Psoriatic arthritis

 

Salient features

• Psoriatic arthritis is a progressive inflammatory arthritis occurring in about a third of people with psoriasis.
• Genetic and environmental factors underlie susceptibility to PsA and immune-mediated inflammation leads to inflammation in musculoskeletal structures.
• Clinical presentation is heterogeneous and includes the following manifestations: peripheral arthritis, spondyloarthritis (inflammatory arthritis of the spine), enthesitis (inflammation at the insertion sites of ligaments and tendons onto bone), dactylitis (full-thickness inflammatory swelling of an entire finger or toe) and tenosynovitis.
• Associated extra musculoskeletal manifestations in addition to skin and nail psoriasis are inflammatory eye disease and inflammatory bowel disease.
• Serology for the rheumatoid factor is usually negative and inflammatory markers may be normal.
• Radiographs may reveal soft-tissue swelling, periostitis, erosions, pencil-in-cup change, ankylosis, sacroiliitis, or syndesmophytes.
• Prompt recognition, pharmacologic treatment, and disease monitoring are necessary to prevent damage and improve long-term outcomes for psoriatic arthritis. 

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Introduction

 

Psoriatic arthritis is a seronegative inflammatory arthritis causing destructive to joints and which occurs in up to 40% of patients with moderate to severe cutaneous psoriasis with usually a negative serological test for rheumatoid factor and the absence of rheumatoid nodules. Genetic and environmental factors underlie susceptibility to PsA and immune-mediated inflammation leads to inflammation in musculoskeletal structures.

Psoriatic arthritis appears more common in individuals with type 1 early-onset psoriasis vulgaris. In contrast to rheumatoid arthritis, where females predominate 3: 1, in psoriatic arthritis the sexes appear equally affected, although men may have more axial disease and less peripheral arthritis. In 70% of patients, the skin psoriasis develop prior to joint disease, in 20% of patients, the joint disease presents first and in 10% the skin and joints are affected concurrently. Currently, there are no specific serologic tests for establishing the diagnosis of psoriatic arthritis, but an important hallmark is erosive change radio graphically, which may occur years after the presenting peri-articular inflammation. Psoriatic arthritis is more prevalent among patients with relatively severe psoriasis. Risk factors for a more severe course of the arthritis include: initial presentation at an early age, female gender, polyarticular involvement, genetic predisposition, and radiographic signs of the disease early on.

 

Classification of Psoriatic Arthritis (CASPAR) criteria for psoriatic arthritis

To be characterized as having psoriatic arthritis, a patient with inflammatory articular disease (joint, spine or entheseal) must have three or more points from five categories. Each category scores a maximum of 1 point, except category 1, which scores 2 points for current psoriasis

Psoriasis	Current psoriasis	2
	Personal history of psoriasis	1
	Psoriasis in a first‐ or second‐degree relative	1
Typical psoriatic nail involvement		1
A negative test for rheumatoid factor		1
Dactylitis (inflammation of an entire finger or toe)	Current dactylitis	1
	History of dactylitis	1
Radiological evidence of juxta‐articular new bone formation of hands or feet		1

 

 

Current psoriasis is defined as psoriatic skin or scalp disease present today as judged by a rheumatologist or dermatologist. A personal history of psoriasis is defined as a history of psoriasis that may be obtained from a patient, family physician, dermatologist, rheumatologist, or other qualified health care provider. A family history of psoriasis is defined as a history of psoriasis in a first- or second-degree relative according to patient report.

Typical psoriatic nail dystrophy including onycholysis, pitting, and hyperkeratosis observed on current physical examination. A negative test result for the presence of rheumatoid factor by any method except latex but preferably by enzyme-linked immunosorbent assay or nephelometry, according to the local laboratory reference range.

Either current dactylitis, defined as swelling of an entire digit, or a history of dactylitis recorded by a rheumatologist. Radiographic evidence of juxtaarticular new bone formation, appearing as ill-defined ossification near joint margins (but excluding osteophyte formation) on plain radiographs of the hand or foot.

