigoid there were 10 solitary solid cancers. There was a temporal association (14 months before or after the onset of the tumor in 9 out of 10 patients). The control groups indicated a relative risk of 15.4 (5.7-33.6). Ascertainment bias and treatment bias are unlikely because of time course. If a patient’s antibody goes the dermal side of salt split skin on indirect immunoflourescence, and binds to laminin 332 on immunoblot, that patient has a one in three chance of having cancer.

Type VII Collagen

The epidermolysis bullosa acquisita antigen (type VII collagen), which is present in the skin, is also present in the wall of the normal human colon. Research has shown that type VII collagen antibodies are associated with Crohns disease.  What does this mean? If you have antibodies to type VII collagen and epidermolysis bullosa acquisita (IgG antibodies that go to the dermal side of salt split skin on indirect immunoflourescence ) then you have a very significant chance of having Crohn’s disease or ulcerative colitis. If Dr Zone finds out that these people have antibodies to type VII collagen, then he screens them for Crohn’s and ulcerative colitis .

Clinical Pearls- Biopsy for direct Immunofluorescence if considering immunobullous disease; Biopsy clinically normal appearing skin adjacent to a lesion; Identify antigen if possible; Monitor response with serial antibody levels

Dr Zone prefers a topical steroidal therapy to control mild disease, especially in the mouth, and little to no systemic steroids. Dr Zone has found that over the years, systemic steroids have caused more problems to patients. If systemic steroids are required, Dr Zone suggests starting patients on a bisphosphonate, prior to starting the steroids, possibly alendronate (70 mg/wk). Patients should also be started on an H2 blocker or a proton pump inhibitor, the risk of gastritis is very high and it is very real.  A study from the New England Journal of Medicine looked at the comparison of oral and topical corticosteroids in elderly patients with bullous pemphigoid. Since the elderly have a low tolerance for oral corticosteroids the researchers evaluated whether potent topical steroids could decrease mortality and morbidity while controlling disease. Topical steroids were associated with significantly fewer problems with infection, diabetes and psychiatric symptoms.

The above table illustrates all the more reason to utilize topical steroids.

Dr Zone’s Algorithm for the Treatment of Pemphigoid

The dose for doxycycline (if tetracycline is not available) is 100 mg PO BID and niacinamide is 500 mg PO BID. This can be used effectively in mild pemphigoid.

Rituximab should be for any ocular or esophageal pemphigoid. For moderate and severe pemphigus rituximab has a definite benefit and Dr. Zone uses it in this clinical situation.

Rituximab and its Use in Autoimmune Disorders

  • Vaccinations before hand for pneumococcus, influenza, DPT boost 4 weeks earlier if possible
  • Stop immunosuppressives if possible (may have increased complications when used in conjunction with rituximab)
  • Premedicate with steroids and antihistamines to minimize infusion reactions
  • Dosing: 375g/m2 weekly x 4
  • OR 1000mg twice – 2 weeks apart (dosing most often used by rheumatologists)

A study by Joly, et al in the New England Journal of Medicine looked at a single cycle of rituximab for the treatment of severe pemphigus vulgaris in resistant patients (14 PV and 7 PF). The patients received a single cycle of rituximab, 18 of the 21 patients were in complete remission at 3 months and 2 of the 21 patients were in complete remission by 12 months. 9 patients experienced a relapse at 12 months and 2 of the patients required a second cycle. 8 of the 21 patients required no systemic therapy afterward. The Dsg antibody levels correlated with treatment response.

In another study looking at rituximab and autoimmune disorders, the researchers found that serious infections do not appear to be substantially increased but isolated reports are bothersome. Progressive Multifocal Leukoencephalopathy in non-HIV autoimmune patients treated with rituximab has created a significant concern.  Their total serum IgG was not significantly lowered.  When studying rituximab for patients with refractory mucous membrane pemphigoid, Le Roux-Villet et al, looked at 25 patients given 1 or 2 cycles of rituximab (375 mg/m2 weekly for 4 weeks). There were complete responses in all affected sites (ocular and/or extraocular) in 17 patients (68%) by a median time of 12 weeks after the first cycle and 5 additional patients responded completely after a second cycle, yielding an 88% complete response rate. 9 of the 10 patients became noninflammatory within a mean of 10 weeks. Severe infection occurred in 3 patients (12%) who developed severe infectious complications, 2 (8%) died; they had been receiving concomitant conventional immunosuppressants and high-dose corticosteroids. The immunosuppressants were discontinued in all other patients and no other infections were observed. 10 patients experienced a relapse after a mean of 4 (range, 1-16) months after achieving a complete response and were re-treated.

