PSORIASIS

It has been shown that psoriasis has a certain genetic susceptibility. If one parent has it, the risk of their offspring to get it is 10%. If both parents suffer from this disease there is a 40% chance that their children will have it as well.

Over this genetic belief, certain infections may develop like streptococci, staphylococci, candida, trauma (Koebner Phenomenon). Also, some drugs such as β-blockers, lithium, antimalarials and certain antihypertensives, and stress can become triggers.

The lesion is characterized as a red scaling plate, which can sometimes be very pronounced. These lesions may have different sizes. From very small (guttate psoriasis), to very large and confluent (psoriatic erythroderma) which occur when psoriasis affects more than 90% of the skin.

There are several types of psoriasis:

• Guttate psoriasis: It usually presents as small plates between 2-5 mm in diameter, affecting both the trunk and limbs. There may also be lesions on the scalp. Usually affects young people and often produces tonsillitis or a toxicodermia (drug induced cutaneous reactions).
• Psoriasis in small and large plates ("vulgar psoriasis") : is the most common clinical form of psoriasis and is usually chronic with continuous outbreaks. The plates may be small, less than 3 cm, or larger. They are red, circular and may flake a lot. Appears on elbows, knees, scalp (especially behind the ears), back and navel.
• Erythroderma: means when there is an involvement of more than 90% of the skin. It may appear suddenly or progress from a previous psoriasis. It is a serious condition that requires hospitalization.
• Pustule forms: Some patients may have lesions with pus inside (pustules); either localized, for example, only on the palms or on the palms and soles of the feet. However, it may affect different areas of the skin.

Where does Psoriasis develop?

• Psoriasis of the skin folds (inverse psoriasis). Sometimes psoriasis may affect the folds (especially on armpits and buttocks). The lesions in these locations are different from the rest of the skin, characterized by red, moist lesions with sharp edges and no flaking.
• Psoriasis of the scalp. On this location psoriasis develops as a very rich, pearly peeling forming a thick layer which can sometimes cross the hairline and become visible.
• Psoriasis of the nails. Often psoriasis affects the nails. The most characteristic feature is the presence of small holes in several nails as if it was done with a pin ("pitting"). It is also common to find a whitish discoloration on the edge of the nail (leukonychia) and also a characteristic lesion called "oil stain" which is a salmon colored stain lining the whitish discoloration. Rare, but possible is the thickening of the end of the nail.
• Palmo Plantar Psoriasis. There may be a lot of scaling and deep fissures and/or swelling may develop on the fingertips (pulpitis).

Psoriasis is a chronic disease so there is no curative treatment. The objective is to try to prevent outbreaks.

Generally, the type of treatment depends on the severity of Psoriasis. When there is a mild psoriasis, topical treatment is used, mainly corticosteroid creams and / or vitamin D derivative (calcipotriol and tacalcitol).

For moderate and severe Psoriasis more potent treatments such as phototherapy or systemic treatments are used. Acitretin (a derivative of vitamin A) and also immune-suppressants such as methotrexate and cyclosporin A. Recently, more specific immune treatments so-called “biological therapy” are used. They are synthesized by biotechnology and are used for severe cases that were not able to be controlled with systemic therapy.

To prevent outbreaks early treatment of infections (especially tonsillitis) is recommended. Trauma due to scratching must be avoided, as these traumas can lead to the appearance of new lesions. It is also recommended to avoid stress and certain drugs such as lithium, beta-blockers, antimalarials, NSAIDs and systemic corticosteroids. Between outbreaks, as maintenance therapy, it is recommended to keep the skin hydrated by applying moisturizers on a daily basis. In some cases it is necessary to apply creams without corticosteroid, such as vitamin D derivatives to keep the disease under control.

Skin cells shed rapidly due to cell hyper proliferation.

Psoriasis is mediated by immune mechanisms with a genetic base. There are also environmental factors involved. Excessive inflammatory response by several mediators such as TNF-alpha occurs. There are different types of triggers:

• Physicists such as trauma
• Viral or bacterial infections
• Medication: beta blockers, ACE inhibitors, lithium, antimalarials among others
• Emotional stress

• Vulgar
• Gutatta
• Facial
• Erythrodermic
• Nail
• Scalp
• Arthropathic

It is a chronic disease for which there is no cure, but there are periods of remission.