 

Epidemiology

 

Age at onset

 

The majority of patients develop psoriatic arthritis before the age of 40 years. Childhood onset is rare.

 

Associated diseases

 

There is an association between more severe cutaneous psoriasis and the development of psoriatic arthritis. The prevalence of psoriatic arthritis is also increased in patients with nail and scalp psoriasis.

 

Extra-articular involvement in addition to skin and nail involvement may include ocular and inflammatory bowel disease. Ocular diseases occur in up to 30% of patients with psoriatic arthritis. The majority of these patients develop conjunctivitis with uveitis. Iridocyclitis, keratoconjunctivitis sicca and cataracts have also been reported. 

 

Causes

 

Psoriatic arthritis may be triggered by trauma to a joint or tendon – the so‐called deep Koebner effect. Cigarette smoking and excess alcohol intake is also associated with the disease. HIV infection is associated with the initiation or worsening of psoriatic arthritis whereas rheumatoid arthritis improves in HIV infection. In contrast to cutaneous psoriasis, streptococcal infection, medications such as lithium or psychological stress do not appear to be triggers of psoriatic arthritis. Similar to psoriasis, there is an increased incidence of obesity and the metabolic syndrome in patients with psoriatic arthritis. Premature cardiovascular disease is also associated with psoriatic arthritis.

 

Pathophysiology

 

The pathophysiology of psoriatic arthritis is similar to psoriasis with immune activation in the synovium and enthesis of affected joints. There is activation of both innate and adaptive immune cells with overproduction of multiple cytokines including TNF‐α, IL‐17 and IL‐23. Angiogenesis is increased in the synovium and appears to be more prominent than in rheumatoid arthritis. In response to the inflammation, joint fibrosis occurs. There may be erosion of bone with abnormal bone formation occurring simultaneously, resulting in joint deformities and loss of function.

There are important differences, however, in the inflammatory process in the joint compared to the skin. IL‐17, Th17 cells and IL‐23 production appear to be less prominent in psoriatic synovitis compared to the skin. These differences in pathophysiology may influence the observed differential therapeutic responses between the skin and joints to systemic and biological treatments.

 

Clinical features

 

Clinical features of PsA include peripheral and axial arthritis, enthesitis, dactylitis, and tenosynovitis.

Symptoms of inflammatory joint disease (early morning stiffness and joint swelling) should be ascertained. Early morning back stiffness may be the only clinical feature of sacro‐iliitis or cervical spondylitis. Heel pain (a manifestation of enthesitis of the Achilles tendon) or plantar fasciitis may also be a presenting feature.

 

Identifying Patients with Active Psoriatic Arthritis (PsA)

Patients with active PsA may experience a largely musculoskeletal disease course involving joint erosion/damage, enthesitis, dactylitis, tenderness and swelling, and may present with skin lesions. Irreversible joint damage and PsA progression begin within the first 2 years after disease onset.

 

Patients may present with:

·        Worsening symptoms

·        Synovitis

·        Dactylitis

·        Enthesitis

·        Skin lesions

 

 

Psoriatic arthritis phenotypes according to Moll and Wright

1.   Asymmetric oligoarthritis >70%

2.   Symmetric polyarthritis similar to rheumatoid arthritis 5%

3.   Spondyloarthritis    5%

4.   Distal interphalangeal joint arthritis   5%

5.   Arthritis mutilans    5%

 

Mono- and asymmetric oligoarthritis

Inflammation of the interphalangeal joints – both distal (DIP) and proximal (PIP) – of the hands and feet is the most common presentation of psoriatic arthritis. Involvement of the PIP or both the DIP and PIP joints of a single digit can result in the classic “sausage” digit. In contrast to rheumatoid arthritis, the metacarpophalangeal (MCP) joint is an unusual site for psoriatic arthritis. This form may be accompanied by inflammation of larger joints.

 

Arthritis of the distal interphalangeal joints

Exclusive involvement of the DIP joints is a classic but uncommon presentation of psoriatic arthritis and it may occur in conjunction with contiguous nail involvement. In some patients, these joints will become fixed in a flexed position.

