*2.3.1 Methotrexate*

Methotrexate is a folic acid analogue employed in psoriasis for its anti-proliferative, anti-inflammatory and immunosuppressive actions [40].

*Dosage and administration*. Methotrexate comes as a self-injectable solution administered by the patient weekly, with the added proposal of coupling with folic acid supplements. Initiation dosage is typically 10–25 mg once per week. Maximum dose should not surpass 30 mg/week. Folate intake should be about 1–5 mg daily, except on the day of methotrexate intake [41].

*Adverse effects*. In case of pregnancy, it may lead to foetal death or to teratogenic effects; also, it can be toxic to the gastrointestinal tube, liver and kidneys, and it can cause myelosuppression, malignant lymphomas, pulmonary fibrosis, severe infections, fatigue, headaches, alopecia or oligospermia [42, 43].

*Laboratory tests recommended*. To start therapy with methotrexate correspondingly, the following evaluations are compulsory: physical exam, patient history, QuantiFERON-TB Gold for latent TB infection, complete blood count with differential and thrombocytes count, renal function tests, hepatic enzymes and pregnancy test.

*Drug interactions*. Methotrexate has been shown to interact with cyclosporine, proton pump inhibitors, oral antibiotics, salicylates, mercaptopurine, nonsteroidal anti-inflammatory drugs, cisplatin, probenecid, phenylbutazone, sulfonamides, theophylline, live vaccines, retinoids and azathioprine [43].

As anticipated, this drug is contraindicated in pregnancy and while breastfeeding due to its teratogenic effects. Therefore, the use of contraception is highly advocated in the course of treatment. Other contraindications include blood dyscrasia, chronic liver disease, immune deficiency syndromes or alcohol abuse [44].

### *2.3.2 Cyclosporine*

Cyclosporine is a calcineurin inhibitor agent that is used in psoriasis for its immunosuppressing action and its capability to prevent the T cell proliferation by reversibly inhibiting the activation of CD4+ T cells, leading to a block on the synthesis of interleukin 2 [45].

*Dosage and administration*. To induct psoriasis remission, the everyday dosage varies between 2.5 and 5 mg/kg, administered in two divided doses each day. Experts recommend it not be used continuously for longer than 1 whole year [46].

*Adverse effects*. Among the most important reported adverse effects of cyclosporine are renal toxicity, structural kidney damage, hypertension, liver toxicity, severe infections, high potassium levels, low magnesium levels, acne, tremors, headache, pneumonitis and gastrointestinal toxicity [47, 48].

*Laboratory tests recommended***.** Physical exam, patient history, QuantiFERON-TB Gold for latent TB infection, renal function tests, complete blood count with differential and platelet count, magnesium level, potassium level, uric acid, lipids, glycaemia, bilirubin and liver enzymes are necessary before initiating therapy. The serum creatinine should be measured on two distinct occasions. Contraception has to be ensured.

*Drug interactions*. Cyclosporine interacts with a large number of drugs such as antibiotics (ciprofloxacin, gentamicin, tobramycin, vancomycin, trimethoprim with sulfamethoxazole, azithromycin, erythromycin), nonsteroidal anti-inflammatory drugs, antifungals (amphotericin B, ketoconazole, fluconazole, itraconazole, terbinafine), ranitidine, cimetidine, birth control pills, tacrolimus, methotrexate, methylprednisone, allopurinol, colchicine, fenofibrate, gemfibrozil, statins, calcium channel blockers, amiodarone, bromocriptine, anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital), protease inhibitors (indinavir, nelfinavir, ritonavir, saquinavir) and octreotide [48].

It is contraindicated in the case of poorly controlled arterial hypertension, known malignancies or renal dysfunctions. As of yet, there have not been enough studies performed in humans to certify whether the drug affects the foetus or not. Nonetheless, the treatment is still to be avoided in pregnant women due to the role calcineurin inhibitors are believed to play in neural development. As such, cyclosporine should only be used in pregnancy if the benefits justify the hypothetical risk to the foetus [49].

#### *2.3.3 Acitretin*

Acitretin is a retinoid agent with substantial immunomodulatory and antiinflammatory effects, advocated in psoriasis for its capacity to modulate the proliferation and differentiation of keratinocytes [50].

