[ed note: Michael Jorrin, who I like to call “Doc Gumshoe,” writes non-investment articles for us about medical and health topics a couple times a month. He is a medical writer, not a doctor, and his words and thoughts are his own.]
Just possibly a tiny few of the Gumshoe faithful may remember that advertising campaign, way back in the Golden Years of the Twentieth Century, that touted a preparation as a sure-fire remedy for the so-called “Heartbreak of Psoriasis.” The ads and TV spots definitely made a valid point, that psoriasis was not merely an episode of dry skin, that it was not a temporary allergy, that it was not akin to poison ivy, that it was not contagious, that it was not leprosy, et cetera, et cetera. They observed, correctly, that it was a chronic skin condition that would not go away on its own, and, not so correctly, that this wondrous drug would quell it once and for all.
In case you don’t remember, that miracle stuff was called Tegrin. And Tegrin is nothing more than a topical coal-tar preparation, which, for some people with psoriasis, may provide some relief of the skin symptoms of psoriasis – the skin symptoms, and only the skin symptoms.
Unfortunately, there is frequently a lot more to psoriasis than skin symptoms, and that’s where the term, “the heartbreak of psoriasis,” has more meaning than the makers of Tegrin intended.
To hoist the black flag right at the start, here are some nasty facts about psoriasis (the good news will come later on in this piece):
- First, a substantial fraction (perhaps as high as 40%) of all people with psoriasis have psoriatic arthritis, which means that in addition to surface involvement (skin, nails, scalp), the joints are also affected. Psoriatic arthritis is generally classified as a spondyloarthropathy, meaning that the joint symptoms are somewhat different than those in rheumatoid arthritis (RA). Psoriatic arthritis symptoms are more likely to be in the lower spine and the connections between the spine and the pelvis (the sacroiliac joints), although there is a good deal of overlap between psoriatic arthritis (PsA) symptoms and RA symptoms.
- Second, persons with Pso/PsA are also more likely to have other conditions that affect not only quality of life, but survival. These include cardiovascular disease, diabetes, and inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis. These other diseases and conditions are related to the degree of inflammation resulting from the underlying PsA; controlling PsA reduces the likelihood of these complications.
- Third, psoriasis itself (PsO) has a considerable impact on the general well-being of persons affected with this condition. It’s not only that patients are upset about how they look; patients with PsO are more likely to suffer from depression. In a study of the effects of psoriasis on well-being, 60% of patients with PsO reported being depressed, and 10% reported a wish to be dead.
Let’s start with a few facts about the PsO / PsA spectrum.
The common presenting symptoms of PsO are patches of reddened, rough, scaly skin, which may have papules and pustules (papules are small, raised pimples that do not contain pus; pustules contain pus.) There may be rough, scaly patches in the scalp, and persons with PsO may also have little pits in their finger- or toenails. The joint involvement characteristic of PsA is associated with more severe or long-standing cases of PsO.
Psoriasis is one of the autoimmune diseases, meaning that the disease process is mediated by one of the many agents in the body’s immune system. In psoriasis, the mediating agents are CD4+ and CD8+ T lymphocytes. PsO/PsA is now recognized as the most common T-cell- mediated disease in humans, and is the most prevalent autoimmune disease in the U. S. The psoriasis disease process essentially is inflammatory, and the inflammatory process can take place not only at the skin surface, but, if it is allowed to progress unchecked, at other body sites, especially the joints. One of the effects of the inflammatory process in psoriasis is proliferation of keratinocytes, which underlies the manifestation of the psoriatic skin lesions. In fact, before PsO was understood as an autoimmune disease, keratinocyte proliferation was thought to account for the symptoms.
According to a National Health and Nutrition Examination Survey (NHANES), approximately 7.5 million persons in the US are diagnosed with psoriasis, amounting to about 3.2% of the US adult population. Prevalence is highest in Caucasians (3.6%), followed by African-Americans (1.9%), Hispanics (1.6%), and others (1.4%). We should note that NHANES data is based on voluntary surveys; respondents were counted as having psoriasis only if they had received a diagnosis; an unknown but probably considerable percentage of persons with psoriasis have not been diagnosed, and this percentage may vary with socio-economic status and ethnicity.
(In other words, well-to-do Caucasians are perhaps more likely to seek medical intervention for a smallish patch of rough, scaly skin than are other cohorts of the US population.)
