Given that the diagnosis of psoriatic arthritis is often missed and the potential impact of delayed treatment, this author reviews the pathophysiology and classifications of this condition. She also offers pertinent treatment pointers and insightful case studies.

       Psoriatic arthritis is an inflammatory arthritis with a unique presentation. Unfortunately, clinicians often miss this diagnosis, which leads to delayed treatment. It was once believed that psoriatic arthritis was not as disabling as rheumatoid arthritis. However, the more we learn about this condition, the more we learn that this is not accurate. Psoriatic arthritis can lead to severe bony erosion and deformity. It is a condition that requires aggressive treatment.
       While the overall prevalence of psoriatic arthritis (PsA) in the United States is 0.1 percent, between 7 to 42 percent of patients with psoriasis also have psoriatic arthritis. For this condition, the peak age of onset occurs between the ages of 30 and 55 for both men and women. Psoriatic arthritis affects Caucasians more often than African-Americans. The prevalence increases 19-fold if a first degree relative has psoriasis.1-6
       There are three classifications of PsA. There is asymmetric monoarthritis or oligoarthritis with enthesitis, inflammation at the insertion site of the Achilles and plantar fascia. This is the most common initial presentation, accounting for between 30 to 50 percent of patients who present with PsA. Distal interphalangeal joints (DIP) are involved in 25 percent of PsA cases.

Here one can see a psoriatic rash of both hands with distal interphalangeal joint (DIP) synovitis. Note the erythema over the DIPs and the right fifth metacarpophalangeal joint dislocation. (Photo courtesy of the American College of Rheumatology)

       A second form of PsA is symmetric polyarthritis. While this condition appears similar to rheumatoid arthritis (RA), PsA patients tend to demonstrate less tender joints and smaller effusions than patients with RA. Common joints affected include small joints of the hand, feet, wrist and ankle. Dactylitis is common with this type of PsA. This is a combination of tenosynovitis, digital edema and arthritis of the distal interphalangeal joint (DIP) or proximal interphalangeal joint (PIP), giving a “sausage digit” appearance, which is also a hallmark of PsA. Five percent of all patients who have PsA develop arthritis mutilans. While this is rare, it is characteristic of PsA. Osteolysis of the phalanges and MCPs causes the digits to shorten and telescope.
       Axial disease is the last PsA classification and usually occurs several years after a patient develops peripheral arthritis. One-third of patients with PsA have sacroiliitis, which is usually asymmetric and asymptomatic. Forty percent of patients have spondylitis, which affects any portion of the spine and results in fusion. Patients often seque from one classification into another. Other diseases associated with PsA include iritis, uveitis, conjunctivitis, urethritis, pulmonary fibrosis and aortic insufficiency.

Here is a view of fifth digit telescoping. The old bony deformities are consistent with psoriatic arthritis. (Photo courtesy of the American College of Rheumatology)

       In 70 percent of PsA cases, psoriasis develops several years (10 and more) after the arthritis. The rash of psoriasis is comprised of sharply demarcated erythematous plaques with a well-marked silvery scale. One will typically find these rashes on extensor surfaces of elbows and knees, the scalp, ears and presacral region. However, clinicians may see these plaques anywhere on the body, including the palms, soles, flexor sites, back, hairline and genitalia. Nail pitting is the only predictor of patients with psoriasis who will develop the associated arthritis. These patients usually present with DIP involvement as well. Other nail changes include onycholysis, transverse depression, cracking, subungal keratosis, leukonychia and brown-yellow discoloration. Clinicians also need to search for areas of hidden psoriasis in the umbilicus, scalp and perianal regions.
       PsA is a diagnosis of exclusion. Exclusion criteria include a negative rheumatoid factor (RF) and rheumatoid nodules. Clinicians should rule out osteoarthritis, gout, RA, reactive arthritis, ankylosing spondylitis (AS) and inflammatory bowel disease. Unfortunately, there is no good lab value to make this diagnosis although normal acute phase reactants help differentiate PsA from RA. However, one-third of PsA patients do have an increased sedimentation rate (ESR) or C reactive protein (CRP) and leukocytosis.
       Radiographs of PsA deformities are unique with a combination of large, eccentric and marginal erosions with bone production and normal bone mineralization. Fusiform soft tissue swelling is usually asymmetric. One may note joint space destruction with both narrowing and widening of IPs with bony proliferation at the base of the distal phalanx. Resorption of the tufts of DIPs gives the classic “pencil in cup” deformity. One-third of patients with PsA have radiographic damage at the time of presentation. Within two years of presentation, 47 percent of these patients have at least one erosion. Fifty percent of patients have sacroiliitis with large erosions (small erosions are more common in ankylosing spondylitis), which can be asymmetric or bilateral. Spondylitis and irregular syndesmophytes, which are non-marginal and asymmetric, are also common.
       Clinicians may appreciate new bone formation in bulky syndesmophytes and bony ankylosis. Twenty percent of PsA patients develop a destructive and disabling arthritis. The arthritis severity does not seem to be related to the skin severity. Predictors for progression include polyarticular disease, which requires high levels of medication, symmetric DIP involvement and 20 or more nail pits.2-5,7

