Anti-IL12/23p40 Antibodies in the Treatment of Psoriasis and Psoriatic Arthritis

Craig Leonardi, MD

The much anticipated introduction ustekinumab (Stelara®) for the treatment of moderate to severe psoriasis came about in 2010.  This fully humanized monoclonal antibody directed against the p40 subunit of IL 12 and 23 has demonstrated in phase II and III studies that it is a “high performance” drug: fast acting, long duration of action and great efficacy.  However, according to Craig Leonardi, MD, a principal investigator for ustekinumab, there appears to be a potential cardiovascular safety signal which came in the form of MACE events (Major Adverse Cardiovascular Events ie myocardial infarction, stroke and sudden death).  These MACE events appear to be a “class effect” as it is also found in the other anti p40 antibody briakinumab, which is in phase III development.  When both phase II and III data were analyzed for both anti-IL12/23 blockers there were 10 MACE events in the 3,100 drug treated patients and none in the 1,400 placebo treated control group. Because these studies are not powered to demonstrate statistical significance of this small but finite signal none was found.   It should be noted that MACE events do not encompass other cardiovascular signals such as angina, coronary bypass surgery or TIAs. The incidence of these non-MACE events is unknown.  This MACE safety signal has not found in the numerous trials involving thousands of moderate to severe psoriasis patients who received anti-TNF therapies who presumably have the same metabolic risk factors for MACE events.  Comparator groups such as those found in the Framingham study population really do not apply. Drug study populations preselect for healthy patients.  The placebo-controlled group is still the best comparator group and there were at least 1,400 patients in that group for both.

Dr Leonardi pointed out that MACE events occur early in the course of the drug therapy, usually within the first 8 months and level off.  Speculation regarding a mechanism for the MACE events would likely involve some form of plaque disruption. There is some independent investigational data that demonstrate a significant rise (a 13-fold increase) in serum p40 levels at week 12 which decrease back to baseline by 8 months after injection of these anti- p40 molecules.  This finding seems counter intuitive to what one would expect after introducing an antibody against p40 cytokines.   The elevation likely comes from an intracellular reservoir that enters into the serum over a period of time. Interestingly, the course of p40 subunits in the serum roughly parallels the development of MACE events. It is known that p40 can dimerize and become pro-inflammatory which if we continue on our speculator path could lead to plaque disruption and a MACE event.

Briakinumab’s application to the FDA for approval has been pulled and in July of 2011 Abbott halted all clinical trials involving briakinumab pending further evaluation of MACE events. Additionally there are many questions to be answered including regarding briakinumab’s early SAE’s such as infections  cutaneous and systemic squamous cell carcinomas reported in the first 28 weeks following the introduction of the drug in study patients.

Unlike the history behind TNF inhibitors which had long-term safety profile in the rheumatology and gastrointestinal field the IL 12/23 blockers are new and dermatology specific. In light of the current cardiovascular signal where does ustekinumab fit in our therapeutic tool box for psoriasis patients?

Dr. Leonardi’s Recommendations:  It should be understood that this is a “class effect” of the IL 12/23 blockers not observed in analysis of TNF inhibitor safety data.  Consider all options when selecting a biologic therapy.  Patients with moderate to severe psoriasis typically have cardiac risk factors.  Consider starting with a low dose regardless of the patient’s weight.  Although there is not data to support its use consider starting a patient on 81 mg of ASA.  Await further analysis of the safety data. Unlike the anti TNF therapies that came to us from rheumatology and gastroenterology, the IL 12/23 blockers have no point of reference.  Scientific analysis of the p40, IL 12 and IL 23 serum levels during long term treatment.

To add to Dr. Leonardi’s recommendations, in my patients with early signs of psoriatic arthritis such as enthesitis (inflammation of the insertions of ligaments and tendons into bone) with possible early join involvement I still favor the use of anti-TNF therapy when considering a biologic agent because of their longstanding efficacy in psoriasis patients with early signs of psoriatic arthritis.

Post Maui Derm Footnotes:

Since Dr. Leonardi’s presentation a paper co-authored by Dr. Leonardi discussing this potential safety signal among antii-IL 12/23 antibodies was published in JAMA (JAMA Aug 24/31 Vol 306 No. 8 (864 -871).  The article concluded: “Compared with placebo, there was no significant difference in the rate of MACEs observed in patients receiving anti–IL-12/IL-23 antibodies or anti–TNF treatments. This study may have been underpowered to identify a significant difference.”

Centocor recently released Stelara’s 4-year safety data, which did not demonstrate any new safety signals. This comes as good news particularly when one considers that the appearance of Raptiva’s (efalizumab) safety signal (PML) occurred at year 4.

 

Telomeres and Human Aging

Barbara Gilchrest, MD

Telomeres and Human Aging

In this year’s session on “The Science of Aging Skin” Dr. Barbara Gilchrest asked the question:  “Why do we age and what does aging mean?”  After posing this rhetorical question she went on to explain that there are two essential components to aging. The first is that there is a genetic program that assures that cells likely to be damaged over many decades stop dividing after a finite number of divisions and will not carry on their dysregulated program.  The second component is “wear and tear” and refers to the environmental insults to individual cells and organized tissue that cause cells to advance to a senescent state more rapidly.