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We should add that undiagnosed PsO is apt to be mild, as measured by the percentage of skin area affected. The National Psoriasis Foundation has defined mild PsO as disease affecting less than 3% of the total body skin area. Disease affecting 3% to 10% of total body skin area is considered moderate, and more than 10% involvement is considered severe. As a point of comparison, the amount of skin covered by the palm of your hand is about 1% of total skin area, so as much 3% skin area affected by PsO is not likely to be overlooked.
How should psoriasis be treated?
You notice that, in posing that question, Doc Gumshoe is separating PsO from PsA. Perhaps we can address the question of PsO treatment by means of a hypothetical case study.
Our patient, Jeanette, is a 42-year old Caucasian woman in generally good health; a non-smoker, moderate drinker, somewhat overweight, and not given to exercise programs. She notices a small patch of reddened, scaly skin on her upper torso and at first suspects that she may have developed an allergy to a new skin moisturizer. She switches to another product without success; in fact, the red patch seems to be growing. It is now about two inches square.
Jeanette is not much of a worrier, but warm weather is coming, and the red patch will be visible above her bathing suit, which she thinks is disfiguring and will make people think she has some kind of loathsome contagious disease. She decides to go to a dermatologist. Her objective is clear: she wants the red patch gone – she wants her skin to be clear and nice and attractive.
The dermatologist immediately recognizes her condition to be plaque psoriasis, which is the most common form. If the dermatologist had significant doubts as to the diagnosis, he could have taken a small skin sample for biopsy, but in Jeanette’s case, the diagnosis is clear. Also, it is consistent with her general physical condition: overweight, inactive persons are more likely to develop PsO.
The dermatologist carefully explains to Jeanette that psoriasis is a systemic condition – not an allergy, not an infection, not contagious – which will not go away on its own. Jeanette’s red, scaly skin patch can almost certainly be successfully treated, but Jeanette has to be on the lookout for deeper involvement even if the skin lesion goes away. He explains, briefly, about joint pain and the possibility of progression to psoriatic arthritis, which could be a genuinely life-altering disease.
What Jeanette takes from this is that her skin condition can be successfully treated. Her horrible, disfiguring patch of scaly, red skin will go away. This is what she wants to hear.
Topical treatment options for psoriasis
Dermatologists are likely to be fully up-to-date on the topical treatments for psoriasis. Currently, the most favored treatment is a combination which includes a corticosteroid and a vitamin D analogue. Corticosteroids are ranked in seven classes, according to strength, with the lowest strength (class 1) being over-the-counter 1% hydrocortisone preparations, and the highest (class 7) being clobetasol propionate. The efficacy of corticosteroids in treating psoriasis is due to their anti-inflammatory and immunosuppressive action. The other component of the combination treatment, Vitamin D analogues, inhibits keratinocyte proliferation, which is one of the specific physiologic reactions to the underlying disease process in psoriasis. The keratinocyte proliferation accounts for much of the visible skin manifestation of PsO.
The corticosteroid/vitamin D analogue preparation consists of betamethasone propionate in combination with calcipotriol (Calcipotriene). It is available as an ointment or a gel, and marketed under a number of different trade names.
Another effective topical treatment is tazarotene, a third-generation retinoid. Retinoids are forms of Vitamin A, and they can be used to treat a number of skin conditions including PsO. Their mechanism of action is the regulation of cell growth in the skin, which is disrupted in PsO. Earlier retinoids include retinol, tretinoin, isotretinoin, and others; tazarotene has been shown to be more effective than those.
Patients with more extensive disease – i.e., more skin area affected – are sometimes treated with a combination of psoralen and ultraviolet A light, called PUVA. Psoralen is a naturally-occurring substance found in many fruits and vegetables, including all citrus fruits. It makes the skin more sensitive to the UVA, and UVA exposure then induces apoptosis (cell death) in the proliferating keratinocytes in the PsO skin lesions. A drawback of PUVA treatment, however, is that it increases the risk for a range of skin cancers.
In terms of effectiveness, coal tar preparations lag behind these others.
Jeanette’s dermatologist prescribes the combination calcipotriol – betamethasone propionate preparation. She should apply the ointment twice a day and return in four weeks.
At her four-week appointment, Jeanette’s skin lesion has greatly diminished in intensity, and after another four weeks of treatment, the dermatologist judges that it has cleared up, and further treatment is not necessary. He reminds her of the possibility of recurrence, and tells her to be on the lookout for other symptoms that might signal complications, although mild cases such as Jeanette’s are less likely to progress to psoriatic arthritis.
But what if it does progress to PsA?
A short digression
A project that helped to get me launched in my current career as a medical writer was a documentary film that I made some decades ago. The assignment landed in my lap – a business friend popped into my office and told me that she needed me to produce a film about systemic lupus erythematosus. I confessed that I had never heard of it. I knew, but only vaguely, that “lupus” (Latin, meaning “wolf”) was a kind of rash on the cheeks, because the rash looked like a wolf mask.
