Managing psoriatic arthritis during Covid-19

A detailed overview of the clinical features, diagnosis, and management of psoriatic arthritis and the impact of Covid-19

Psoriatic arthritis (PsA) is a chronic inflammatory disease of the musculoskeletal system that, not unlike rheumatoid arthritis, can lead to joint damage, deformity, functional impairment and disability. However, PsA is a distinct entity from rheumatoid arthritis, with a differing pattern and distribution of peripheral and axial joint involvement in the majority of cases.

Unlike rheumatoid arthritis, PsA is associated with psoriasis, dactylitis and enthesitis. The pathogenesis of PsA also differs with a prominent role played by the pro-inflammatory cytokines IL-17 and IL-23, by Th17 and CD8+ lymphocytes and the genotypes HLA-C*0602 and HLA-B27.

Epidemiology

There is an even distribution of PSA between males and females. Prevalence of psoriasis is reported to be between 1 and 10 per cent of the general population, while between 15 and 30 of those with psoriasis have associated arthritis. Prevalence of PsA is estimated to be between one and two per 1,000 of the general population.

Nail and scalp psoriasis may be associated with a higher risk of PsA, however, there is no apparent association between the severity of skin disease and the risk or severity of PsA. Most patients with PsA have nail disease, specifically nail pitting and/or onycholysis.

Clinical features and diagnosis

The symptoms of PsA include pain, stiffness and swelling of peripheral joints while stiffness and pain of axial elements (including the spine, sacroiliac joints and chest wall articulations) also feature. Pain is not restricted to joints alone and can involve entheseal sites, characteristically that of the Achilles or the plantar fascial insertion to the calcaneus, and the common extensor origin at the lateral epicondyle of the elbow (enthesitis).

Stiffness tends to be most prominent in the morning after waking, after prolonged immobility, eg, sitting in work or driving longer distances, and lasts at least 30 minutes, generally improving with activity. Sleep disturbance from pain and stiffness is common. Swelling can involve individual joints or entire digits, giving the appearance of so-called ‘sausage’ swelling, or dactylitis. Fatigue is common.

Characteristic patterns of musculoskeletal involvement in PsA have been described. These are:

• Distal interphalangeal (DIP) joint or ‘distal’ PsA (hands).
• Mono/oligoarthritis affecting four joints or less (often large joints including knees, ankles).
• Symmetrical distribution, similar to rheumatoid arthritis.
• Arthritis mutilans.
• Axial predominance (affecting the cervical spine and sacroiliac joints).

Co-morbidities to consider include the severity of psoriasis, inflammatory eye or bowel disease (uveitis, conjunctivitis, ulcerative colitis/Crohn’s), the metabolic syndrome and its individual elements (obesity, hypercholesterolaemia, hypertension) and risk factors for cardiovascular disease.

Autoantibodies, including anti-nuclear antibody (ANA), rheumatoid factor and anti-citrullinated protein antibodies (ACPA or CCP antibody) have been shown to occur uncommonly in PSA, with studies suggesting prevalence in approximately 10 per cent or less of cases. Inflammatory markers, particularly C-reactive protein (CRP), will be normal in almost 50 per cent of cases. Raised CRP is a marker of poor prognosis.

Characteristic radiographic changes are seen in PsA and include periarticular erosion, phalangeal osteolysis, periostitis (‘fluffy’ appearance of periarticular bone), ankylosis, pencil-in-cup deformity, sacroiliitis, and syndesmophyte formation. Bone spurs at sites of enthesitis are also seen.
While less studied than x-ray, MRI findings include peri-articular bone marrow oedema, tenosynovitis, enthesitis, and erosion (McQueen F, Lassere M, Østergaard M, 2006).

The CASPAR (Classification for Psoriatic Arthritis) criteria have been designed to improve the accuracy of PsA classification and may also have a role in diagnosis, demonstrating a sensitivity of 95 per cent and specificity >95 per cent. The criteria take account of the following clinical features in those with peripheral inflammatory arthritis, enthesitis or axial symptoms:

• Personal history of psoriasis or psoriasis in a first-degree family member (parent or sibling).
• Psoriatic nail lesions.
• Dactylitis.
• Negative rheumatoid factor.
• Juxta-articular bone formation on x-ray.