In 2009, Jones, et al published a multicenter survey of ritxumab therapy for refractory anti-neutrophil cytoplasmic antibody-associated vasculitis (ANCA vasculitis) in Arthritis and Rheumatism. 49 of the 65 patients (75%) achieved complete remission. 15 of the 65 (23%) achieved a partial response and 1 (2%) had no response. The median time to remission was 2 months (range, 1-5 months). Immunosuppressive therapy was withdrawn in 37 of 60 patients (62%). 28 of 49 patients experienced a relapse (median 11.5 months) and B cell return preceded the relapse in 14 of 27 patients (52%).  Serious adverse events seemed to be associated with the underlying disease so it is important to remember that the underlying disease is still a problem for several months. 46 SAEs occurred in 25 patients, and some patients experienced more than 1 SAE. Most patients received immunosuppression either immediately before (37) or during (14) rituximab therapy.  This study was reviewed to allow understanding of potential side effects of rituximab independent of the presence of pemphigus or pemphigoid.

Take Home Points

  • Make certain of the diagnosis
    • DIF and serology
    • Identify specific antigen whenever possible and follow antibody levels
    • Minimize systemic steroids
      • Use bone and stomach protection
      • Rituximab for severe disease
        • Sooner rather than later
        • Rituximab is the best initial treatment in ocular pemphigoid
        • The underlying disease is still a problem for months
        • Beware of simultaneous immunosuppressive therapy

 

 

The future of personalized medicine could be monoclonal antibodies that are directed against antigen specific B cells. Dr Zone feels that we will see a lot more of this over the years to come.

Cutaneous Oncology: Recent Drug Approvals Part 2

Keith Flaherty, MD & George Martin, MD

Vismodegib (ErivedgeTM) for the Treatment of Advanced Basal Cell Carcinoma (BCC)

Dr Keith Flaherty, an oncologist at MGH, spoke on ErivedgeTM for the treatment of advanced and metastatic BCC.   Historically,  the treatment of patients with advanced BCC with either metastatic or locally advanced disease employed standard chemotherapeutic regimens using agents such as cis-platinum. Reports of success were few and generally limited to individual case reports until the recent FDA approval of Erivedge® a hedgehog pathway inhibitor.

The “hedgehog pathway” (Hh pathway: Figures 1 & 2) and its role in the development of basal cell carcinomas (BCC) has been the subject of intense research over the last decade.  Aberrant activation of the Hh pathway (Figures 3 & 4) has been identified in both hereditary BCC syndrome ie Gorlin syndrome (Basal Cell Nevus Syndrome) as well as sporadic BCCs.  Gorlin syndrome patients carry a germ-line heterozygous mutation in the PTCH gene and are highly predisposed to developing multiple BCCs. Mutations in the PTCH gene (Figure 3), remove its ability to inhibit the Hh pathway through its inhibition of SMO (Smoothened protein).  Approximately 90% of sporadic BCCs have a PTCH gene mutation and an additional 10% of sporadic BCC have activating mutations in the SMO gene (Figure 4), which is downstream of PTCH, and this mutation leads to overstimulation of the Hh pathway.

Vismodegib (Erivedge®) is a hedgehog pathway inhibitor (figure 5), which binds to and inactivates SMO.  Its use is indicated for the treatment of adults with metastatic basal cell carcinoma (mBCC), or with locally advanced basal cell carcinoma (laBCC) that has recurred following surgery or who are not candidates for surgery or radiation.

Dr Flaherty presented data evaluating the safety and efficacy of Erivedge in mBCC and laBCC obtained from an international, single-arm, multi-center, open-label, 2-cohort phase II study involving 104 patients (Erivance BCC/SHH447g). Patients with laBCC either had histologically-confirmed BCC that was unresectable or were not appropriate candidates for surgery: >1 cm or 2 or more recurrences after surgery; curative resection unlikely; anticipated substantial morbidity and/or deformity after surgery.  mBCC patients had histologic confirmation of mBCC and radiographically measurable tumors. The patient demographics are listed in figure 6. Patients received vismodegib 150 mg/day orally until tumor progression or intolerable drug toxicity.