When we speak about aging of the skin we refer to two components: intrinsic and extrinsic aging.

Intrinsic aging refers to the clinical, histologic, and physiologic changes in sun-protected skin of older adults. This is also called chronological aging.

Extrinsic aging, which is also referred to as “photoaging”, refers to the clinical, histologic, and physiologic changes in habitually sun-exposed skin of older adults.  Photoaging occurs primarily on the face.  There are striking differences between chronological aging and photoaged skin in chronically sun-exposed areas.

Intrinsic aging has a minor impact on the appearance of the skin but over time results in multiple functional deficits such as slow wound healing and the loss of immune competence observed in older skin. By contrast photoaging has a major impact on the appearance of the skin, results in a further loss of immune function, and probably exaggerates the loss of other cellular functions.  Most importantly, photoaging is strongly associated with photocarcinogenesis.

Extrinsic aging is not only the result of UV light but also cigarette smoke, which accelerates the aging process. The effect of cigarette smoking on aging skin has been repeatedly documented since the 1960’s.  Very recently the role of air pollution in extrinsic aging of the skin has been documented in middle-aged women.  The study involved a comparison between women living in the countryside away from highways vs. those living in cities closer to highways.  The women experiencing air pollution near roadways were found to have accelerated skin aging.

Current Concept: “The processes of aging and photoaging are consequences of safeguarding the genome”

Dr. Gilchrest contends that nature is concerned about the genome with little regard to the actual aging process. Cancer is the failure of this safeguard mechanism.

Research in the later half of the 20th century has identified and documented major mechanisms of aging.   These include “signaling imbalance” due to the inter-related factors of retinoic acid deficiency, corrected by retinoic acid replacement (Voorhees); increased activity of NFκB (a transcription factor that contributes to dysfunction of senescent cells); oxidative stress due in part to aerobic metabolism; UV damage; and other cumulative DNA damage to cells of body, particularly the skin.  More recently telomere shortening, a newly understood aspect of aging, has led to a greater understanding of the aging process.  The Nobel prize in 2009 was given to 3 scientists whose work beginning in the 1980s greatly advanced our understanding of telomeres. Appreciating their role in the aging process promises to lead to novel therapies for aging.

The Role of Telomeres:

Chromosome Caps

Figure 2: Chromosome Caps

Telomeres (Figures 1 and 2) are the terminal portions of chromosomes, in man about 10,000 DNA base pairs that shorten to around 6,000-7,000 base pairs with age.  Telomeres are composed of a repeating base pair sequence of TTAGGG and its complement.  Telomeres form a loop structure that caps the end of DNA strands that are otherwise interpreted as double stand breaks. Without telomeres you get chromosomal fusion, mutations and cell death.  (Figure 2)

Telomere caps on chromesomes

Figure 1: Telomere caps on chromesomes

Critically short telomere lengths cause cells to go into a senescent state such that the cell stops dividing after 50 – 60 post natal cell divisions.  Nothing is capable of stimulating the cell to divide at that point.

In addition to their role as a “biologic cellular clock” in which telomeres limit the number of cell divisions (Harley et al. Nature 1990), it has been found that telomeres also trigger DNA repair responses   (Karlseder et al. Science, 1998).

The Role of Telomerase:

Telomerase is the enzyme complex responsible for lengthening telomeres by adding TTAGGG sequences to the tips of chromosomes.  Telomerase is expressed in germline cells, stem cells and >90% of malignant cells. Telomerase is also expressed transiently in S (DNA synthesis) phase in normal cells (Masutomi et al. Cell, 2003).  Telomerase slows but does not prevent telomere shortening in normal cells. However, its absence in genetically engineered mice is associated with acceleration of the intrinsic aging program.

Telomerase Activation

Telomerase activation in otherwise normal cells immortalizes the cells, which then divide indefinitely but are not malignant because these cells are still subject to the local environmental commands.  In an animal you get a younger animal but promote carcinogenesis because you remove the essential telomerase shortening that turns off cell division and limits the life of the environmentally mutated cell.

Increased Telomerase Activity in Combination
with Cancer Resistance Delays Aging in Mice

Experiments were performed in which mice were genetically modified and made transgenic for TERT (catalytic component of telomerase) and also over-expressed the tumor suppressors p53, p16 and/or p19 ARF. The combination of increasing telomerase activity while overexpressing cancer resistance gene activity resulted in mice with an increase in median and maximum lifespan without an increase in cancer, an increase in telomere length and an improvement in clinical and molecular aging markers, including in the skin. {Tomas-Loba et al. Cell, 2008}

Compared to old wild type or other control mice Telomerase Reactivation Reverses Tissue Degeneration in Aged Telomerase-Deficient Mice

Dr. Gilchrest described a study involving 4th generation telomerase-deficient adult mice which were infertile with widespread tissue atrophy. Four weeks of conditional telomerase expression (TERT knock-in) resulted in: skin fibroblast proliferation increased telomere length, organ cellularity, including brain; increased fertility and litter size; increased olfactory responses; increased survival time and no carcinogenesis and a reduction in DNA damage signaling in tissues. (Jaskelioff et al. Nature, 2011)

