PSORIASIS AND PSORIATIC ARTHRITIS

• ACRONYMS AND DEFINITIONS

• AAD - American Academy of Dermatology
• ACR - American College of Rheumatology
• IL - Interleukin
• MTX - Methotrexate
• NPF - National Psoriasis Foundation
• PA - Psoriatic arthritis
• PASI - Psoriasis area and severity index
• PP - Plaque psoriasis
• RA - Rheumatoid arthritis
• RCT - Randomized controlled trial
• RF - Rheumatoid factors
• TNF - Tumor necrosis factor
• ULN - Upper limit of normal

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• EPIDEMIOLOGY

• Psoriasis affects approximately 3% of the U.S. population. Worldwide, around 125 million people have psoriasis. Men and women are affected equally, and there is a bimodal peak age of incidence at 18 - 39 years and 50 - 69 years.
• Psoriatic arthritis is thought to affect up to 30% of patients with psoriasis. It's prevalence in the general population is 0.1 - 0.2%, and it has an annual incidence of 2 - 3% among patients with psoriasis. [1,2]

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• RISK FACTORS

• Psoriasis
• Family history (most important) - risk is as high as 40% with two affected parents, 14% with one affected parent, and 6% if a sibling is affected
• Inflammatory bowel disease - the prevalence of psoriasis is much higher in patients with inflammatory bowel disease


• Psoriatic arthritis
• Severe psoriasis
• Obesity
• Scalp, genital, and intertriginous psoriasis
• Nail disease
• Deep lesions at sites of trauma


• Psoriasis triggers
• Stress
• Skin trauma
• Upper respiratory infections - upper respiratory infections like strep throat often precede the onset of guttate psoriasis
• Weather - dry and cold weather may worsen psoriasis
• Certain foods and alcohol (less common) [1,2,3]

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• TYPES AND SYMPTOMS

• Psoriasis

• Plaque psoriasis - plaque psoriasis is the most common type of psoriasis comprising 80 - 90% of all psoriasis cases. Plaque psoriasis presents as well circumscribed, itchy, scaly pink-to-red plaques that can range in size from < 1 cm to many inches wide. The scalp, trunk, gluteal fold, and extensor surfaces of the elbows and knees are most commonly affected. Lesions can also develop at sites of trauma (e.g. scratching, cuts, pressure), something known as the Koebner phenomenon. Psoriasis that occurs in the intertriginous areas (also called inverse psoriasis) often lacks the characteristic scaly appearance and is sometimes misdiagnosed as tinea. Genital psoriasis occurs in about 1/3 of affected individuals. Nail disease causes pitting, onycholysis (separation of the nail plate from the nail bed), and dystrophy. [1,3]
• Plaque psoriasis images
• Inverse psoriasis (intertriginous) images
• Psoriatic nail images

• Guttate psoriasis - guttate psoriasis accounts for 2 - 8% of psoriasis cases. Guttate psoriasis is characterized by the sudden appearance of small (3 - 5 mm), round, pink papules that are sometimes scaly. They have a scattered appearance and typically occur on the arms, legs and torso; however, the face, scalp, and ears can also be affected. Guttate psoriasis is preceded by an upper respiratory infection in 66% of cases, typically strep throat. Most cases resolve spontaneously after weeks to months, but it can become a chronic condition that requires treatment. [1,3]
• Guttate psoriasis images

• Pustular psoriasis - pustular psoriasis accounts for about 3% of psoriasis cases and is characterized by white, fluid-filled bumps surrounded by red or discolored skin. Pustular psoriasis may be generalized or localized. The localized type is typically confined to the hands and feet, where generalized pustular psoriasis (GPP) is marked by acute widespread eruptions of pustules that often coalesce to form large areas of weeping scaly skin. Episodes are typically recurrent and may be triggered by medications (e.g. lithium, aspirin, indomethacin, iodide), the sudden withdrawal of corticosteroids, pregnancy, hypocalcemia, and infections. In severe GPP, septic shock and cardiorespiratory failure can occur with a mortality of 2 - 16%. The underlying pathology in pustular psoriasis is genetic abnormalities in interleukin-36 (IL-36) receptor antagonist signaling. In 2022, a drug called Spevigo (spesolimab-sbzo) was FDA-approved to treat GPP. Spevigo is an antibody that binds IL-36 receptors, inhibiting their signaling. [Spevigo PI] [1,3,11]
• Generalized pustular psoriasis images
• Palmar and plantar pustular psoriasis images