 

Rheumatoid arthritis-like presentation (difficult to distinguish from RA clinically)

The clinical manifestations consist of a symmetric polyarthritis that involves small and medium-sized joints, in particular the PIP, MCP, wrist, ankle and elbow. Patients are usually seronegative, but some have a positive rheumatoid factor.

 

Arthritis mutilans

Fortunately, this is the least common variant of psoriatic arthritis. Patients have severe, rapidly progressive joint inflammation that results in destruction of the joints and permanent deformity. The digits become shorter, wider and softer to palpation because of osteolysis and a telescoping phenomenon.

 

Spondylitis and sacroiliitis (also have peripheral joint involvement)

The spondylitis resembles that seen in ankylosing spondylitis, with axial arthritis as well as involvement of the knees and sacroiliac joints; many patients also have peripheral joint involvement. Individuals are often HLA-B27-positive and may have associated inflammatory bowel disease and/or uveitis.

Asymmetric oligo‐arthritis is the commonest variety followed by symmetric polyarthritis.

 

DIP involvement is observed in ~40% of the patients with arthritis, and 5% suffered from arthritis mutilans. Patients with psoriatic arthritis can have involvement of juxta-articular tendons and the sites where they insert into bone (entheses) as well as swelling of the fingers (dactylitis). Enthesitis and dactylitis have been reported in about ~20% of patients with psoriatic arthritis.

 

 

 

 

Investigations

 

Investigations include tests for inflammation (including C‐reactive protein and erythrocyte sedimentation rate), uric acid, rheumatoid factor and anticyclic citrillated peptide (CCP) antibodies. Plain X‐rays of the hands and feet may be useful in detecting erosive disease but plain X‐rays have a low diagnostic sensitivity in early disease. Other imaging modalities such as ultrasound or magnetic resonance imaging (MRI) are useful in assessing enthesitis, and MRI is the modality of choice for assessing axial disease.

 

Treatment

 

Pharmacotherapy is the cornerstone of management of PsA. Drug therapy depends on the severity and stage of the arthritis and severity of skin disease. Patients should ideally be under the care of a team of health professional comprising rheumatologists, dermatologists, physiotherapists, and occupational therapists. However, if the primary problem is skin disease and the arthritis is mild, the subject may be managed by a dermatologist after a complete assessment by a rheumatologist. Periodic assessment by a rheumatologist in such cases would be ideal. On the other hand, if the primary problem is joint disease, the rheumatologist should primarily manage the patient, with the dermatologist confirming the diagnosis of psoriasis and providing input if skin disease remains poorly controlled.

 

 

Drug Therapy for PsA 

·       Symptom modifying therapy ·       Therapy with “Disease modifying” Antirheumatic Drugs (DMARDs) ·       Therapy with biologic agents

 

Early treatment is important as early interventions may prevent irreversible joint damage.

The main treatments have been NSAIDs, oral corticosteroids, methotrexate, sulphasalazine, leflunomide and TNFi. Ustekinumab and apremilast have been licensed recently for the treatment of psoriatic arthritis. A single agent that combines efficacy on both the skin disease and the arthritis is preferred. In practice, in those patients with moderate to severe skin disease this currently means either methotrexate or TNFi.

 

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs are useful in the treatment of PsA and give relief to symptoms such as pain and stiffness. However, NSAIDs do not prevent disease progression, and may worsen skin lesions. They may be used as sole therapy in treating mild PsA and for symptomatic management of pain, inflammatory swelling and morning stiffness. With the recent reports of increased risk of myocardial infarction and stroke with long term use of COX-2 inhibitors, the use of nonselective NSAIDs like naproxen, ibuprofen, diclofenac, indomethacin, or aspirin (with or without misoprostol/H2-blockers/proton pump inhibitors) is preferable. If symptoms persist, or if more joints accrue after adequate trials with two different NSAIDs, Disease Modifying Antirheumatic Drug (DMARD) use should be considered.

