Chapter 19. Psoriatic Arthritis

Psoriatic arthritis (PsA) is an inflammatory musculoskeletal disease that affects people with psoriasis or their near relatives. It affects musculoskeletal structures such as the peripheral and axial joints, entheses, and tendon sheaths. The eye and mucous membranes are also often involved. Thus, the disease has varied manifestations that make diagnosis and assessment sometimes difficult.

The original case definition for PsA was provided by Moll and Wright in 1973.1 They defined PsA as an inflammatory arthritis associated with cutaneous psoriasis, seronegative for rheumatoid factor. Rheumatoid factor is a marker for rheumatoid arthritis (RA); thus, the definition was meant to help distinguish PsA from RA, which at that time was a more recognized form of inflammatory arthritis. The CASPAR study group recently developed a new set of criteria for classification of PsA using data collected prospectively in patients with long-standing disease (Box 19-1).2 The CASPAR criteria had specificity of 98.7% and sensitivity of 91.4% in the original study, with excellent sensitivity in both early and late disease. The criteria allow classifying patients even when they do not have current, past, or family history of psoriasis and are now used in epidemiologic and genetic studies in PsA.

Genetics

PsA has a strong genetic component. The estimated recurrence risk ratio (λ) in first-degree relatives (FDRs) of probands with PsA ranges from 30.4 to 55, indicating a high genetic contribution to disease susceptibility.8 Strong heritability was also demonstrated in a recent study from Iceland where patients known to have PsA in Reykjavik were linked to the Icelandic genealogy database.9 FDRs to fourth-degree relatives of patients with PsA had relative risks of 39, 12, 3.6, and 2.3, respectively, reflecting a strong genetic component. The decrease of λ-1 more rapidly than by a factor of 2 with the degree of relationship indicates that multiple genes contribute to susceptibility with some interaction of effects. Genes associated with PsA include HLA alleles, MHC Class I related chain (MIC) genes, TNFA, IL23R, IL1, and killer-cell immunoglobulin-like receptor (KIR) genes. HLA-B13, -B16 and its splits -B38 and -B39, -B17, and -Cw6 are associated with psoriasis, with or without arthritis, -B27 and -B7 are specifically associated with PsA.8 However, since most patients with PsA have cutaneous psoriasis it is difficult to determine whether genetic associations found in patients with PsA when compared to healthy controls is associated with psoriasis or with PsA. A recent genome-wide association study was able to investigate association with PsA and differences between PsA and psoriasis alone.10 HLA-C, IL12B, and TNIP1 were associated with PsA when compared to normal controls. There was a statistically significant difference between PsA and psoriasis alone at three loci [(1) HLA-C, (2) IL12B, and (3) IL23R]. HLA-C and IL23R were more strongly associated with psoriasis alone, and IL12B with PsA. A smaller GWAS also identified a novel PsA (and potentially psoriasis) locus on chromosome 4q27 that harbors the interleukin 2 (IL2) and interleukin 21 (IL21) genes.11

Genetic polymorphisms can also influence PsA phenotype. HLA-B39 alone, HLA-B27 in the presence of HLA-DR7, and HLA-DQ3 only in the absence of HLA-DR7, confers increased risk for disease progression.12 TNF polymorphisms are associated with erosive disease and joint damage progression in early PsA.13 The interleukin-4 receptor gene (IL4R) I50V SNP is associated with erosive PsA, although the association was not consistently shown.14,15