• Erythrodermic psoriasis - erythrodermic psoriasis is a very rare, severe form of psoriasis that is marked by intense redness and shedding of the skin over large parts of the body. It can be fatal if not treated promptly. Triggers of erythrodermic psoriasis include allergic reactions to medications and infections. [1,3]
• Erythrodermic psoriasis images

• Psoriatic arthritis
• There is no single clinical or laboratory finding that definitively establishes a diagnosis of psoriatic arthritis, so it is important to distinguish psoriatic arthritis from other types of arthritis (see arthritis differential below). The diagnosis is based on a constellation of symptoms and clinical features that are discussed below.


• Psoriasis - psoriasis typically precedes the onset of psoriatic arthritis by an average of 10 years. In about 15% of patients, the rash and arthritis appear simultaneously or the arthritis precedes the rash.
• Arthritis - psoriatic arthritis is typically asymmetric and involves ≤ 4 joints. Unlike rheumatoid arthritis, the distal joints of the fingers and toes are commonly affected, and every joint in a digit may be affected while other digits are completely spared. Spine involvement and sacroiliitis are common (50% of patients). On X-ray, joint disease is marked by bone loss, joint-space narrowing, eccentric erosions, and periosteal new bone formation (e.g. ankylosis, enthesophytes) that does not include osteophytes.
• Psoriatic nail disease - psoriatic nail disease (e.g. pitting, onycholysis) is seen in 80 - 90% of patients with psoriatic arthritis
• Enthesitis - enthesitis is inflammation of the site where a tendon or ligament inserts on a bone. It is seen in 30 - 50% of patients with psoriatic arthritis, and the plantar fascia and Achilles' tendon are most commonly affected.
• Dactylitis - dactylitis is diffuse swelling of a toe or finger. Dactylitis may be acute or chronic, and it is seen in 40 - 50% of patients with psoriatic arthritis. The third and fourth toes are most commonly affected, but it also occurs in the fingers. Dactylitis is associated with a more severe disease course. [1,2]

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• PATHOLOGY

• Psoriasis
• The pathology behind psoriasis is complex and not completely understood. In short, the steps listed below are believed to represent the major processes by which the disease occurs.
• Plasmacytoid dendritic cells, macrophages, and natural killer T cells become inappropriately activated in the dermis causing them to secrete inflammatory cytokines (e.g. TNF, Interferon, Interleukin)
• Inflammatory cytokines stimulate dermal dendritic cells to migrate to lymph nodes where they release IL-12 and IL-23
• IL-12 and IL-23 stimulate naïve T cells to differentiate into subtypes 1, 17, and 22
• T-helper 17 cells secrete IL-17, which along with the other inflammatory mediators, stimulates keratinocytes to divide, promotes recruitment of immune cells into the dermis, and propagates inflammation


• Psoriatic arthritis
• In psoriatic arthritis, the abnormal signaling and immune stimulation that occurs in psoriasis progresses to involve joint synovial tissue and the surrounding bone [1,2]

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• DIAGNOSIS

• Psoriasis
• Psoriasis is typically diagnosed clinically by the appearance of the characteristic rash. If clinical diagnosis is uncertain, a biopsy can be performed. Other conditions to consider when diagnosing psoriasis include the following:
• Atopic dermatitis
• Seborrheic dermatitis
• Pityriasis rosea (may appear similar to guttate psoriasis)
• Syphilis (may appear similar to palmar and plantar pustular psoriasis)
• Cutaneous T-cell lymphoma [1]

• Psoriatic arthritis
• No diagnostic criteria for psoriatic arthritis have been published or endorsed by major professional organizations. The condition also lacks a defining laboratory or pathognomonic feature. Given this, most experts use the Classification Criteria for Psoriatic Arthritis (CASPAR) which is a set of criteria that was published in 2006 and is widely used when enrolling patients in clinical trials. The CASPAR criteria are presented in the table below. An online calculator for the criteria is available here - CASPAR online calculator. Other arthritis syndromes (see differential below) should be excluded when considering a diagnosis of psoriatic arthritis. [1,2]

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• TREATMENT

• Psoriatic arthritis
• The ACR/NPF published guidelines on the treatment of psoriatic arthritis in 2018. The guidelines divide patients into treatment-naïve and those who are already receiving therapy. Most of the recommendations are based on "low" to "very low" evidence, and they don't offer much guidance beyond the fact that TNF inhibitors are the recommended first-line biologic followed by IL-17 inhibitors and IL-12/23 inhibitors. The table below outlines the major points from the guideline. See biologics and nonbiologic systemic therapies below for a review of the different therapies.