There was a meeting scheduled for the next day, and in the meantime I had to learn everything I could about this strange disease. I went to the library of the New York Academy of Medicine, up at Fifth Avenue and 103rd Street, and immersed myself.
The objective of the film was to educate dermatologists about the potentially serious and even fatal consequences of systemic lupus erythematosus, which I would from now on breezily refer to as “SLE.” Dermatologists were quickly treating SLE patients with corticosteroids. In fact, treatment was almost becoming routine. Those wolf-like rashes could reliably be made to disappear.
But then, in some cases, after the rash had been suppressed, serious complications appeared. SLE can affect many parts of the body and organ systems besides the skin. The other areas include the brain, the digestive tract, the heart, the lungs, the kidneys, and, most often, the joints. Persons with SLE whose disease initially hits one of those other parts of the body would not normally initially seek help from dermatologists, but those with the typical rash – usually called a “butterfly rash” – quite logically saw it as a skin condition and went to dermatologists. And the dermatologists treated them and went on to the next case.
The film followed several SLE patients who had developed serious complications, including one who had required a kidney transplant after her successful treatment for the skin lesions. In the film, dermatologists were urged to conduct several tests in their SLE patients, especially for anti-nuclear antibodies (ANA), and also erythrocyte sedimentation rates (ESR) – tests that dermatologists, especially in those bygone years, were not accustomed to ordering.
The unfortunate emergence of significant complications after the resolution of the skin symptoms of lupus should not be viewed as a major dereliction of responsibility on the part of the dermatology community. At the time that I delved into SLE, the etiology of this disease as an autoimmune disease had only recently been accepted, and the topical corticosteroids that addressed the skin rashes were only starting to become widely available. It’s no wonder that dermatologists did what they were trained to do and no more – i.e., treat the cutaneous conditions.
The parallels with PsO/PsA are obvious. Until recently, psoriasis was seen as no more than a skin disease, and topical treatments were only (despite the Tegrin advertising) partially effective. It’s not surprising that both dermatologists and their patients were grateful for the introduction of the current highly effective topical treatment options, and may have been content to look no further.
… but then, what to do if & when systemic complications appear?
To which, the answer – once again obvious – is, look for systemic treatment options.
In considering systemic treatment options, let’s first distinguish between the possibility that PsO progresses to PsA, and the possibility that some of the other complications mentioned earlier emerge, such as heart disease, diabetes, or inflammatory bowel diseases. In the latter case, those diseases or conditions would be treated independently from PsO – if Jeanette begins to show the signs that put her at significant risk for a heart attack or a stroke, she gets sent to a cardiologist and treated accordingly. Her dermatologist is not going to manage her cardiac risk factors.
But if she begins to have joint symptoms, it’s another matter altogether. Some dermatologists are certainly competent and comfortable in treating PsA patients systemically, but by no means are all dermatologists fully prepared to do so. Dermatologists may be somewhat more familiar with the systemic therapies that have been in use for longer, those being methotrexate (MTX) and cyclosporine. Let’s first discuss those two before moving on to the more recent options.
Cyclosporine is not a good option – it is FDA approved for psoriasis for a maximum of 1 year, but brings increased risk of kidney damage, hypertension, and lymphoma.
MTX was first used, at very high doses, as a treatment for several types of cancer. In cancer treatment, MTX functions as a cytotoxic agent – it is poisonous to cells, particularly cancer cells, but to other cells as well. MTX inhibits the synthesis of folic acid precursors, and because folic acid is essential to DNA replication in cancer cells (as well as in normal cells), MTX blocks the reproduction of cancer cells. However, the anti-cancer effects of MTX are linked to its other clearly undesirable effects, limiting the usefulness of MTX in cancer treatment.
The mechanism of MTX in treating auto-immune diseases such as RA and PsO/PsA is entirely different. MTX inhibits T cells and downregulates B cells, both of which are involved in autoimmune diseases, and also inhibits purine metabolism. In autoimmune diseases, MTX is used at much lower doses, and is considered, on balance, safe. Because of MTX’s effect on folic acid synthesis, when it is given for autoimmune diseases, it is given with folic acid supplements.
MTX is a somewhat tricky drug to manage, and some physicians, certainly including some dermatologists, may be reluctant to prescribe MTX. Even at the lower doses used in treating autoimmune diseases, patients on MTX require more attentive monitoring, especially monitoring of liver enzymes, and in some cases, liver biopsies. MTX is contraindicated in pregnancy, and can cause a range of adverse effects, including hair loss.