Environmental Factors

Pathogenesis

The immune system, especially the lymphocytes, play an important role in the pathogenesis of PsA. The traditional model of the pathogenesis is that autoimmunity directed against a common skin and joint autoantigen(s) leads to chronic autoreactive T-cell driven inflammation. Genetic susceptibility predisposes the T-cell receptor repertoire to recognition of target self-peptides expressed in target tissues. Prior response to exogenous ligands encoded by pathogens as well as prior episodes of inflammation result in expansion of memory effector CD8+ T cells that recognize stress-related self-antigens and initiates and maintains pathways of inflammation mediated by the expression of transcription factors such as nuclear factor-κB and activator protein-1, resulting in skin and synovial inflammation.18 The primary defects in this model involve expression of an autoantigen, binding of autoantigen peptides by MHC Class 1 molecules leading to initial clonal activation and expansion of an adaptive immune response. However, recent imaging, histological, and genetic studies have made us reconsider this view, especially with respect to joint and nail diseases. Clinically unrecognized enthesitis is commonly seen in PsA and in psoriasis without arthritis.19 Enthesitis is associated with adjacent osteitis or bone and synovial inflammation. Nail disease is a marker for PsA in patients with psoriasis, since it occurs in almost 90% of patients with PsA, but less than 50% of those with psoriasis alone. The nail is closely related to the distal interphalangeal (DIP) joints and the related extensor tendon insertion sites, and the association between DIP joint disease, adjacent nail lesions, and entheseal inflammation was recently demonstrated.20 It is proposed that the synovial membrane and entheses form a “synovioentheseal complex,” and that enthesitis is the unifying pathologic lesion that may explain the varied clinical manifestations of PsA.21 In this model, tissue specific factors, including microtrauma, lead to regional innate immune activation and persistent inflammation. The genetic association of PsA with Class 1 HLA alleles and KIR genes as well as the association between juvenile PsA and Mediterranean Fever (MEFV) and NLR family, pyrin domain containing 3 (NLRP3) genes indicate that PsA is closer to the “autoinflammatory” end rather than the “autoimmune” end of the spectrum of immune-mediated diseases.22 Disease localization in autoinflammatory diseases is determined predominantly by the innate immune response to local tissue specific factors.

There is also evidence that the monocyte–macrophage system plays a major role in the initiation and perpetuation of joint inflammation. Monocytes differentiate into macrophages, osteoclasts, Langerhans cells, or dendritic cells in response to microenvironmental signals.23 In entheseal tissues, monocytes are the principal cells that infiltrate fibrocartilage. Monocytes are also present in the synovial lining of psoriatic joints, and they infiltrate the subsynovial lining. An increased frequency of circulating osteoclast precursors was identified in the circulation and synovial tissues of PsA patients. These precursors, derived from circulating CD14+ monocytes, differentiate into osteoclasts after exposure to monocyte colony stimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANKL) expressed by synovial lining cells in inflamed psoriatic synovium, and is responsible for bone erosions. The frequency of circulating osteoclast precursors in PsA patients decline rapidly following treatment with anti-TNF agents and may explain its antierosive effects.

Synovial Histopathology

The CASPAR classification criteria define PsA as an inflammatory musculoskeletal disease that can involve the joints, spine or entheses. Clinical features of PsA include peripheral arthritis, axial arthritis (spondylitis), enthesitis, dactylitis, and tenosynovitis. The typical features of inflammatory arthritis are joint pain, swelling, stiffness, redness, and reduction in mobility. The arthritis of PsA is often of gradual onset and involves one or more joints. Typically early PsA is oligoarticular (affecting less than five joints) (Fig. 19-1). Early PsA often involves the joints of the lower limbs, but any joint of the body may be affected. Oligoarticular PsA subsequently evolves into polyarthritis. Joints that are typically affected in patients with PsA include the DIP joints (Fig. 19-2). Commonly the nails near these affected jointsdemonstrate the nail changes that are typical for psoriasis. The distribution of the joint involvement in PsA is often asymmetric. However, as the number of joints affected increases, there is a tendency toward symmetry.26 Patients with PsA have less pain than those with RA.27 Therefore, they may be oblivious to the degree of inflammation in their joint. In addition to peripheral arthritis, PsA affects the axial joints in 30%–50% of patients with PsA. Axial inflammatory arthritis presents with inflammatory back and/or neck pain, typically associated with stiffness and worse after periods of prolonged inactivity such as nighttime sleep. Inflammatory axial pain and stiffness usually improve with activity. However, evidence of radiographic involvement of the axial joints may be present in a substantial proportion of patients presenting with peripheral PsA in the absence of axial symptoms.28 Axial arthritis leads to restriction in the mobility of the spine. The process can lead to a completely fused and immobile spine, sometimes called “bamboo spine.”