*Dosage and administration*. Acitretin is taken in a single oral dose, alongside the main meal. Therapeutic dosage varies between 25 and 50 mg/day. A simultaneous topical therapy is also suggested due to the slow onset of action, needing as long as 3–6 months for a maximal response to acitretin [51].

*Adverse effects***.** It can cause serious teratogenic effects on the exposed foetus, mucocutaneous dryness, hypertriglyceridemia, hepatotoxicity, toxic hepatitis, pancreatitis, hyperostosis, intracranial hypertension, alopecia, arthralgia and fatigue [52].

*Laboratory tests recommended*. It is compulsory to take a pregnancy test before initiating the treatment; liver enzymes, lipid profile, renal function and complete blood count should also be included.

*Drug interactions***.** Acitretin interacts with retinoic acid supplements, methotrexate, doxycycline, oral retinoids and phenytoin [53].

The high teratogenicity of retinoids severely restricts their use in fertile women who should be appropriately counselled on the methods and importance of contraception [54]. Moreover, pregnancy should be circumvented for at least 3 years after

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*Medical Management of Chronic Plaque Psoriasis in the Modern Age*

halting treatment. A pregnancy test is to be performed regularly every 3 months

Fumaric acid esters and dimethyl fumarate have been employed in the treatment of psoriasis for five decades, with substantial outcomes for patients [55]. Seemingly, dimethyl fumarate affects multiple cytokines and lymphocyte pathways, i.e. inhibiting the nuclear translocation and the transcriptional activity of the nuclear factor kappa-light-chain-enhancer of activated B-cells through its interaction with the intracellular reduced glutathione. It also transforms the T helper cells from the Th1 and the Th17 profile to a Th2 phenotype, subsequently reducing cytokine produc-

*Dosage and administration*. It is available as gastro-resistant tablets, being recommended to start with a low initial dose that may be subsequently increased in the following manner: in the first week, it is advised to take one 30 mg tablet, in the second week one 30 mg tablet can be taken twice daily, and during the third week one 30 mg tablet is taken three times per day. From the fourth week onwards, it can be switched to one 120 mg tablet, taken in the evening. Depending on the results, this dose can be increased with one 120 mg tablet per week, but the maximum daily

*Adverse effects*. Among more regularly reported events are gastrointestinal disorders, flushing, haematological disturbances (lymphopenia, leukopenia, eosinophilia), loss of appetite, headache, paraesthesia, proteinuria, renal failure,

*Reference tests*. Complete blood count, renal function and liver enzymes should

*Drug interactions***.** Fumaric acid esters may interact with live vaccines, methotrexate, retinoids, cyclosporine, aminoglycosides, lithium, diuretics and nonsteroi-

Apremilast, operating as a selective inhibitor of phosphodiesterase 4, on the one hand downregulates the expression of specific proinflammatory cytokines like IL-17, IL-23 and TNF-α that each plays a crucial role in the pathophysiological chain of events in psoriasis. On the other hand, using the same mechanism, it increases

*Dosage and administration*. Presented in tablet form, apremilast is administered orally, with an indicated dose of 30 mg two times per day. The treatment should begin with a low starting dose of 10 mg in the morning, and then from the second day of therapy onward the dosage is increased daily by 10 mg until reaching the

*Adverse effects*. Diarrhoea, nausea and vomiting, depression and weight loss are

*Laboratory tests recommended*. Physical exam, patient history (with an emphasis

*Drug interactions*. Apremilast interacts with cytochrome P450 enzyme inducers

on psychiatric disorders such as depression), renal function and liver enzymes

Patients over 65 years old appear to be more vulnerable to develop the aforementioned side effects. Hence, supervision is very important in these cases, patients being warned regarding undesirable events. They should also be

such as rifampin, phenobarbital, carbamazepine and phenytoin [61].

the expression of anti-inflammatory cytokines such as IL-10 [59].

the most frequently noted adverse effects of apremilast [62].

therapeutic dose of 30 mg twice daily [60, 61].

*DOI: http://dx.doi.org/10.5772/intechopen.90626*

*2.3.4 Fumaric acid esters and dimethyl fumarate*

tion and the proliferation of epithelial cells [56].

dose should not exceed 720 mg [57].

Fanconi syndrome and fatigue [58].

dal anti-inflammatory drugs [59].

be included.

*2.3.5 Apremilast*

should be performed.

during the course of therapy.

halting treatment. A pregnancy test is to be performed regularly every 3 months during the course of therapy.