• Reference [10]

2018 ACR/NPF Recommendations for the Treatment of Psoriatic Arthritis
Therapy classes Oral small molecules✝ Methotrexate Sulfasalazine Cyclosporine Leflunomide Apremilast TNF inhibitors Etanercept Infliximab Adalimumab Golimumab Certolizumab IL-12/23 inhibitor Ustekinumab IL-17 inhibitors Secukinumab Ixekizumab T-cell agent Abatacept JAK inhibitor Tofacitinib Upadacitinib (Rinvoq®) ✝Only apremilast is FDA-approved to treat psoriatic arthritis
All patients Weight loss if overweight Exercise Smoking cessation
Treatment-naïve patients TNF inhibitor (first-line) Oral small molecule (second-line) IL-17 inhibitor (third-line) IL-12/23 inhibitor (fourth-line)
TNF inhibitor failure Switch to different TNF inhibitor (first-line) IL-17 inhibitor (second-line) IL-12/23 inhibitor (third-line)
Oral small molecule failure TNF inhibitor (first-line) IL-17 inhibitor (second-line) IL-12/23 inhibitor (third-line)
IL-17 failure TNF inhibitor (first-line) IL-12/23 inhibitor (second-line)
IL-12/23 failure TNF inhibitor (first-line) IL-17 inhibitor (second-line)
TNF inhibitor + MTX failure Switch to different TNF inhibitor + MTX IL-17 inhibitor monotherapy IL-12/23 inhibitor monotherapy

• AAD/NPF psoriasis treatment recommendations
• The AAD/NPF psoriasis guidelines divide psoriasis therapy into 4 categories: topical, phototherapy, biologics, and nonbiologic systemic therapies. The guidelines state that most cases of mild to moderate psoriasis can be controlled with topical medications or phototherapy and that patients with moderate to severe psoriasis may require a biologic or nonbiologic systemic therapy. The topical therapy guidelines give some specifics on treatment approaches, but the biologic and nonbiologic guidelines are mainly a review of available therapies, and they do not recommend one treatment over another.
• Therapy choices in psoriasis should be individualized and take into account disease severity, disease location, medication access, costs, and patient motivation

• Disease categories
• In psoriasis, disease severity is often categorized as low, moderate, or severe, but the specifics that define these classes are inconsistent across the medical literature. Body surface area (BSA) affected is one of the more common methods for categorizing patients, and it is defined below.
• Psoriasis categories based on body surface area (BSA):
• Mild psoriasis: < 3% of BSA
• Moderate psoriasis: 3 - 10% of BSA
• Severe psoriasis: > 10% of BSA
• Body surface area of 1% = Surface area of the palmar surface of an individual's hand

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• TOPICAL THERAPY

• Overview
• The AAD/NPF guidelines for the topical treatment of psoriasis are presented in the table below. The guidelines do not recommend one therapy over another, but they do offer some guidance in treating different types of psoriasis.

• ^✝Steroid-sparing agents include vitamin D analogues, topical retinoids, and calcineurin inhibitors
• Reference [7]