Dactylitis, defined as inflammatory swelling of an entire finger or toe, is a characteristic manifestation of PsA (Fig. 19-3). This is due to inflammation of the joints, tendons, bones, and soft tissues in the digit(s). Persistent dactylitis leads to destruction of the joints in that digit. Dactylitis is a marker of severity of psoriatic arthritis. Enthesitis, defined as inflammation at the entheses (site where ligaments or tendons attach to bone), is another important manifestation of PsA. The most common sites to be affected by enthesitis are the plantar fascia on the sole of the feet (plantar fasciitis) and Achilles tendon insertion at the back of the heel (Achilles enthesitis). Enthesitis can also affect other sites including tendon insertion sites on the patella, shoulder, elbows, pelvis, spinous processes, and chest wall. Tenosynovitis, or inflammation of the tendon sheath, may affect tendons in the hands, wrists, and around the ankles. (Box 19-2).

The category of asymmetric oligoarthritis includes those patients with four or less joints affected by arthritis. The joints involved are usually of the lower limbs and there is lack of symmetry. In the category of symmetric polyarthritis, five or more joints are involved in a symmetric fashion. Therefore, it is sometimes difficult to distinguish it from RA. The spondyloarthritis category includes patients with predominant involvement of the spine (axial arthritis), similar to the involvement in patients with AS. As the name suggests, the category of distal interphalangeal joint arthritis includes those patients with predominant involvement of the DIP joints. Arthritis mutilans describes a category with severe arthritis leading to shortening and destruction of fingers and toes (see eFig. 19-3.1). Although, these categories were described initially, it was soon realized that as the longer the duration of the disease the higher the number of joints involved and the involvement becomes more symmetric. Distal joint involvement also is common and is seen in all categories. Arthritis mutilans is also a manifestation of severity of the arthritis process and not an exclusive category. Therefore, experts nowadays tend to classify the disease as peripheral arthritis alone, peripheral arthritis with axial arthritis, and axial arthritis alone.29

Skin Involvement

Most patients with PsA have psoriasis vulgaris. In about 70% of people with PsA, psoriasis develops first and the arthritis manifests itself after a variable duration, on average within 10 years. However, in about 15%, both arthritis and psoriasis develops simultaneously, and in the remaining, the arthritis develops first, and cutaneous psoriasis manifests itself a few years later. Patients seen in dermatology clinics and those hospitalized with psoriasis have high prevalence of PsA compared to patients with psoriasis seen in the community. Patients reporting greater extent of psoriasis also reported a higher prevalence of PsA when surveyed in a telephone interview.30 Thus, patients with more severe psoriasis may have a higher prevalence of PsA. However, most patients attending rheumatology clinics for their arthritis have only mild to moderate psoriasis.

Nail Involvement

Psoriatic nail dystrophy usually manifests as pitting and onycholysis (see Chapter 18). Although 40% of patients with psoriasis without PsA have nail lesions, nail involvement is much more frequent in patients with PsA affecting close to 90% of patients.31 Thus, nail lesions are the only clinical feature that distinguishes patients with psoriatic arthritis from those with uncomplicated psoriasis. The nail bed is closely linked to the DIP joints; nail involvement is associated with arthritis of these joints.

Extra-Articular Manifestations

Apart from the involvement of the skin, nails, and joints, people with PsA also have involvement of other important organs. Eye involvement is not infrequent. Conjunctivitis is occasionally seen and uveitis may occur in 2.3% of patients.32 Mucous membrane inflammation presents with painful mouth ulcers and urethritis. Inflammatory bowel disease in PsA may resemble Crohn disease and/or ulcerative colitis and can cause abdominal pain, loose stools, and bleeding.