The objective response rates (ORR) were assessed by an independent review facility (IRF) and were 42.9% for laBCC and 30.3% for mBCC.  The median duration of response was 7.6 months and the median progression-free survival was 9.5 months for both cohorts.

The rate of severe toxicities (grade III + IV) for vismodegib is quite low. Mild to moderate toxicity (grades I + II toxicity) seen with vismodegib included fatigue, muscle spasms and dysgeusia (altered taste).

In summary, vismodegib is dramatically effective for BCC treatment in patients with advanced.  Approximately 80% of patients with advanced BCC have regression of disease with 30 – 60% of patients having objective responses.  Now FDA approved for patients with advanced BCC, it will be interesting to see how this drug will be used both therapeutically and in an adjuvant setting in combination with other surgical and non-surgical modalities.

 

 

Immunogenicity

Bruce Strober, MD, PhD

In this presentation, Dr Strober discusses the important concept of immunogenicity as it relates to the management of psoriasis and the use of biologic therapy. There are several factors that lead to the loss of therapeutic response. These factors include drug level reduction, specifically immunogenicity, suboptimal dosing schedules (e.g. etanercept step-down dosing, infliximab every eight weeks and ustekinumab given every 84 days)  and poor patient adherence. Another issue is that of altered pathophysiology of the disease in the face of the therapy applied, i.e., one can see a loss of therapeutic response without immunogenicity.

What is Immunogenicity?

By definition, foreign proteins are immunogenic. Biologic therapies for the treatment of psoriasis are all foreign, even though they are based on natural forming molecules. Immunogenicity requires that a protein has to be more than just “foreign”, i.e., different biologic drugs exhibit different degrees of immunogenicity. Immunogenicity inhibits therapeutic response and may increase risk.

Do Biologic Medications Lose Efficacy When Treating Psoriasis?

Infliximab begins with very high efficacy, PASI 75 scores are nearly 80%; however, after about one year of Q 8 week dosing, one loses about one third of patients who initially achieved a PASI 75. This could be due to pharmacokinetics; however, in part, it is probably due to immunogenicity.

Initially, 100 % of adalimumab responders achieved a score of PASI 75, but after about two years, only three quarters of those patients were still at a PASI 75.

At week 48, 61% and 63% of patients on etanercept achieved a PASI 75; however, at week 96, that number had fallen by 18%.

Ustekinumab also demonstrated a drop-off regarding therapeutic efficacy.

Clinical Pearl-Loss of therapeutic response is part of the issue when treating psoriasis patients with biologic therapies

The Manufacturers of Biologics Acknowledge Immunogencity

 Infliximab

In psoriasis clinical trials, antibodies were observed in 20-36% of patients treated with 5 mg/kg every eight weeks for one year. A higher incidence of antibodies to infliximab was observed in Crohn’s disease patients receiving infliximab after drug free intervals for more than 16 weeks. In psoriatic arthritis studies, patients who were antibody-positive were more likely to have higher rates of clearance, reduced efficacy and infusion reactions, which is an important safety issue. Antibody development was lower among RA and Crohn’s disease patients receiving immunosuppressant therapies such as 6-MP/azathioprine or methotrexate.

Adalimumab

Approximately 5% of RA patients developed low-titer antibodies to adalimumab at least once during one year of treatment, which were neutralizing in vitro. Patients who were treated with concomitant methotrexate had a lower rate of antibody development than patients on adalimumab monotherapy (1% versus 12%). With monotherapy, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. ACR 20 responses are lower among antibody-positive patients than among those patients who are anti-body negative.

Etanercept

Antibodies to the TNF receptor portion or other protein components of etanercept were detected at least once in sera of approximately 6% of adult patients with RA, PsA, AS, or PsO. Antibodies were all non-neutralizing. The percentage of patients testing positive increases with an increase in the duration of study. There was not a correlation of antibody development to clinical response nor were there any adverse events. There was no effect with methotrexate.

Ustekinumab

In Study 1 and Study 2 looking at ustekinumab and immunogenicity, 3-5% of patients, respectively, showed antibodies against drug. 48% to 90% of patients studied were inconclusive. Data presented at a recent EADV meeting demonstrates that immunogenicity against ustekinumab correlates with reduction in response long-term.