Essential Treatment Insights
       Non-pharmacologic treatments for PsA include physical therapy, occupational therapy, therapeutic exercise, splinting and assistive devices. PUVA therapy is also effective for skin involvement. Non-steroidal antiinflammatory drugs (NSAIDs) comprise the initial pharmacologic treatment. For patients who do not have a therapeutic response, it is sometimes helpful to perform intraarticular steroid injections. Be aware that oral corticosteroids may exacerbate skin disease and are usually avoided. Most patients will require the use of disease-modifying agents (DMARDs), including cyclosporine, hydrochloroquinolone, methotrexate, sulfasalazine, imuran and leflunomide.
       Our treatment options for psoriatic arthritis significantly improved with the development of anti-TNF a agents, including etanercept and infliximab. Etanercept is a recombinant fusion protein that binds to TNF and was the first agent approved for the treatment of PsA. This is a subcutaneous injection 25 mg twice weekly or 50 mg weekly. Mild and temporary administration reactions have been noted with the subcutaneous injection.
       Infliximab is a chimeric monoclonal antibody, which is infused at week zero, two, six and then every six to eight weeks thereafter. Clinicians should avoid using infliximab for patients who also suffer with congestive heart failure (CHF). Infusion reactions include bronchospasm, hypotension, fever and chest pain. Patients can also develop a lupus like syndrome from antibody formation. Rare cases of demyelinating disorders have also been reported. Adalimumab is another anti-TNF agent, which is approved for RA and has recently received FDA approval for treating PsA.
       To date, these agents are the only medications to slow the disease progression radiographically. One should give the patient a PPD test prior to starting either of these medications. The emergence of latent tuberculosis (TB) is possible. If the patient does have a positive PPD, treatment is required for least one month prior to infusion. Patients on TNF-a blockers are more likely to develop bacterial infections, which can quickly escalate. Opportunistic infections, such as coccidiodomycosis, histoplasmosis and listeriosis, are also more likely and need to be monitored closely. Leukopenia and aplasia rarely occur.4,5,8-10