AAD / NPF 2020 Guidelines for Topical Therapy in Psoriasis
Plaque psoriasis Steroids and vitamin D analogues Class 1 - 5 topical steroids twice daily (see topical steroid table) for up to 4 weeks is recommended. Topical steroids for > 12 weeks can be considered if under close supervision of a physician. Use of combination treatments with vitamin D analogues and potent Class II and Class III topical steroids up to 52 weeks is recommended for the treatment of psoriasis The application of morning high potency topical steroids and evening topical vitamin D analogues is an effective treatment regimen Tacrolimus The combination of Tacrolimus 0.1% and 6% salicylic acid for 12 weeks may be considered Tazarotene Topical tazarotene can be used for the treatment of mild to moderate psoriasis. The use of mid-potency or high-potency topical steroid in combination with tazarotene for 8 - 16 weeks is more effective than monotherapy with tazarotene and is recommended for the treatment of mild to moderate psoriasis. The use of topical steroids along with tazarotene is recommended to decrease the duration of treatment as well as increase the length of remission Salicylic acid Topical salicylic acid can be used for 8 - 16 weeks for the treatment of mild to moderate psoriasis The combination of salicylic acid with topical corticosteroids can be used for the treatment of moderate to severe psoriasis (BSA ≤ 20%) Other Non-medicated moisturizers (i.e., creams, ointments, lotions, gels, etc.) can be used with steroids to help reduce itching, desquamation, and total body surface area and prevent quick relapse of psoriasis when topical corticosteroids are discontinued Coal tar preparations are recommended for the treatment of mild to moderate psoriasis
Maintenance therapy regimens Steroid-sparing agent✝ twice daily on weekdays and steroid twice daily on weekends is one regimen that may prevent relapses. Twice weekly treatment of areas that are prone to flares is another approach that may be effective. The long-term use of topical vitamin D analogues (up to 52 weeks) including calcipotriene, calcitriol, tacalcitol, and maxacalcitol is recommended for the treatment of mild to moderate psoriasis. Tacalcitol and maxacalcitol are not available in the U.S.
Scalp psoriasis Class 1 - 7 topical steroids (see topical steroid table) for a minimum of up to 4 weeks is recommended as initial and maintenance treatment of scalp psoriasis Use of calcipotriene foam and calcipotriene plus betamethasone dipropionate gel is recommended for 4 - 12 weeks for the treatment of mild to moderate scalp psoriasis Foams and solutions may be preferred on the scalp because they are less greasy than ointments and creams
Intertriginous (inverse) psoriasis Tacrolimus 0.1% or Pimecrolimus 1% for up to 8 weeks. Long-term use can be considered.
Facial psoriasis Tacrolimus 0.1% for up to 8 weeks Topical tacalcitol ointment or calcipotriene combined with hydrocortisone for 8 weeks can be used for the treatment of facial psoriasis
Nail psoriasis Topical vitamin D analogues combined with betamethasone dipropionate can be used Topical tazarotene can be used for the treatment of nail psoriasis
In combination with systemic therapies Biologics The addition of an ultra-high potency (Class 1) topical corticosteroid to standard dose etanercept for 12 weeks is recommended for the treatment of moderate to severe psoriasis The addition of calcipotriene/betamethasone to standard dose adalimumab for 16 weeks is recommended for the treatment of moderate to severe psoriasis to accelerate clearance of psoriatic plaques All topical steroids can be used in combination with any biologics for the treatment of moderate to severe psoriasis Methotrexate The addition of topical calcipotriene to standard dose methotrexate therapy is recommended for the treatment of moderate to severe psoriasis. It may lead to lower cumulative doses of methotrexate and increased time to relapse following methotrexate discontinuation. Cyclosporine The addition of calcipotriene/betamethasone dipropionate ointment to low dose (2 mg/kg/day) cyclosporine can be used for the treatment of moderate to severe psoriasis Acitretin The addition of calcipotriene to standard dose acitretin is recommended for the treatment of moderate to severe psoriasis.

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• BIOLOGIC THERAPY

• Overview
• Biologic therapies have revolutionized the treatment of psoriasis. Four classes of biologics are approved to treat psoriasis, and five classes are approved to treat psoriatic arthritis. The table below lists each biologic by class and includes results from studies where the drug was compared to placebo and other therapies if available. Endpoints in psoriasis trials are typically measured by improvement in the Psoriasis Area and Severity Index (PASI). The index is explained here - PASI score explanation - and an online calculator is available here - PASI online calculator. Endpoints in psoriatic arthritis trials typically use the ACR20 response which is explained here - ACR20 response.