Clinical Pearl-More frequent administration of a biologic tends to reduce immunogenicity

Should we care about “neutralizing” vs. “non-neutralizing” antibodies?

Dr Strober feels that dermatologists should really care about whether or not a drug has an antibody raised against it and if so, does the body remove the drug from circulation…?

In patients, antibodies against adalimumab and infliximab usually bind to the antigen (TNF) binding domain; therefore, they “neutralize” the ability of the drug to bind to TNF. Antibodies that are raised against etanercept fall into what’s referred to as the hinge domain that really mediates the linkage between the Fc domain and the TNF receptor domain. So, while they bind to the molecule, they do not neutralize its ability to block TNF, i.e. “non-neutralizing”.

Open Label Studies

Switching to Etanercept after Failure to either Adalimumab or Infliximab for Treatment of RA

This study evaluated 292 patients with rheumatoid arthritis. 203 patients were anti-TNF naïve. 89 of the patients had been previously treated with either infliximab (n=30) or adalimumab (n=59), and then switched to etanercept. 32% of the patients were non-responders since the start of the treatment with either infliximab or adalimumab and 68% of the patients had lost the initial response. Out of the 89 patients who switched to etanercept, 47 patients (53%) had antibodies against adalimumab or infliximab as measured at baseline prior to the start of etanercept treatment. Patients with detectable anti-drug antibodies had significantly lower doses of methotrexate at baseline compared to patients without antibodies (p=0.031).

Patients who were anti-TNF naive were compared to switchers without antibodies and a DAS28 improvement was significantly larger in patients who were anti-TNF naïve after 28 weeks of etanercept treatment. There was no significant difference in the improvement in DAS28 between patients who were TNF naïve compared to switchers with antibodies. The improvement in DAS28 was significantly larger in switchers with anti-drug antibodies compared to switchers without antibodies. This study concludes that altered disease pathophysiology may play a greater role in patients who lose response without showing immunogenicity. Immunogenicity is only part of the equation.

Anti-adalimumab Antibodies are Associated with Lower Adalimumab Concentrations and Treatment Non-response

This was a prospective observational cohort study looking at 121 consecutive RA patients treated with adalimumab and a concomitant DMARD or adalimumab alone. During 28 weeks of follow-up, antibodies were detected in 21 (17%) of patients. Serum adalimumab concentrations in patients with anti-adalimumab antibodies were significantly lower than in patients without these antibodies (median 1.2 mg/l, range 0.0–5.6 vs median 11.0 mg/ l, range 2.0–33.0; p,0.001). Non-responders had anti-adalimumab antibodies significantly more often than good responders (p=0.006).

Higher concentrations correlate with better clinical response

Extent and Clinical Consequences of Antibody Formation Against Adalimumab in Patients with Plaque Psoriasis

This was a prospective observational cohort study looking at 29 psoriasis patients, 17% (5 of 29) also had psoriatic arthritis. Patients were given standard adalimumab dosing (40 mg) every other week after an initial dose of 80 mg and a dose of 40 mg the week thereafter. Adalimumab trough concentration was measured 12 and 24 weeks after the initiation of treatment. This study correlates with the data presented above (RA) in that the lower the concentration of drug, the lower the response and low antibodies to drug demonstrates better clinical response. Three patients used concomitant methotrexate and none of these patients developed antibodies to adalimumab.

There are a lot of data that suggest that methotrexate blocks immunogenicity. There should be no doubt regarding methotrexate and therapeutic efficacy.

Patients Not Responding to Etanercept Show Lower Trough Etanercept Concentrations Compared to Responding Patients

This was a prospective, single center observational cohort study from Amsterdam. The study looked at 292 consecutive patients with active RA who were given a new etanercept prescription. Clinical response and etanercept levels were collected at baseline and after 1, 4 and 6 months of etanercept treatment. Trough serum etanercept levels were measured by ELISA.

The study showed that patients with good clinical response display significantly higher levels of etanercept than patients who were not responding. Anti-etanercept antibodies were measured by 4 different assays and no anti-etanercept antibodies were detected which is a different response from that of infliximab and adalimumab. The absolute differences in etanercept levels between responding and non-responding patients were small. Immunogenicity may not explain the lack of response in RA patients treated with etanercept.