Diagnosis of PsA can be challenging. The disease should be considered in those with a protracted history of plantar fasciitis, ‘tennis elbow’ or Achilles enthesitis, especially when standard treatments have failed. It is essential to enquire about the family history in these cases. Distal PsA, affecting the DIP joints, can be difficult to differentiate from nodular or inflammatory osteoarthritis, particularly in those over 50 years of age.

Clues to PsA as a cause include periostitis on x-ray (often subtle and unreported), symmetrical DIP joint involvement, and/or tender erythematous swelling. The presence of severe nail disease is also a feature of distal PsA. As outlined in the case report in this article, fusiform tender swelling of the toe(s) with a questionable history of trauma could be acute dactylitis. Once again, in the absence of a personal history of psoriasis, family history is important.

Treatment

The aim of treatment of PsA in the early 21st century is remission-induction in the shortest amount of time practicable. This approach can prevent joint damage, preserving joint function and patient independence. Joint damage manifests radiographically as articular erosion and/or ankylosis and clinically as reduction in the normal range of movement of the joint and physical deformity.

As joint damage can proceed rapidly after the onset of symptoms, assessing clinicians should maintain a high index of suspicion in patients with psoriasis presenting with joint and/or musculoskeletal complaints. Early referral to a rheumatologist is the first step in treating PsA.

Disease modification in rheumatic disease refers to the ability of a therapy to arrest the pathological process of joint inflammation and subsequent destruction of the articular structures. Two specific treatment targets have been identified to maximise patients’ prognosis. Remission is the ideal therapeutic target, loosely defined as the absence of clinical and serological inflammatory activity, while minimal disease activity or MDA is felt to be an acceptable alternative to remission.

International PsA research groups assert that all facets of PsA be targeted by treatment, including psoriasis and associated nail disease, dactylitis, enthesitis, axial disease (eg, sacroiliitis) and relevant co-morbidities.
While the armamentarium of therapeutics to treat PsA has expanded considerably in the last decade, patient preference remains a key consideration in medication selection.

Initial medications

NSAIDs

The non-steroidal anti-inflammatory drugs (NSAIDs) continue to have a role to play in the treatment of PsA, particularly on first presentation to the primary care provider. The efficacy of the various NSAIDs in PsA is equivalent. While not disease-modifying, the introduction of an NSAID will reduce pain and stiffness for many, and unless contraindications exist, they should be considered in patients presenting for the first time.

Corticosteroids

While prescription of systemic corticosteroid medication for peripheral arthritis in PsA in not uncommon, it should be done with caution due to the potential risk of exacerbation of psoriasis, including provoking the onset of erythroderma.

Oral DMARDs

Methotrexate

Methotrexate is the first DMARD most commonly prescribed by rheumatologists for PsA. It has an established safety profile, is low in cost and taken once-weekly, available in both oral and parenteral formulations, and treats both psoriasis and PsA. There remains, however, a lack of convincing clinical trial data of any true disease-modifying effect attributable to methotrexate in PsA, although a number of cohort studies have reported positive outcomes with its use.

It has no effect on PsA-related axial inflammation, while its effect on enthesitis is limited. Onset of action is slow; taking between eight and 12 weeks for benefits to be seen. Nonetheless, it has a role to play in those with moderate disease activity. Patients are advised to abstain from or limit alcohol intake.

Pregnancy planning is important due to its teratogenicity. A ‘washout’ period of between three and six months is advised before safe conception can be considered. A blood monitoring schedule should also be provided to patients taking methotrexate with regular review of liver function and full blood count.

Leflunomide

Of the oral ‘traditional’ DMARDs, leflunomide has the strongest evidence for use in PsA. It is taken as a single daily dose with a similar side effect profile to methotrexate. Blood monitoring is also required. In women of child-bearing potential considering pregnancy, it may not be the best choice as it requires a prolonged washout period of up to two years. It has a lesser effect on psoriasis compared with methotrexate and, as with the other traditional DMARDs, has no effect on PsA-related axial disease.