Pertinent Insights On The Pathophysiology Of PsA

- The exact pathophysiology of PsA is still unknown but it seems to be a combination of genetic, environmental and immunological factors. Monozygotic twins have a 70 percent greater risk of developing psoriatic arthritis and this increases 50 times when they have a first degree relative who has psoriasis. The human leukocyte antigen (HLA) B27 is associated with both peripheral and spinal disease. The initial presentation of PsA often develops after an infection. Psoriatic arthritis is associated with HIV. Bony deformities often develop at a site of previous injury from trauma (Koebner effect). Patients with PsA may have an accumulation of inflammatory cells, including T cells (CD4 & CD8), B cells, macrophages and neutrophils, in their synovium and synovial fluid. Cytokines, including tumor necrosis factor alpha (TNF a) and interleukin (IL)-12, IL-6, IL-15, IL-16, IL-8 & IL-1b are also associated with PsA. Researchers have found IL-1, IL-6, IL-8, TNF a, CD8 and CD45 at entheseal insertion sites. Enthesitis is a hallmark of PsA and one may appreciate increased TNF a in the synovium, entheses and osteoclasts of these patients. The most abundant type of inflammatory cell is the T lymphocyte with the ratio of CD8:CD4 at 1:2 in affected synovial fluid. The dominant CD8 may drive the immune response in PsA. This theory is also supported by the association of PsA with HIV. CD8 and CD4 both interact with antigen presenting cells (i.e. Langerhan’s cell). Treatment with methotrexate (MTX) greatly reduces both CD4 and CD8 in the synovium. With PsA patients, clinicians will note dysregulated bone remodeling, noted as erosions and new bone formation on X-rays. One will see RANKL on the osteoblast surface and this binds to RANK, which is expressed on osteoclasts. RANKL and RANK, in the presence of macrophage colony stimulating factor (M-CSF), are both necessary for bone resorption. This pathway is altered in PsA with increased osteoclast precursors and increased TNF. These pathway alterations increase the circulating osteoclasts, which subsequently migrate into the joint unopposed to RANKL. This causes osteolysis. Dysregulated angiogenesis produces immature vessels, which are novel to PsA. Increased levels of vascular endothelial growth factor (VEGF) and angiopoietin-2 are both involved with the synovial vasculature. Increased myeloid-related protein (MRP) 8 and MRP 14 are in the sublining of perivascular areas and in the endothelium as well. MRP 8 and 14 are calcium-binding proteins, which are expressed by granulocytes and monocytes. Again, treatment with MTX markedly reduces MRP expression.1-6,11

What Is The Prognosis For Patients With PsA?
       Patients with PsA have a higher risk of death with a mortality ratio of 1.62. Cardiovascular disease is the most common cause of death. Premature death is associated with severe disease, higher medication requirements and increased ESR.
       PsA patients also report increased limitations, more so than patients affected by RA. Some believe this is related to the emotional problems and psychosocial disability associated with psoriasis.
Remission is defined as no actively inflamed joints for 12 months. This usually occurs in men with less active joints at the time of presentation. Only 6 percent of patients with PsA sustain a complete and prolonged remission without medications.2-4

When A Patient Presents With Chronic Pain And Significant Nail Pitting
       A 54-year-old, Caucasian female presented to our office in December of 2004 for a second opinion regarding polyarthralgias. She had a history of bilateral shoulder “freezing” since 2002 and her left shoulder still demonstrated limited motion. She then developed bilateral elbow, left wrist and right knee pain four months ago with swelling of the wrist. She denied any erythema or warmth with these periods of swelling. She was using Arthrotec with minimal improvement. She complains of one hour of morning stiffness. The review of systems (ROS) was unremarkable.

Here is a close-up view of nail pitting. Nail pitting is the only predictor of patients with psoriasis who will develop the associated arthritis, according to the author. (Photo courtesy of the American College of Rheumatology)

       During the physical examination, we noted numerous nail pits of her right fifth and left first fingernails, which she had not noticed previously. She had poor grip strength of her left hand. The patient had sausage digits with all PIPs. Her bilateral second and third MCPs and both wrists demonstrated synovitis. She had poor shoulder movement and the left shoulder had a positive impingement sign.
       Recent labs, including uric acid, rheumatoid factor (RF), ESR, creatine kinase blood test (CK), aldolase and antinuclear antibody (ANA) were unremarkable. Bilateral hand X-rays were also normal.
       We recommended that the patient have her sacroiliac joints evaluated by radiology and also felt that joint aspiration would be helpful. We recommended that she try colchicine, which would improve any existing gout or pseudogout. We also recommended a clinical trial of prednisone.