Effect of MTX on Efficacy with Etanercept

When looking at patients who are methotrexate non-responders and who were either given methotrexate with etanercept and then tapered off the methotrexate or continued the methotrexate, it is clear that those who tapered off the methotrexate did not respond as well; therefore, demonstrating that methotrexate has some effect on etanercept response.

A Basic Approach to Moderate to Severe Psoriasis or Psoriatic Arthritis

Healthcare providers should initiate therapy with methotrexate and allow 12 weeks to demonstrate a response. If methotrexate monotherapy is inadequate, a biologic should be added. Dr Strober continues the methotrexate indefinitely because of the data that demonstrates a better clinical response.

Conclusions

  • Biologics should be dosed without interruption and at intervals that make sense with regard to the drug’s half-life.
  • Concomitant MTX (or, possibly, azathioprine) blunts immunogenicity
  • When given with MTX, biologic agents invariably show greater and more durable efficacy, even when MTX is ineffective as monotherapy
  • A sensible practice is to add a biologic therapy to MTX, not vice versa, as once immunogenicity occurs it may be difficult to reverse

 

 

 

 

 

 

 

 

Filler Complications

Joel Cohen, MD; Director, About Skin Dermatology and DermSurgery; Englewood and Lonetree, Colorado

Dermatologists across the country are using dermal fillers on a daily basis and the products available in the US are believed to be safe and effective provided that they are used correctly. In his presentation, Dr. Joel Cohen discussed the importance of understanding, avoiding and managing dermal filler complications. Filler complications can be stratified into something that doesn’t look very aesthetic when it is superficially or inappropriately placed to situations involving skin necrosis and infection. Regarding aesthetics, Dr. Cohen commented that unfortunately many patients are still walking around with features due to inappropriate use of dermal fillers, which can create an artificial look. This has resulted in patients tending to shy away from using fillers. Dermatologists need to be aware of the agents available and what has been reported as well as different injection techniques.

The key for clinicians, with regards to dermal fillers, is to make things appear natural. Dr. Steve Mandy wrote a review in April 2007 in Dermatological Surgery which reviewed the lip and how important is to place the filler in the right area so that it looks natural.

Injecting the Infra-Orbital Area

Many people prefer different agents to be used in this area and it is important to keep in mind that, in general, this is a very deep injection. If one is to inject superficially, then there is a risk to having the appearance of nodules. There are various hyaluronidase agents available, for example, Vitrase, Amphadase, compounded hyaluronidase, and Hylenex (human hyaluronidase that is currently off the market) . Most of these products are of animal origin, so it is important to do a skin test.

Other issues regarding superficial injection include Artecoll and Artefill. Research has shown that there was not consistency in the particle size of Artecoll; therefore, they were easily ingested which could lead to fibrosis. Some people have had great experiences with Artefill as there is much more consistency in the particle size.

Radiesse (calcium hydroxyappetite) became available in 2003/2004, and many clinicians initially believed that it could be used anywhere.  However, we have learned that it can’t be used in the lips. Sculptra (poly-L-lactic acid) has shown great results as a volumizing dermal filler for the cheeks.  As is the case with all dermal fillers the key to success is knowing how it should be injected.  Careful attention needs to be paid to reconstitution time, volume of injection per location, and the proper injection depth. Sculptra requires longer reconstitution times (at least eight hours prior); higher volume reconstitution, i.e., mix the solution with 5+ cc of sterile water and add 1 cc 1% lidocaine prior to injection; and, inject deeper, i.e., into high fat. It is also important to be careful to avoid injecting precipitate at the end of the syringe. Following these simple points will help in avoiding SQ papules.

Dr. Cohen and others wrote a protocal on the management of visible granulomas following periorbital injection of Poly-L-Lactic Acid in Plastic and Reconstructive Surgery.

Bruising and swelling happens to many patients. It is unfortunate, but it does happen from time to time. There are some things that patients can avoid, such aspirin. Patients on anticoagulants also have to be managed; however, it can be done. There is also a whole list of vitamins that can potentially interfere with bleeding; so again, something to keep in mind.  Clinicians need to be realistic with their patients, so that can expect some bruising and/or swelling which may last up to ten days. It is really important to talk with your patients prior to the procedure.