Sulphasalazine

Although still prescribed, sulphasalazine has lost favour as a treatment in PsA and it has minimal effect on psoriasis. Clinical trial data has been unconvincing in terms of disease modification.

Apremilast

Apremilast, mentioned in the case report herein, is an oral medication targeting phosphodiesterase 4 (PDE4), an enzyme ‘upstream’ in the psoriatic inflammatory pathway. Blockade of this enzyme has resultant downstream effects, including on the expression of key pro-inflammatory cytokines, TNFα and IL-17. It is taken twice daily.

It has proven efficacy in both psoriasis and in symptom control in PsA, however, it has not yet been shown to be truly disease-modifying. It often suits patients with milder disease with no evidence of erosion or clinical damage at baseline. It may also be useful in patients with dactylitis or enthesitis-dominant disease. Routine blood monitoring and alcohol abstinence are not a necessity.

Diarrhoea is a notable adverse effect reported on initiation and affecting up to 50 per cent of patients for a short period after introduction of the drug. Less commonly, unexplained weight loss has been reported, while caution should be applied in prescribing the drug in those with depression.

Apremilast was this writer’s favoured medication for mild-to-moderate PsA during the initial months of the Covid-19 pandemic because of its short half-life and modest effect on protective immunity.

Biological DMARDs

TNF inhibitors (TNFi)

The TNFi prescribed for PsA include etanercept, adalimumab, golimumab and certolizumab pegol. They have established their place as the ‘gold standard’ in treating psoriatic disease. The TNFi are truly ‘disease-modifying’ with clinical trial data consistently reporting delay in joint damage progression. They are also effective against the other facets of psoriatic disease, including nail and cutaneous psoriasis, axial disease, enthesitis and dactylitis.

Other advantages include a less rigorous schedule of administration for patients, being prescribed as weekly, fortnightly or monthly depending on the individual drug being taken. Adverse effects can occur but gastrointestinal intolerance, as seen with the oral DMARDs, is very uncommon. Localised cutaneous reaction at the site of injection occurs in half of patients with initial use of these drugs but tends to lessen with ongoing use.

Leukopaenia is also seen and many rheumatologists choose to monitor a full blood count at regular intervals. There is a greater risk of infection with TNFi use and patients are screened for latent tuberculosis and hepatitis B and C prior to prescription. Vaccination against influenza and pneumococcus is recommended. The TNFi are frequently co-prescribed with an oral DMARD, most commonly methotrexate. While evidence exists for greater drug survival with TNFi and methotrexate co-prescription, an additive effect of the combination is generally not seen.

A major disadvantage to TNFi prescription is cost to the patient and the state healthcare provider. Introduction of biosimilar etanercept and adalimumab has helped lower costs, however, not as significantly as was initially expected. Nonetheless, the TNFi are appropriate as first-line medications in more severe PsA, particularly in those with many symptomatic joints and in those with early and established radiographic damage.

IL-17 blockade

IL-17 is a pro-inflammatory cytokine particularly abundant in both psoriatic skin lesions and the synovium of those with PsA. Secukinumab and ixekizumab are IL-17 blockers licenced for treating both psoriasis and PsA. Clinical trial data have been extremely impressive in those with severe psoriasis, with many patients achieving complete clearance of their disease after weeks to months of treatment.

They are also effective in treating PsA in both peripheral and axial joints, also with disease-modifying effects. Both drugs have a loading dose schedule followed by regular injections every four weeks. As with the TNFi, patients are screened for latent TB while greater risk of infection exists, including that from candida species.

Ustekinumab

Ustekinumab is a monoclonal antibody against the p40 subunit that is shared by both IL-12 and IL-23, two cytokines with immunopathological roles in psoriatic disease. Clinical trial data suggests that its effect on joint disease doesn’t quite match that of the TNFi and this experience is borne out in clinical practice, however, it has a disease-modifying effect with a role to play, particularly in patients where psoriasis is more prominent than arthritis.

New DMARDs

Janus kinase (JAK) inhibitors

Tofacitinib is a JAK inhibitor currently licenced for PsA. It is an oral preparation taken twice daily and inhibits the inflammatory cytokine pathways of psoriasis and PsA. Although not a biologic drug, screening for latent tuberculosis and hepatitis is required before prescription, along with regular monitoring for leukopaenia and hepatic enzyme derangement. Risk of infection is increased, including that of herpes zoster.