Patients go through outbreaks and stability phases. Outbreaks typically affect the self-esteem of most patients.

Psoriasis is one of the conditions in which I have invested more effort and dedication.

Until recently dermatologists had the perception that we could not do much against a dermatosis that responded poorly to topical and systemic treatments, and had an unpredictable course. Patients felt hopeless, as if it were a biblical disease.

In my years of residence in Dermatology, during a vacation in London, I had the opportunity to learn about a treatment that offered satisfactory results known as Goekerman. It consists of applying a tar (mineral) and radiate with UVB (311 nm). Upon my return, I convinced the professor of the Clinical Hospital of Barcelona, Professor Piñol Aguadé, and my father, who had his office in Corachán Clinic, that we should introduce this treatment in our country. So the first lamps were imported to Spain.

At this time photobiology began in Dermatology; in fact, a few years after the photochemotherapy or PUVA was introduced, which consisted of associating the wall with oral psoralens and using long length (230 nm) radiation. This treatment achieved unprecedented results and extensive recalcitrant psoriasis.

As part of my training, I was also at the Mayo Clinic in U.S.A. Upon my return to Barcelona another promising treatment was introduced; oral retinoids derived from vitamin A.

I formed a Psoriasis unit at the Sagrat Cor Hospital in Barcelona, whose treatments were mostly outpatient and together with the Hospital of Sant Pau, we became the pioneers in Spain in puva therapy (therapeutic modality using long wave UV Rays).

The equipment required for this treatment is very costly such as the German Waldman Cabins. New models continue to be developed with different wavelengths, such as ultraviolet narrowband UV-B radiation. Unlike classical PUVA, the puva therapy (psoriasis) does not require administration of psoralens being a significant advantage. For instance, it does not require eye protection against ultraviolet rays during the day and does not produce digestive discomfort.

Topical treatments remain the first choice for localized psoriasis. Today they have been discovering new molecules, such as derivatives of vitamin D, potent corticosteroids or biological immunomodulators (tacrolimus), that are able to clear stubborn areas such as the scalp, nails, etc.

In these cases, our collaborators and we prescribe customized topical formulations in which we associate various active ingredients that enhance its effectiveness compared with commercial formulas. The difference is because commercial formulas use very rigid excipients and only one active principle, which reduce the efficiency on certain locations such as the scalp, nails, elbows, knees, etc.

Today we know that this is a chronic inflammatory disease of autoimmune etiology. Before we only knew part of the mechanism: the keratinocyte hyperproliferation and impaired epidermal differentiation. So we administered Methotrexate (antiproliferative cytostatic) and were getting effective results even though by then we were unaware that T lymphocytes, macrophages and different cytokines (ILK) are the main actors of the pathophysiology of the disease. Psoriasis and other autoimmune diseases benefit from biological treatments that inhibit cytokines (TNF-alpha) or monoclonal antibodies that act in other interleukin cells.

Currently the available drugs for systemic treatments are methotrexate, cyclosporine A, retinoids, photochemotherapy (PUVA) and new biological agents. Each has its indications and contraindications.

The objective is not only to clear the area in the shortest time avoiding possible side effects, but also in keeping the patient under control over an extended period of time without suffering from the disease.

Today there is no cure for psoriasis. So our goal is to keep the disease in remission. The type of treatment is decided according to the size, location and general condition of the patient.

Our residents and employees have protocols on how these drugs should be used. Below is a summary of these protocols.

Before using a systemic treatment, we usually begin with classic treatments we know best: topical retinoid treatment, puva therapy, methotrexate and cyclosporine.

“I distrust new medications on the market. I use medications that have been on the market for at least two years so that there is enough evidence of having advantages over those previously used”.

Topical treatments

Topical corticosteroids are one of the most effective treatments, if used correctly. They have different strengths and are often used in combination with other active ingredients, to multiply their effectiveness and reduce side effects.

"Patients should not be afraid to use topical corticosteroids. They are essential in treating the early stages of multiple dermatosis and if administered correctly by a specialist it should not produce side effects."

Topical corticosteroids may be associated with derivatives of vitamin D3. The skin is an organ metabolically active and can synthesize this vitamin along with ultraviolet radiation. There are vitamin D receptors in the skin.