The advent of the biologics: where the good news starts
The first of the biologics to be approved for psoriasis was etanercept (Enbrel, from Amgen), which gained FDA approval for this indication in 2004. Etanercept was introduced about five years before that date, for the treatment of RA. Etanercept was followed by infliximab (Remicade, from Janssen/Johnson & Johnson) in 2006, adalimumab (Humira, from AbbVie), ustekizumab (Stelara, also Janssen/J & J) in 2009, and most recently secukinumab (Cosentyx, from Novartis) in 2015. And several others are getting very close to the finish line, including ixekizumab, from Lilly, and brodalumab, also from Amgen/AstraZeneca.
The first three of those – etanercept, infliximab, and adalimumab – are inhibitors of tumor necrosis factor alpha (TNFα), an inflammatory cytokine triggered by the release of T-cells. TNFα plays a valuable role in that it attacks some malignant growths, but it also attacks the surfaces of joints and causes inflammation. The TNFα inhibitors are particularly effective in addressing the joint symptoms in PsA; their effectiveness in reducing skin symptoms is based on their underlying mechanism of action. Patients with PsA who have extensive skin involvement may require treatment that specifically addresses the skin symptoms, in addition to systemic treatment.
Ustekizumab’s targets are two cytokines, interleukin 12 and 23 (IL-12, IL-23), which are also involved in the inflammatory process. In comparison with the TNFα inhibitors, ustekizumab demonstrates a high degree of efficacy in treating the skin symptoms as well as the joint symptoms. Many practitioners consider ustekizumab a significant advance over the TNFα agents.
The newest agents, secukinumab, ixekizumab, and brodalumab are IL-17 inhibitors. IL-17 is yet another pro-inflammatory cytokine involved in the pathogenesis of PsO/PsA.
Those three IL-17 agents have demonstrated better efficacy than comparable biologics, e.g.:
- In a head-to-head trial comparing secukinumab (Cosentyx) with ustekinumab (Stelara), 79% of patients treated with secukinumab attained 90% clearance of symptoms as measured by the commonly-used psoriasis area and severity index (PASI 90). It also achieved results very rapidly: 50% of secukinumab patients reached the PASI 75 marker, meaning 75% clearance, by week 4 of treatment, compared with 20.6% of those on ustekinumab.
- In a similar head-to-head trial comparing ixekizumab with etanercept, 41% of the ixekinumab patients attained PASI 90 at 12 weeks, compared with only 7% of etanercept patients, and 90% of the ixekizumab patients attained PASI 75 at that point.
- Brodalumab also trumped ustekizumab, with the endpoint being complete clearance of PsO symptoms, or PASI 100; 36% attained that marker at 12 weeks compared with 18.5% of ustekizumab patients. And 85% reached the PASI 75 marker. More recently, brodalumab has suffered a severe set-back: in a clinical trial, some patients taking brodalumab reported suicidal ideation, prompting Amgen to opt out of its collaboration with AstraZeneca. It’s worth noting that suicidal ideation, as well as completed suicides, had been observed in patients taking brodalumab, but the considered view of clinicians with long experience with the PsO/PsA spectrum has been that what is at the root of this behavior is the disease itself and not the drug used to treat it. However, the most recent news of suicidal ideation in patients taking brodalumab was obviously considered toxic to the prospects of the drug, prompting Amgen to jump ship. My guess is that brodalumab is not dead – the efficacy data are just too good.
Another candidate, Celgene’s apremilast (Otezia) has been a disappointment in the PsO/PsA spectrum; apremilast has so far demonstrated superior efficacy to placebo, but not to current biologics.
And another recent agent in this increasingly well-populated (not to say crowded) field is tofacitinib (Xeljanz, from Pfizer). It is not a biologic, but a so-called “small molecule” agent, which can be taken orally, and inhibits yet another inflammatory cytokine, called janus kinase (JAK).
The more recent agents appear to have clear advantages over the earlier agents, at least as regards the treatment of PsA. The TNFα antagonists will likely continue to be the mainstay of therapy for RA, but the drugs that target other autoimmune factors may be more effective for the treatment of the psoriasis spectrum.
… but some complications remain
The biologics have been an unquestionable boon to patients, especially patients with PsA, but at the same time, they have also unquestionably complicated the treatment decisions of dermatologists.