What can patients do to minimize bruising and what to do when it occurs?

Dr. Kevin Smith wrote an article on the role of ice. Not only will ice decrease pain, it also decreases the bruising and swelling. There are also agents that patients can rub directly onto their skin. Topical Arnica has not proven to be very effective however, oral Arnica may also help regarding swelling and bruising. What is most practical and most helpful solution to resolving bruising quickly in Dr Cohen’s experience is to use a pulsed-dye laser to treat bruising.

Filler Bruising: Treatment with PDL
At 2 days post-filler

  • PDL
  • 7.5 J
  • 6 ms
  • 10 mm spot 1

There is really about a two-day window to treat patients who experience significant bruising. There are also other devices that can be used such as IPL, which is done at short pulse durations (10 ms).

Injection speed is something else that clinicians need to consider.  A clinical trial with Glogau, et al, they found that if healthcare providers inject quickly, it could actually lead to more bruising and swelling (about .3 cc per minute). The study also found that a fan-like injection leads to more bruising and swelling.

Dermatologists need to be aware of potential infection, as it can occur. Treatment includes I & D of the suspected infection, culturing the material, and initiating oral antibiotics.

Necrosis is another important issue to be aware of. There are certain areas that clinicians must pay a particular interest in, e.g. the glabella. It is important to watch the skin as you inject. You should aim superficial and medial, and aspirate. Regarding treatment of a pending area of necrosis if you identify sudden blanching of the skin following injection is to immediately apply warm gauze, repeatedly tap the injected area, apply nitro paste to the treatment site immediately while the patient isin the office and heparin treatment (low MW, SQ). Regarding impending necrosis, hyaluronidase in multiple stabs along and perhaps into the adjacent artery has shown to be a novel treatment. It is very important as a healthcare provider to intervene immediately and not “wait and see what happens” in the cases of impending necrosis.

Sudden blindness has also been reported with different injectable agents around the eyes. Healthcare providers should inject shallow in this area and be extremely careful, keeping the facial arteries in mind.

The risk of sensitivity with the newer agents is extremely low.

In conclusion, clinicians must pay careful attention to the injection site area, take all precautions, and talk to their patients in order to set realist expectations.

  1. Karen JH, Hale EK, Geronemus RG. A simple solution to the common problem Ecchymosis. Arch Dermatol. 2010;146(1):94-95.

Update in the Management of Rosacea

Panelists: James DelRosso, MD; Alan Shalita, MD; Guy Webster, MD, PhD

The diagnosis of rosacea is based upon clinical findings; there are no specific diagnostic tests. The National Rosacea Society Expert Committee on the classification and staging of rosacea has developed provisional diagnostic guidelines for rosacea.1

The guidelines recommend the presence of one or more of the following primary features:

  • Flushing (transient erythema)
  • Non-transient erythema
  • Papules and pustules
  • Telangiectasia

In addition, one or more of the following secondary features often appear with the primary features listed above, although can occur independently in some patients:

  • Burning or stinging
  • Plaque
  • Dry appearance and scale
  • Edema
  • Ocular manifestations
  • Peripheral location
  • Phymatous changes

 

 

 

 

 

Case 1

The panel was presented with the case of a 41 year old white female with a 6-7 year history of waxing/waning facial redness that waxes and wanes and is associated with red bumps and pustules on the nose, cheeks and forehead.  She has “sensitive skin” which is often dry and flaky. Her skin improved on an oral antibiotic for a respiratory infection. She is seeing you to “get rid of the condition”.

It is important to identify the subtype of the disease as that will help dictate the response to treatment. Clinicians should recognize that these patients have increased transepidermal water loss (TEWL) from the central face. Dermatologists need to understand the importance of appropriate skin care in order to address the symptoms and, ultimately reduce the baseline symptoms. Studies have demonstrated that the skin characteristics of patients with rosacea show that about half of the patients scale and become itchy, about one third of the patients experience stinging and burning and these patients do not always have seborrheic dermatitis.