Derivatives of vitamin D significantly improve psoriatic lesions since they inhibit keratinocyte proliferation. The most effective ones are analogs such as tacalcitol and calcitriol.

Systemic Treatments

Retinoids + topical treatment

Psoriasis patients have dry skin and suffer from water loss. Therefore it is important to moisturize the skin.

I recommend emollient oils or moisturizers without synthetic ingredients made for sensitive skin, followed by an emollient cream. I often use custom design formulations tailored to the patient’s specific needs. The formula may be an ointment, a cream, a gel, a lotion or an aerosol. May contain 2-10% urea, kola extract, aloe vera, salicylic acid, propylene glycol, corticosteroids, and derivatives of vitamin D.

By administering oral retinoids or acid-acitretino 13 retinoico- cis along with a topical treatment we can expect to get a better response than administering them separately.

Photochemotherapy: PUVA

It is associated with the administration of psoralens 8 MOP or 5 MOP taken orally 2 hours before exposure to UVA, topically ½ hour before or by the use of suppositories to avoid possible digestive problems.A series of requirements must be followed such as the energy level to be administered and the ocular protection from sunlight to be used among other conditions. Results are usually achieved with two weekly sessions for a period of 5-7 weeks.

Action mechanism: Act by forming photoactive dimers in which after irradiation cells are eliminated with suitable results for psoriatic cells: mutagenicity (interacts with DNA), immunosuppressive and antiproliferative action.

Repuva

Involves the administration of oral retinoids 10 days prior to treatment with PUVA and during treatment obtaining better results in less time than with PUVA therapy. As with other treatments, a series of recommendations must be followed.

Narrow UVB Band

This light spectrum is the most effective for psoriasis achieving similar results to PUVA therapy with additional advantages:

• Does not require administration of psoralens
• The narrowband radiation may be used in pregnant women and children. It can also be combined with oral retinoids for better results.

Methotrexate

[Protocol prepared by: Dr. V. Expósito, Dr. M. Sánchez Regaña, Dra. Maribel Iglesias, Prof. Pau Umbert]

Necessary information from each patient.

Liver disease

Kidney Disease

Gastroduodenal ulcer

Colitis

Arthropathy

Alcohol

Drugs that patients might take may interact with treatment by increasing the toxicity of methotrexate or reduce renal elimination.

Administration and Dosage

Initial dose: 5 mg with CBC before and within the next 7 days.

Maximum dose: 0.5 mg / kg (approximately 20-30 mg)

Weekly doses 5-15 mg v.o. and 25-30 mg i.m.

Taking medications orally, intramuscular or subcutaneously are equally effective.

Results may be seen in the first 7-14 days; however best results take between 4-8 weeks, although generalized pustular psoriasis may respond in 24 hours.

Folinic acid is effective if there is an MTX overdose because it reduces the absorption of dihydrofolate induced by MTX interfering in its effectiveness. Folic acid is recommended 24 hours after methotrexate administration, 1 mg / day or 5-7mg / week to reduce methotrexate toxicity.

Side Effects

Some patients have mild discomfort within 24 hours of taking the medication, but in general the side effects are less frequent.

Patient follow-up

Blood tests are taken: before treatment, seven days after starting treatment and 4-6 weeks thereafter: CBC, B12 and folic acid, urea, creatinine, transaminases, alkaline phosphatase, total bilirubin, albumin (or protein) serology hepatitis B and C (first time) and terminal peptide of procollagen III (nonspecific marker of liver fibrosis, not isolated but useful increase. Progressive elevation. Risk when above 4).

Preferably creatinine clearance or glomerular filtration rate: annual.

Chest x-ray: At beginning of treatment and annually.

Hepatic ultrasonography: every 3-4 months to see if there are any fibrosis fatty changes. If there is a change, a liver biopsy is done.

Liver biopsy (1/1000 bleeding risk and risk of death 1/10000):

Liver ultrasound (fibrosis, fatty changes).

Elevated transaminases (hepatic enzymes) (5 from 9 or 6 from 12 annual high determinations).

1,5 g of methotrexate accumulated.