 Telomeres Are Strongly Implicated in Human Aging

 Telomeres shorten with age in vitro (50-150 base pairs per mitosis) and in vivo. {Lindsay et al. Mut Res, 1991; Vaziri et al. PNAS, 1994; Dimri et al. PNAS, 1995}. Telomere shortening correlates with progression of age-associated diseases such as diabetes.  Telomere length (measured in peripheral blood lymphocytes) correlates with longevity in persons >60 years old.  {Cawthon et al. Lancet, 2003;  Valdes et al. Lancet, 2005}.  Progeria, Werner syndrome and other progeroid syndromes are characterized by short telomeres.

New information on Telomeres:

Over the last few years new information regarding the activation of telomeres and telomere associated proteins involved in DNA repair have been uncovered.  Telomeres are replicated throughout S phase and DNA damage repair proteins associate with telomeres during S phase and are activated. Homologous recombination proteins help to reconstitute the protective telomeric t-loop in the G2 phase  (Masutomi et al. Cell, 2003; Crabbe et al. Science, 2004; Verdun & Karlseder. Cell, 2006; Verdun & Karlseder. Nature, 2007)

Interpretation for telomere-based activation of DNA damage repair proteins during S phase:

According to Dr. Gilchrest, cumulative evidence regarding the role of telomere-based activation of DNA repair proteins suggests that this process might function as the cell’s final “quality check” before dividing.  This pathway is activated during replication in which telomere-based signaling first acts to reduce DNA damage, to slow senescence, and to protect the genome.  If acute damage is overwhelming or many cycles of cell division make cumulative damage likely, cells are pushed to apoptosis or senescence.  Cancer develops when this mechanism fails.

Melanoma

What’s your strategy in managing this lesion?

  1. In 1970 the overall melanoma survival rate was less than 60%. Today the overall survival rate is over 90%. Much of this improvement in melanoma survival can be attributed to earlier diagnosis.
  2. Diagnosis of melanoma at earlier stages of evolution is, in part, due to increased awareness and increased surveillance.
  3. The notion that the in vivo diagnosis of melanoma is solely dependent on its clinical primary morphology derides the true complexity involved in diagnosing this malignancy. Components of the clinical examination used in the evaluation of skin lesions include touch, patient-derived anamnestic data, analytical reasoning (e.g., ABCD), comparative recognition (e.g, change), and differential recognition (e.g., ugly duckling sign).  The human cognitive process integrates this clinical information, extracting the pertinent information and rendering a diagnosis.
  4. Utilizing total body photography, dermoscopy, and dermoscopic short-term mole monitoring has contributed to the detection of many clinically subtle melanomas (improved sensitivity) and has also increased our diagnostic specificity. This translates into an improved ability to detect melanoma while concomitantly decreasing the number of unnecessary biopsies being performed on benign lesions.  Pigmented lesion experts utilizing baseline photography and dermoscopy remove approximately 5 benign nevi for every MM found. In contrast, non-experts remove as many as 30 benign nevi for every MM found.
  5. Future technologies such as confocal microscopy, computer vision, telemedicine, etc. are likely to continue to enhance the sensitivity and specificity for diagnosing early melanomas.

Maui Derm 2010: Surgical Management of Melanoma   K. Tanabe MD

In the surgical management of melanoma it is critically important to obtain adequate surgical margins. Ken Tanabe, oncology surgeon at MGH, discussed surgical margins for melanoma and the role of sentinel node biopsy and lymphatic mapping.  Recommended margins: melanoma in situ – 0.5 cm;  < 1 mm thickness – 1 cm;  1 – 2 mm thickness – 1 – 2 cm;  > 2 mm thickness – 2 cm.  These recommendations have been developed from the results of prospective randomized trials.  These margins may be modified to accommodate for anatomic or functional considerations in cases of melanomas of the face and hands.

In patients who are potential candidates for lymphatic mapping and sentinel node biopsy what does one need to know?   Dr Tanabe stated that while both offer clear advantages in enhancing accuracy of staging and regional disease control, their value in improving likelihood of long term survival remains a subject of debate. Sentinel node biopsy should be discussed with all patients with invasive, clinically localized melanoma before definitive wide local excision. Sentinel node biopsy should be considered in the following groups of patients with clinically localized melanoma > 1 mm Breslow thickness; < 1 mm Breslow thickness with positive deep margin, or > 1 mitoses, or ulceration. Patients with metastatic melanoma identified in their sentinel nodes should undergo completion lymphadenectomy, since approximately 20% of these patients will have additional (non-sentinel) nodes with melanoma. What can we offer our patients with advanced disease?  According to Dr Tanabe, in patients with hematogenous metastases, immunotherapy with IL-2 produces rare, but durable complete responses.  Conventional chemotherapy (e.g. dacarbazine) has limited activity.  Based on early trial results there is much interest in agents that target specific molecular pathways, such as Braf mutant tumors.