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• NONBIOLOGIC SYSTEMIC THERAPY

• Overview
• Some nonbiologic systemic therapies have been used for many years to treat psoriasis and psoriatic arthritis (e.g. methotrexate, cyclosporine, acitretin) while others have only become available recently (e.g. apremilast, tofacitinib). Nonbiologic therapies have largely been replaced by biologics which are typically less toxic and more effective, but nonbiologics like methotrexate are very cheap and may still be preferred in cost-sensitive patients.
• The table below details the available therapies

• Reference [9,10]

Nonbiologic Systemic Therapies for Psoriasis
FDA-approved therapies
Methotrexate (MTX) MTX is FDA-approved for the treatment of psoriasis The ACR/NPF guidelines list MTX as a possible treatment for psoriatic arthritis MTX has a cheap generic Dosing See methotrexate Efficacy (PASI 75% for PP | ACR20 for PA) PP: Adalimumab - 80%, MTX - 35.5% (16 weeks) [PMID 18047523] PP: Infliximab - 78%, MTX - 42% (16 weeks) [PMID 21910713] PA: Etanercept - 60.9%, MTX - 50.7%, Etanercept + MTX - 65% (24 weeks) [PMID 30747501] Contraindications / Precautions / Drug interactions Patients with psoriasis are more susceptible to liver toxicity from methotrexate, and monitoring recommendations differ from other indications See methotrexate Side effects See methotrexate
Apremilast (Otezla®) Apremilast is FDA-approved for the treatment of psoriasis and psoriatic arthritis Apremilst is an oral small-molecule inhibitor of phosphodiesterase 4 Apremilast has no generic, and it is very expensive Dosing See apremilast Efficacy (PASI 75% for PP | ACR20 for PA) PP: Placebo - 6%, Apremilast - 41% (16 weeks) [PMID 22748702] PP: Etanercept - 48.2%, Apremilast - 39.8% (16 weeks) [PMID 27768242] PA: Placebo - 19%, Apremilast - 40% (16 weeks) [PMID 24595547] Contraindications / Precautions / Drug interactions See apremilast Side effects See apremilast
Cyclosporine (Neoral®, Sandimmune®) Cyclosporine is FDA-approved for the treatment of psoriasis The ACR/NPF guidelines list cyclosporine as a possible treatment for psoriatic arthritis Cyclosporine has many side effects and is only recommended in severe, recalcitrant psoriasis Cyclosporine has a generic Dosing See cyclosporine Efficacy (PASI 75%) A systematic review found that cyclosporine doses of 5 mg/kg produced PASI 75 responses in 50 - 97% of patients and doses of 2.5 mg/kg produced a response in 28 - 85% [PMID 21388455] Contraindications / Precautions / Drug interactions See cyclosporine Side effects See cyclosporine
Tofacitinib (Xeljanz®) Tofacitinib is FDA-approved for the treatment of psoriatic arthritis Tofacitinib is a janus kinase (JAK) inhibitor Tofacitinib does not have a generic and is expensive Dosing See tofacitinib Efficacy (PASI 75% for PP | ACR20 for PA) PA: Adalimumab - 52%, Placebo - 33%, Tofacitinib (5 mg) - 50%, Tofacitinib (10 mg) - 61% (3 months) [PMID 29045212] PP: Etanercept - 58.8%, Placebo 5.6%, Tofacitinib (5 mg) - 39.5%, Tofacitinib (10 mg) - 63.6% (12 weeks) [PMID 26051365] Contraindications / Precautions / Drug interactions See tofacitinib Side effects See tofacitinib
Upatacitinib (Rinvoq®) Upadacitinib is FDA-approved for the treatment of psoriatic arthritis Upadacitinib is a janus kinase (JAK) inhibitor Upadacitinib does not have a generic and is expensive Dosing See upadacitinib Efficacy (ACR20) PA: Adalimumab - 65%, Placebo - 36%, Upadacitinib - 71% (12 weeks) [PMID 33789011] Contraindications / Precautions / Drug interactions See upadacitinib Side effects See upadacitinib
Acitretin (Soriatane®) Acitretin is FDA-approved for the treatment of psoriasis Acitretin is a retinoid much like the drug isotretinoin (Accutane®) that is used to treat acne Acitretin has a generic, but is still somewhat expensive (> $200/month) Dosing 10 - 50 mg once daily Efficacy (PASI 75%) PP: Acitretin 25 mg/day - 47%, Acitretin 35 mg/day - 69%, Acitretin 50 mg/day - 53% (12 weeks) [PMID 22816881] Contraindications / Precautions / Drug interactions Acitretin is teratogenic and has strict prescribing guidelines (see acitretin prescribing program) See Soriatane PI Side effects Like isotretinoin, acitretin can have a significant drying effect See Soriatane PI
Non-FDA approved therapies
Dimethyl fumarate The AAD/NPF guidelines list dimethyl fumarate as a possible treatment for psoriasis Dimethyl fumarate activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. Nrf2 activation leads to a reduction in the release of inflammatory cytokines, and it also has antioxidant effects. Dimethyl fumarate is FDA-approved to treat multiple sclerosis but not psoriasis Patients with multiple sclerosis and psoriasis may want to try dimethyl fumarate to treat both Dimethyl fumarate has a generic but is still very expensive
Azathioprine The AAD/NPF guidelines list azathioprine as a possible treatment for psoriasis. They recommend a starting dose of 0.5 mg/kg and state that the usual dose in psoriasis is 75 - 150 mg/day. Azathioprine inhibits ribonucleotide synthesis which either directly or indirectly leads to T-cell suppression Azathioprine has a generic and is cheap
Leflunomide The AAD/NPF guidelines list leflunomide as a possible treatment for psoriasis, and the ACR/NPF guidelines list it as a possible treatment for psoriatic arthritis Leflunomide is an isoxazole immunomodulatory agent which inhibits dihydroorotate dehydrogenase, an enzyme involved in de novo pyrimidine synthesis Leflunomide was compared to placebo for the treatment of psoriasis and psoriatic arthritis in this trial - PMID 15188371 Leflunomide has a generic and is cheap
Sulfasalazine The ACR/NPF guidelines list sulfasalazine as a possible treatment for psoriatic arthritis Sulfasalazine was compared to placebo for the treatment of psoriatic arthritis in these trials - PMID 8670601, PMID 8587078, PMID 8961906 Sulfasalazine has a generic and is cheap
Hydroxyurea The AAD/NPF guidelines list hydroxyurea as a possible treatment for psoriasis Hydroxyurea is an antineoplastic agent that inhibits ribonucleotide reductase. Hydroxyurea is primarily used to treat sickle cell disease. The AAD/NPF recommend an initial dose of 500 mg twice daily with titration to 1500 mg/day as tolerated Hydroxyurea has a generic and is cheap