Cyclosporine

[Protocol prepared by: Dr. Manuel Sánchez Regaña, Dr. Cristian Fischer Levancini, Prof. Pau Umbert - Dermatology Department of Hospital Sagrat Cor. Universitat de Barcelona]

Action Mechanism

Lipophilic cyclic peptide is isolated from fungi. Inhibits the synthesis and action of T helper lymphocytes, not so much the T suppressors or other cells such as B lymphocytes or NK cells. This differentiates it from other immunosuppressants. It interferes with the synthesis of interleukin 2. Does not alter the synthesis of red blood cells or platelets. No bone marrow toxicity occurs. Can be used during pregnancy.

Pharmacokinetics

Cyclosporine (Sandimun Neoral) is in the form of soft gelatin capsules of 25, 50 and 100 mg and 100mg oily suspension which equals 1 ml.

Capsules appear to have greater bioavailability.

Lipophilic drug: Its absorption is minimally affected by food EXCEPT for grapefruit juice which modifies it.

It is metabolized in the liver and excreted in the bile.

In children there is an increased renal depuration.

Drug Interactions

Attention with nephrotoxic drugs: aminoglycosides, anfoericina B, ciprofloxacin, trimethoprim.

Non-steroid anti-inflammatory (Minimum dose).

You can enhance the effect of lovastatin, colchicines, and neuro-muscular toxicity.

Attention with agents that intervene with cytochrome P 450.

Levels of Cyclosporine can be increased: Ketoconazole, macrolides (erythromycin, josamycin, doxycycline), oral contraceptives, calcium channel blockers (dilitiazem, nicardipine). It may be taken during pregnancy but not during breastfeeding.

Main indications

Psoriasis: dose 3-5 mg / kg / day; beginning with low dose. If within 3 weeks goal is not achieved dose is increased to 5 mg / kg. Cyclosporine starts being effective in 15 days.

It is recommended to do short courses of treatment. 3 months maximum with abrupt or gradual discontinuation (it is indifferent). Do not continue with treatment after 2 years (maximum time for therapy). It is useful in arthropathy and nail psoriasis.

Side Effects

Renal impairment: the most serious is interstitial fibrosis if treatment is continued after 2 years and high doses are administered.

Hypertension: same as above.

Hypertrichosis, gingival hyperplasia, acne, seborrhea, periungual pyogenic granulomas.

Neurological Complications

Tremor, dysesthesia and paresthesias appear at 3 months and accentuate. These are linked to a magnesium and cholesterol deficiency. It is associated with high blood pressure and peripheral vasoconstriction.

Major symptoms: seizures, hallucinations, ataxia, aphasia.

Minor symptoms: tremor, insomnia, anxiety, amnesia and headache.

Contraindications

Renal-function abnormalities.

Hepatic impairment.

Uncontrolled hypertension.

Infections with an ongoing evolution such as HIV, hepatitis B and C.

Old or concurrent cutaneous neoplasms (except BCC).

Immune deficits.

It is not teratogenic. Therefore, if necessary it may be administered during pregnancy.

Therapeutic Monitoring

Before treatment:

Blood Pressure.

Creatinine, potassium, uric acid.

Cholesterol, triglycerides.

Magnesium.

GOT, GPT, bilirubin.

HIV, HBV, HCV.

Pregnancy.

During treatment: Same as above. At first every 15 days and thereafter on a monthly basis.

Changes or Modification depending on the Therapeutic Control

If diastolic hypertension is greater than 95 (maintained): reduce dose or administer nifedipine; if there is no change within 15 days, stop treatment.

If there is an increase in creatinine (rises 30%), the dose is decreased. If treatment will last one year a glomerular filtration rate is requested.

In case of hyperlipidemia: special diet must be followed and fibrate acid will be evaluated, never HMG CoA reductase.

In case of hypomagnesemia there is a potential risk of neuro and nephrotoxicity. It is administered orally.

Biological Treatments

We are near the etiopathogenic problem of psoriasis; therefore we can act specifically on the intricacies of the inflammatory mechanism. There are 3 options:

• Modulating agents acting on T cells: alfacept and efalizumab
• Inhibitors of Factor-alpha tumor necrosis: etanercept, infliximab
• Interleukin inhibitors L12 and IL 23: Ustekinumab

Instructions for the Patient with Adalimumab, Etanercept, and Infliximab Ustekinumab

Your dermatologist will prescribe a specific treatment for patients psoriasis skin lesions. His/her quality of life will greatly improve. One of the possible risks is the development of infections. Below is a list of recommendations to prevent infections:

• Let your family doctor know that you are doing this treatment
• Avoid, if possible, contact with persons suffering from infectious diseases.
• Do not smoke
• Avoid eating cheese. Blue, roquefort and, in general, unpasteurized dairy products.
• Avoid contact with bird droppings (cleaning cages) or aquariums
• In case of fever, cough, shortness of breath, headache, sore throat or soreness in any other areas of the body or if you notice the appearance of sores or pimples with pus in any part of your body contact your Dermatologist immediately.
• Be cautious when traveling to countries with risk of infectious diseases: drink bottled water, prevent arthropod bites and get vaccinated before traveling (see which ones you can get).
• Avoid live vaccines (others like the flu vaccine, are safe).
• If patient is undergoing surgery, his/her dermatologist must be alerted.
• In case of major surgery, treatment should be discontinued 2 weeks prior and reintroduced after surgical wound has completely closed off.
• Amoxicillin may be recommended (2g 1 hour before) if going through a minor surgery.

Etanercept (Enbrel)

Since 2003 we know its safety when being used for severe rheumatoid arthritis and in severe psoriasis and 4 years the safety in severe psoriasis that has been unresponsive to conventional treatments and especially Arthropatic Psoriasis. The results appear on ¾ of patients at 3 months. In those achieved recapture was interrupted after 5 months.

Before treatment a protocol must be followed to rule out infection (tuberculosis, systemic mycosis, etc.).

There are vaccines and drug interactions with immunosuppressive treatments such as cyclophosphamide. The appearance of tumors is similar to the normal population.

Enbrel

[Protocol developed by: Dr. Sánchez Reñaga, Prof. Pau Umbert]

This is a fusion protein of human IgG1 Fc and soluble TNF receptor. Specialty of hospital diagnosis and dispensed in hospital pharmacy.

Approved indications

Moderate to severe psoriasis plaques in adult

Arthropatic Psoriasis

Rheumatoid Arthritis

Ankylosing spondylitis

Hidradenitis; atopy.

Dosage in psoriasis

50 mg subcutaneous two days a week, for 12 weeks.

Effective from the second week.

Subsequently, 25 mg two days a week, with varying duration.

Monitoring Before and After Treatment

Before treatment:

Always PPD, chest radiography.

CBC; GOT-GPT; HIV; HBV; HCV; Basic anamnesis (underlying malignancy). Discard pregnancy (category B); It is secreted through mother´s milk.

After treatment: does not require any specific monitoring. The possibility of a lymphoma developing is controlled.

Side Effects

Mild reactions at the injection site.

Sd.pseudogripal (45%).

Infections (35%) and usually mild upper respiratory tract.

ANA (11%) anti-Enbrel: rare.

No anaphylaxis.

Onset or exacerbation of heart failure or demyelinating Sd.

Drug Interactions

No drug interaction. Take caution with vaccines.

Special Considerations

It is well tolerated and easy to handle.

It is very effective.

Acts fast.

It can be used with other drugs.

Can be safe if there is a liver disease.

Patient must be evaluated periodically since there is a risk of lymphoma.

Ustekinumab (Stelara)

Stelara is certainly the ideal biological treatment for its high efficiency, safety, and comfort, as stated in the publication (Br. Journal of Dermatology, February 22, 2012).

The American National Institute of Health (NICE) has evaluated its results in clinical trials and found that it is more likely to respond to etanercept or adalimumab, but is less responsive to infliximab.

Its efficiency is 75% with weekly doses of 45-90 mg until the fourth week and thereafter every 3 months until week 40, considering that treatment can be continued or interrupted until a new outbreak.

80% of the 766 patients in the study remained on the treatment up until three years. Among those patients who continued treatment, 82% (90 mg) were receiving it every 3 months.

The comfort and convenience of administering one injection every 12 weeks is important in order to achieve greater compliance.

For all of these reasons, it is a very suitable treatment for those patients who do not respond well to other biological treatments.

The problem is its high cost. For this reason we only prescribe it for those patients that have not responded to other treatments.

BEFORE, MANY THINGS ABOUT PSORIASIS WERE UNKNOWN AND TREATMENTS WERE VERY LIMITED. TODAY THERE ARE DIFFERENT OPTIONS TO TREAT THIS ILLNESS AND GIVE OUR PATIENTS HOPE.