 

Corticosteroids

Corticosteroid therapy in the form of intra-articular injections of corticosteroids (triamcinolone) into the joints either at the bedside in the clinic or under ultrasound guidance is often used for rapid relief of symptoms when only one or a few joints are affected. This form of therapy has been proven effective in PsA. Oral corticosteroids are used occasionally for symptom relief when there is polyarthritis or when there is inadequate response to NSAIDs and there is significant disability. However, oral steroids need to be used with extreme caution with slow taper, since psoriasis worsens in many instances and could occasionally evolve into more severe forms like pustular psoriasis. Treatment with oral steroids is usually resorted to as short-term therapy, until other longer acting drugs take effect. Long-term steroid therapy is associated with significant toxicity such as high blood pressure, cataracts, weight gain, diabetes, osteoporosis, and avascular necrosis of bone.

 

 

Disease Modifying Drug Therapy

“Disease modifying” Antirheumatic Drugs (DMARDs) MTX, sulphasalazine and leflunomide are generally recommended as first-line agents. Methotrexate is used at a dose of 15 mg weekly. Patients on MTX require regular monitoring of blood counts, liver function tests, and creatinine.

Leflunomide has demonstrated efficacy in psoriatic arthritis. Sulphasalazine has been shown to improve psoriatic joint swelling with no effect on psoriasis or enthesitis. Sulphasalazine is the preferred DMARD in peripheral arthritis considering risk and benefits in individual patients. Axial disease appears to be resistant to treatment with conventional systemic therapy.

Apremilast, a phosphodiesterase 4 inhibitor, has shown efficacy in psoriasis and other inflammatory diseases and has been recently licensed for the treatment of psoriatic arthritis. In a study of 204 patients with psoriatic arthritis, apremilast 20 mg taken orally twice daily or 40 mg daily had superior ACR‐20 responses at week 12 compared to placebo.

Tofacitinib, a JAK‐2 inhibitor, is an oral small molecule therapy that is currently undergoing clinical trials in psoriatic arthritis and is licensed for the treatment of rheumatoid arthritis.

 

Biological treatment

 

The use of TNFi has revolutionized the treatment of psoriatic arthritis. These are recommended for patients with active psoriatic arthritis affecting more than three joints that have failed to respond to at least two systemic treatments, or for axial disease that has failed to respond to NSAIDS and/or local corticosteroids. There are currently four agents marketed for the treatment of PsA.

 

Infliximab, at a dose of 5 mg/kg, has been shown to improve psoriatic arthritis. It prevents radiological progression of the disease. Concomitant methotrexate has been shown to prolong retention on treatment.

 

Etanercept, at a dose of 25 mg subcutaneously twice weekly, has been shown to improve psoriatic arthritis. In a study of 60 patients over 12 weeks, 87% of patients treated with etanercept met Ps ARC compared to 23% of placebo‐treated patients. ARC‐20 was achieved by 73% of patients compared to 13% of placebo patients. In a study comparing etanercept 50 mg twice weekly to 50 mg once weekly in patients with severe psoriasis and psoriatic arthritis, the higher dose of etanercept resulted in better PASI outcomes but the PsARC response at 12 weeks was similar in both groups (77% compared to 76%). While the combination of methotrexate and etanercept has demonstrated increased efficacy in rheumatoid arthritis, there are no controlled trials assessing this combination in psoriatic arthritis.

 

Adalimumab, at a dose of 40 mg subcutaneously every 2 weeks, has demonstrated efficacy in psoriatic arthritis. At week 12, 58% of patients treated with adalimumab achieved the primary end point of ACR‐20 compared to 14% of placebo patients. Adalimumab improved the joint manifestations, quality of life and skin disease. It also improved radiological progression of the disease. There are no controlled studies on the use of methotrexate with adalimumab in psoriatic arthritis but registry studies suggest that no additional efficacy is achieved by the addition of methotrexate.