Let’s step back and take a look at the overall situation. First, would a responsible physician – dermatologist, primary care, or any other – have treated Jeanette with a biologic when she presented with her small patch of red, scaly skin, when a highly effective topical preparation was available? One could argue that the biologics address the underlying disease process, and so one would reasonably expect that treatment with a biologic would prevent PsO – the skin involvement – from progressing to PsA – the systemic disease affecting joints. And one could also reasonably expect that biologic treatment would diminish the likelihood that the patients would also develop the other systemic complications that go along with PsO.
On the other hand, the systemic drugs mentioned above all target one or another aspect of the body’s immune defenses, and, although they have generally good safety records, their safe use relies on careful patient monitoring by experienced clinicians. Moreover, they are quite expensive.
For those reasons, it’s unlikely that any physician would treat a patient with PsO of limited extent using a biologic. Yes, those agents are FDA-approved for treating PsO as well as PsA, but the PsO indication is essentially ancillary to the PsA indication; it was vital for those agents to demonstrate that they could treat not only the joint disease, but the cutaneous manifestations. If they had been approved only for PsA – i.e., the joint symptoms – the question would have remained whether they addressed the entire PsO/PsA spectrum. Clinicians could have said, “We already know that these drugs treat joint symptoms – we need something that treats the disease as a whole.”
But the biologics have shown great benefit in treating PsA. The physicians who are most familiar with the biologics are the rheumatologists, who have been using these drugs for a longer time in treating their patients with RA and other autoimmune diseases. This raises an important question:
Who should treat psoriatic arthritis?
Supposing Jeanette’s skin symptoms return, but with a greater degree of severity – a greater percentage of her total surface affected by the psoriatic lesion. And supposing she begins to have joint symptoms – perhaps in her hands and fingers (dactylitis), perhaps at the places where the ligaments attach to her bones (enthesitis), or perhaps in the joints in her pelvis where her hip bones attach to the base of her spine. What should her dermatologist do? Should he escalate her treatment to one of the systemic agents we have mentioned? That depends, more than anything else, on the dermatologist’s experience with these agents. As we said earlier, some dermatologists may have extensive experience, and some may have very little.
But referral to a rheumatologist is not always an option. As of the year 2010, there were only 3,920 rheumatologists in the US. There may be as many as 2.5 to 3 million persons in the US with PsA. Clearly, every patient with PsA cannot be treated by a rheumatologist. Moreover, 90% of rheumatologists practice in urban areas, and only 3% in rural areas; there are many good-sized towns, with populations greater than 200,000, with no rheumatologists, and many parts of the US where a patient would have to travel more than 100 miles to see a rheumatologist.
In contrast, there are 9,600 dermatologists in the US, and membership in the American Academy of Dermatology (AAD) is 17,000, including many physician assistants and nurse practitioners, who could be trained in the management of patients with PsA. The American College of Rheumatology (ACR) has been active in reaching out to the dermatology community to assist in the training of practitioners in the area of PsA treatment, and has also been active in creating and sponsoring training material for residents.
Primary care physicians as well as clinicians in any of a number of other specialty treatment areas can also appropriately treat persons with PsA, once these practitioners have gained a level of confidence in using the systemic agents that are effective in managing this disease.
Flags of a more cheerful hue
We started out with some unwelcome bits of information about the PsO/PsA spectrum – the unfortunate progression to more serious disease in some persons who start with skin lesions, and its overall effect on quality of life. But, even taking those black flags into consideration, your correspondent considers the overall picture to have improved significantly in recent years. Here are some banners that we can welcome:
Recognizing the link between the skin symptoms and systemic involvement increases the chances that the disease can be identified and treated earlier and more effectively.
Topical treatments for psoriasis have improved greatly since the days when coal tar preparations were the best option.
And systemic treatments have also improved greatly, both in terms of efficacy and safety, from the era when MTX was a patient’s best shot, to the current practice, when the TNFα inhibitors and other biologics are in wide use, and now to the introduction of agents that promise even greater efficacy with fewer adverse effects.
What this comes down to is that the person who develops psoriasis is much, much more likely to receive treatment that not only resolves the immediate skin symptoms, but effectively controls the systemic manifestations of this once heartbreaking disease.
* * * * * * * *
To the faithful Doc Gumshoe readers who responded to the piece about my total knee replacement, here’s a quick update: as I write this, I’m exactly seven weeks past surgery. I only need my cane to go down stairs (I can go up without the cane, but then the cane is downstairs and I’ll need it to get back downstairs, so …). I’m in hardly any pain, and my physical therapist (the Cruel Cristina) says I’m doing fabulously. (I hope she’s telling me the truth!) Excelsior! Many thanks & best to all, Michael Jorrin (aka Doc Gumshoe).