Note the third and fourth sausage digits. The first nail changes are consistent with psoriasis. (Photo courtesy of the American College of Rheumatology)

       The patient returned to our office in March, requesting a transfer of her rheumatic care. Since her visit, she had been treated with amoxicillin for sinusitis and noted improvement in her joints while she was on this medication. An orthopaedist had injected her left wrist and right knee with an unknown dose of steroid, which improved her pain temporarily. She continued to have one-hour of morning stiffness.
       During the physical exam, we noted more nail pitting and synovitis that appeared to be worse than the previous visit. We also noted that both wrists and her right knee were swollen and warm to touch. We ordered an X-ray of her sacroiliac joints and lab testing including CMP, CBC, RF, anti-CCP and ANA, all of which were unremarkable. We also started her on a trial of prednisone, starting at 30 mg QD and advised her to closely monitor her type 2 diabetes mellitus. We also obtained a MRI of her left wrist, which demonstrated erosions. We officially diagnosed psoriatic arthritis.

These bilateral hand X-rays are consistent with psoriatic arthritis. Note the pencil in cup deformities of the bilateral third DIPs and right fifth DIP. (Photo courtesy of the American College of Rheumatology)

       We proceeded to start the patient on 10 mg of methotrexate weekly and tapered the prednisone dose. We also injected her left wrist. While there was improvement upon examination, her wrist synovitis persisted.
       Approximately two months later, the patient was unable to taper off of prednisone and continued to have some synovitis and prolonged stiffness. Accordingly, we increased her methotrexate dose to 15 mg weekly. Since that time, the patient has successfully tapered off of the prednisone. At her last visit in September, she no longer had synovitis or prolonged stiffness. In fact, she stated that she “felt like (herself)” again and was able to rise from a sitting position on the floor without difficulty.

When A Teenager Presents With Hand Pain Of Six Months’ Duration
       A 17-year-old Caucasian male with a six-month history of right hand pain. The patient was seen by a local orthopaedist, who treated a right rotator cuff injury. Shortly afterward, the patient developed right hand and ankle pain. The patient occasionally wears a splint. He says Naprosyn and Relafen have not been helpful. The patient’s right ankle, hand and clavicle swell intermittently. The patient notes three hours of stiffness in the morning. The patient notes a rash of his scalp and buttocks, which he treats intermittently with a steroid cream. The ROS was unremarkable.

In this view, one can see the progression of DIP erosion. (Photo courtesy of the American College of Rheumatology)

       During the physical exam, we noted areas of erythematous plaques with silvery scale on both his scalp and gluteal fold. His right second and third PIPs were both swollen and tender as was his right second MCP, right wrist, right midfoot and ankle, and right acromioclavicular joint. The patient’s previous labs included a positive ANA 1:1280 in homogenous and speckled patterns, and a positive RF. Anti-DNA, ENA, BMP and Lyme’s disease tests were unremarkable. We did note right AC joint separation on a previous X-ray.
We diagnosed psoriatic arthritis in light of the patient’s oligoarticular, asymmetric arthritis, which affected his previously injured joints (Koebner phenomenon). He had a rash consistent with psoriasis and three hours of morning stiffness, none of which improved with NSAIDs. We recommended the patient use Mobic 7.5 to 15 mg QD and ordered CMP, CBC, ESR, Hep B, Hep C and HIV tests prior to starting methotrexate. All of these tests were unremarkable.

Here one can note the loss of joint space and bony erosions. (Photo courtesy of the American College of Rheumatology)

       The patient returned to the clinic two weeks later without much improvement and his joints were still active. We started the patient on 10 mg of methotrexate weekly. At his last visit in August, he was doing very well. The patient stated that “he felt like he could do anything now” and returned to school without difficulty. He had no active synovitis, prolonged stiffness or rash. His toxicity screening has thus far been unremarkable.

In Conclusion
       Psoriatic arthritis is an inflammatory arthritis with disabling complications. The initial presentation can vary and can make diagnosis more difficult. Clinicians may confuse PsA with RA but there are characteristic signs and symptoms that can help distinguish between the two conditions. The radiographic appearance is unique to PsA and is very helpful in differentiating the diagnosis.
       The treatment of PsA has improved greatly with the development of anti-TNF agents and this success also supports the theory of TNF-a involvement.