 

Two additional TNFi (golimumab and certolizumab) are licensed for psoriatic arthritis but have not been developed for the treatment of cutaneous psoriasis. In a placebo‐controlled trial of golimumab in psoriatic arthritis, 48% of patients receiving golimumab 50 mg every 4 weeks and 46% of patients receiving 100 mg every 4 weeks achieved the ACR‐20 criteria compared with 9% of placebo patients. Certolizumab, a pegylated humanized TNFi fragment, has shown efficacy in psoriatic arthritis and also in Crohn disease. In a phase 3 study, 368 patients were randomized to receive certolizumab 200 mg every 2 weeks, certolizumab 400 mg every 4 weeks or placebo for 24 weeks. At week 12, 58% of the certolizumab 200 mg every 2 weeks reached the ACR‐20 primary end point compared to 51% of those in the certolizumab 400 mg every 4 weeks group and 24.3% in the placebo group. Certolizumab improved all aspects of the disease including physical function and radiographic progression. The clinical improvements were significant after 1 week of treatment.

 

Ustekinumab, a human monoclonal antibody that inhibits receptor binding of IL-12 and IL-23 has been shown to be very efficacious in treating psoriasis and is marketed for this indication. Ustekinumab has also been shown to be effective for psoriatic arthritis in a randomized controlled trial; 605 patients were randomized to ustekinumab 45 mg, ustekinumab 90 mg or placebo at week 0, 4, 16 and every 12 weeks thereafter. ACR‐20 at week 24 was achieved in 42.4% of the 45 mg group, 49.5% of the 90 mg group and 22.8% of placebo‐treated patients. The response was maintained at 52 weeks. Improvements were also seen in dactylitis and enthesitis and in radiological progression of the disease.

 

Inhibitors of IL‐17 and its receptor are undergoing clinical trials but are not yet licensed for psoriatic arthritis.

 

Brodalumab, a monoclonal antibody to the IL‐17 receptor A, was assessed in a phase 2 randomized placebo‐controlled trial. Patients received either brodalumab 140 mg, 280 mg or placebo over 12 weeks. The ACR‐20 responses at week 12 were 37%, 39% and 18%, respectively. These responses were maintained to week 52.

 

Secukinumab a monoclonal antibody to IL‐17A was assessed in 42 patients with psoriatic arthritis. Patients were given two intravenous doses of 10 mg/kg 3 weeks apart or placebo. The primary end point was the ACR‐20 at 6 weeks. At week 6, there was no difference in ACR‐20 response between secukinumab (39%) and placebo (23%). At week 12, secukinumab was more effective (ACR‐20 of 39% compared to 15% for placebo) but this was not statistically significant. There were significant improvements in quality of life and acute phase reactants. There are ongoing trials of secukinumab in psoriatic arthritis.

 

 

Therapeutic ladder

 

First line

·        NSAIDs

·        Sulphasalazine

·        Methotrexate

·        Leflunomide

Second line

·        Etanercept

·        Adalimumab

·        Infliximab

Third line

·        Golimumab

·        Certolizumab

·        Ustekinumab

 

 

Psoriatic arthritis treatment algorithm – adapted from the EULAR, GRAPPA and UK NICE guidelines. APR, apremilast; ADA, adalimumab; CSA, cyclosporin; DMARD, disease-modifying anti-rheumatic drugs; MTX, methotrexate; NSAIDs, nonsteroidal antiinflammatory drugs; PsA, psoriatic arthritis; TNFi, tumour necrosis factor inhibitors; USTK, ustekinumab.

Patients are categorized according to two major clinical profiles. The first clinical profile would include psoriasis patients for whom skin involvement predominates over PsA. In such patients, it is recommended that adalimumab or ustekinumab are used as first-line biological agents, similarly to patients with plaque psoriasis. The second clinical profile would include patients for whom PsA predominates over cutaneous involvement. In such patients, it is recommended that a TNF inhibitor is used as a first-line biological agent. In case of failure, switching to a second TNF inhibitor or to another class of inhibitors (anti-IL17 or anti-IL12/23) should be considered. At present, secukinumab is the only anti-IL17 treatment approved for PsA. Anti-IL12/23 should be considered in case of peripheral PsA. It is recommend that apremilast, the therapeutic effect of which appears to be limited with no available data on its impact on peripheral bone structural damage, should only be used in PsA when there are contraindications to biotherapy, or in non-severe and non-active forms of the disease.