Increased risk of venous thromboembolism has been reported with JAK inhibitor medication, and caution with prescription should be given in those with risk factors for deep vein thrombosis or pulmonary embolism.

Other considerations

Cardiovascular health

Clinicians involved in caring for patients with psoriatic disease should be encouraged to routinely monitor and treat established risk factors for cardiovascular disease, including hyperlipidaemia, obesity, and hypertension.

Exercise

Exercise prescription is a vital aspect of holistic care provision in rheumatic disease and should take account of patients’ functional limitations with modification as necessary. Nonetheless, encouragement to incorporate elements of the four exercise types (aerobic/cardiovascular, flexibility/stretching, neuromuscular/balance and resistance/strengthening) should be given. Initial supervision with a physiotherapist may be necessary in those introducing an exercise regimen for the first time.

Covid-19

Covid-19, caused by the SARS-CoV-2 virus, has had a significant impact on those with rheumatic disease, including PsA. Reduced healthcare accessibility has caused delays in diagnosis and treatment initiation. The rapid adoption of telehealth provision has helped. Disease flares following temporary interruption of medication for PsA, borne out of patient and clinician fears of Covid-19, have occurred.

While high-quality data remains lacking, case series and observational studies in rheumatic disease in general have not shown an increased risk of contracting SARS-CoV-2 nor of increased risk of hospitalisation or more severe Covid-19 illness, compared with the general population.

Interestingly, one study suggested a lower risk of hospitalisation in those taking TNFi, while prednisolone >/=10mg per day was associated with a higher risk of hospitalisation. Overall, medications used to treat PsA have not been shown to convey a demonstrable increase in risk.

In those who test positive for the virus, or are suspected of having Covid-19, discontinuation of DMARD therapy including biologic and JAK inhibitor medication is recommended with treatment reintroduced approximately 14 days after symptom resolution.

The Irish Society for Rheumatology is advising that patients on ≥5mg or more of prednisolone for ≥two weeks be prioritised for vaccination, ahead of those on the DMARD and biologic medications discussed in this article. The Pfizer/BioNTech mRNA vaccine, currently provisionally licensed, is not a live vaccine and is being recommended for these patients.

Dose interruption of the aforementioned medications can be considered to accommodate the vaccination schedule, however this should be conducted on a case-by-case basis. Interruption of an established steroid regimen is not recommended in those being vaccinated.

Conclusion

PsA is a prevalent disease that often presents in atypical ways, as seen in the case report example in this article. Consideration of family history is key. Treatment of PsA in the early 21st century should focus on remission as an appropriate target. Timely referral and diagnosis are essential. While an array of efficacious and disease-modifying medications is readily available, encouragement of lifestyle modification and exercise prescription complete the holistic approach.

References on request

Case report

A 23-year-old female presented to a rheumatologist with a two-year history of painful, sausage digit swelling of the left fifth toe. There was no notable history of injury and no significant past medical history. Repeat radiographs failed to demonstrate fracture. Inflammatory markers, including CRP, were consistently normal.

She had resigned from her part-time employment as a barista because of significant pain with weight-bearing. She had recently been prescribed an antidepressant medication for sustained low mood resulting from her ambulatory difficulty.

Family history revealed that her father had mild scalp psoriasis.
On examination, a diffusely swollen, mildly erythematous and tender left fifth toe was evident. Her skin, including nails and scalp, was clear. No other abnormality was detected.

Close examination of a recent radiograph revealed subtle periostitis in the interphalangeal joint of the fifth toe. Findings were consistent with acute dactylitis. Psoriasis affecting a first-degree relative suggested a diagnosis of psoriatic arthritis (PsA). She was prescribed naproxen 500mg with esomeprazole 20mg twice daily for two weeks with marginal response.

The NSAID was discontinued and apremilast was introduced (30mg twice daily) with resolution of symptoms and tenderness after six weeks of treatment. She has remained in remission for the last 12 months of treatment.