Etiology of Rosacea

The etiology of rosacea is unknown, although research suggests that symptoms are exacerbated by factors that trigger innate immune responses, such as the release of cathelicidin antimicrobial peptides. Studies have shown that patients with rosacea express abnormally high levels of cathelicidin in their facial skin and the proteolytically processed forms of cathelicidin peptides found in rosacea are different from those present in normal individuals. These cathelicidin peptides are a result of a post-translational processing abnormality associated with an increase in stratum corneum tryptic enzyme in the epidermis.2

Therapeutic Options: Topical Agents for the Treatment of Rosacea

 Metronidazole works through the inhibition of ROS generation from neutrophils. Azelaic Acid also works through the inhibition of ROS generation from neutrophils. Azelaic Acid also has decreased KLK-5 activity (serine protease activity); therefore,  decreasing the cathelicidin. It also downregulates the Toll-like receptor 2 (TLR2), similar to topical retinoids.

Retinoids also have a variety of ways in which they can modulate the disease, for instance they work through the inhibition of ROS generation from neutrophils and also have the downregulation of TLR2 and modulation of MMP activities, i.e., repair of dermal matrix degradation.

The tetracycline derivatives have a variety of down-regulating properties that appear to help with rosacea. They reduce inflammatory cytokines: IL-1b, IL-6, and TNF-1-a. They inhibit the serine protease activation of catheclicidin. They inhibit MMPs collagenase-8, -13, gelatinase -2, -9, elastase -12 and pro MMP activation and protect TIMP. Tetracyclines also inhibit nitric oxide activity and the arachidonic acid pathway.

Data on minocycline show the suppression of serene protease activity. Specifically, when patients were on minocylcine, the serene protease activity decreased, when they stopped it increased, and when they went back on the minocycline, it again decreased. (Yamasaki et al. Nature Medicine (2007) Aug 13 (8) 975-80)

As far as oral therapies for the treatment of rosacea, the tetracyclines are used; however, they are not FDA approved and there is reason to believe that dermatologists only need to use the subantimicrobial doses in order to garner the anti-inflammatory effect. These doses have widespread use and years of clinical experience. There are multiple pharmacokinetic and microbiologic studies. They are FDA-approved with large pivotal trials. Data exists with regards to the combination with topical therapy. Their efficacy is comparable to doxycycline 100 mg daily and there are potential safety advantages.

With the use of doxycycline (40mg Extended Release, QD) once can see demonstrated efficacy in papulopustular rosacea, there is a lack of antibiotic effect, efficacy is the same as that of doxycycline 100mg/QD, and there is a favorable safety profile. One 12-week study looking at doxycycline 40mg demonstrated that by week 4, close to half of the patients achieved clear or near-clear skin and by week 12, about 75% of the patients achieved clear or near-clear skin. The data were similar to that of patients utilizing add-on therapy in addition to doxycycline.

In conclusion, healthcare providers should be aware that there are a lot of data that show the efficacy of these agents for the management of papulopustular rosacea.

When comparing doxycycline 100mg to doxycycline 40mg, the effects were essentially the same based on one trial. Patients do not need to be exposed to changing their bacterial flora unnecessarily by starting with this treatment first, and; therefore, patients are not exposed at an antibiotic effect.

Case 2

The second case presented to the panel was a 42 year-old White female presents with a 7 year history of central facial (nose/malar eminences/chin) redness which waxed and waned in intensity over the years but is now persistently red There is central facial predominance.  She does not relate ever having any “red bumps” or “pus bumps” developing on her face, including during flares.  She has “sensitive skin”. She occasionally complains of itching and burning. She is interested in the correct diagnosis and treatment. Her health history is unremarkable otherwise.

Medical Treatments for the Redness of Rosacea

Erthematotalngiectatic rosacea (ETR) is more common than papulopustular rosacea. Available therapies include topical agents, such as metronidazole, azelaic acid, and oral agents such as the tetracyclines all of which improve primarily perilesional erythema. These products can occasionally help patients with their rosacea, but the background redness type does not always respond very well.  The critical issue is the presence of persistent telangiectatic mats in the affected areas.  The telangiectasias can be reduced when treated with laser/light devices.  Topical vasoconstrictors that can be used to reduce erythema (Oxymetazoline and Brimonidine) are in clinical trials and have shown excellent clincial responses during these clinical trials.

 

References:

1. Wilkin, J, Dahl, M, Detmar, M, et al. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol 2002; 46:584.

2. Yamasaki K, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. 2007. Nat Med;13(8)975-980.