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• PHOTOTHERAPY

• Phototherapy has been used for decades to treat psoriasis, but with the advent of biologic therapies, it is used less frequently today. UV light works by inducing apoptosis in keratinocytes, inhibiting angiogenesis, and decreasing T-cell number in the skin. Phototherapy machines deliver therapeutic wavelengths of light while limiting wavelengths that are carcinogenic. Phototherapy can be targeted if lesions are localized or full body if extensive. Therapy is typically performed 2 - 3 times a week in a healthcare office or at home. UV-B machines are preferred, but UV-A in combination with a topical psoralen (PUVA therapy) can also be used. [1,3]

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• BIBLIOGRAPHY

• 1 - PMID 29893227 - Pathophysiology, Clinical Presentation, and Treatment of Psoriasis, JAMA (2020)
• 2 - PMID 28273019 - Psoriatic Arthritis, NEJM (2017)
• 3 - National Psoriasis Foundation website
• 4 - PMID 15222650 - Spondyloarthropathies, Am Fam Physician, (2004)
• 5 - Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy, Medscape
• 6 - Reactive arthritis, Medscape
• 7 - PMID 32738429 - Joint AAD-NPF Guidelines of care for the management and treatment of psoriasis with topical therapy and alternative medicine modalities for psoriasis severity measures, J Am Acad Dermatol (2020)
• 8 - PMID 30772098 - Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics, J Am Acad Dermatol (2019)
• 9 - PMID 32119894 - Joint American Academy of Dermatology/National Psoriasis Foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies, J Am Acad Dermatol (2020)
• 10 - PMID 30499246 - 2018 American College of Rheumatology/National Psoriasis Foundation Guideline for the Treatment of Psoriatic Arthritis, Arthritis Rheumatol (2019)
• 11 - PMID 34936739 - Trial of Spesolimab for Generalized Pustular Psoriasis, NEJM (2021)