Laboratory Investigations

Laboratory tests are usually done at diagnosis and periodically thereafter. However, there is to date no diagnostic test for PsA. The acute phase reactants [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)] are often normal. ESR and/or CRP are raised in less that 50% of people with PsA. Rheumatoid factor is usually negative and helps exclude RA. HLA-B*27 is positive in 20% of patients with PsA. Radiological investigations (X-ray, ultrasonography, and magnetic resonance imaging) can provide important clues to diagnosis and to the extent of inflammation and damage. However, only the presence of periostitis and new bone formation near joint margins may be considered reasonably specific to PsA.2 Although, these tests are not by themselves diagnostic, they help in ruling out other conditions that may mimic PsA. Synovial fluid if obtained demonstrates inflammation and helps exclude crystal arthritis and infections. Investigations such as blood count, and liver and kidney functions are often obtained to monitor side effects of drug therapy.

Radiologic Features of PsA

Imaging is an important modality in the assessment of patients with PsA. Imaging complements clinical assessment and helps in confirming the diagnosis as well as in determining disease severity. The various modalities used in assessment of PsA include X-rays, ultrasound, computerized-tomography scan (CT scan), magnetic resonance imaging (MRI), and bone scan.

Plain Radiographs (X-Rays)

X-rays are the mainstay in the radiologic assessment of PsA. X-rays are relatively cheap, easily available, and can be read by most physicians. Once PsA is suspected clinically, radiographs of the hands, feet, pelvis, spine, and other affected joints are done to look for changes suggestive of PsA. X-rays are also used to assess disease severity, as well as to follow disease progression. Radiographic changes generally reflect damage to the joints rather than acute inflammation. In early disease, X-rays of the hands and feet show soft tissue swelling around the joints involved. If dactylitis is present, soft tissue swelling will involve the whole finger or toe. In more severe disease, erosions develop near the joint margin and are markers of disease severity (Fig. 19-4). Erosions may be paramarginal, in contrast to RA were the erosions are usually marginal. In PsA erosions are often accompanied by new bone formation. The combination of erosions and new bone formation at joint margins is characteristic of PsA (Fig. 19-5). Following the development of erosions there may be joint space narrowing, and finally total joint destruction may occur, either total joint lysis and the so called “pencil-in-cup” change or complete bony bridging through the joint termed ankylosis (Fig. 19-6).

X-rays of the pelvis often show changes reflecting the presence of sacroiliitis. Earliest notable changes include widening of the joint space, which is often difficult to appreciate (eFig. 19-6.1). Subsequently, erosions develop, followed by sclerosis and subsequent bony bridging across the joints, ultimately leading to complete fusion of the joint (eFig. 19-6.2). X-rays of the neck and the back often show changes that reflect consequences of inflammation at the spinal joints. The earliest changes on lateral view of the spine include shiny vertebral corners, erosions, and squaring of vertebrae. This is followed by bone bridging, or marginal syndesmophytes, beginning from the ends of the vertebrae across the disc space. Complete bony bridging can occur. If most of the vertebrae are bridged, it is called “bamboo” spine. These changes closely resemble the changes in AS (Fig. 19-7). Often in PsA, the syndesmophytes can develop from sites away from the vertebral body. The presence of these “nonmarginal” syndesmophytes is characteristic of PsA (eFig. 19-7.1). The changes described can at occur at any site—cervical and lumbar vertebrae are frequently involved. In the cervical spine, occasionally atlanto-axial subluxation may be present and can lead to serious consequences.

Ultrasound Imaging

Ultrasound combined with Doppler evaluation, can detect active inflammation in joints and entheses. Ultrasound can also detect erosions before they appear on X-rays especially in the hand joints. It can also be used to guide injections into joints.33

Magnetic Resonance Imaging (MRI)

MRI scans along with contrast can detect active inflammation. MRI can also show erosions in the bone even before they are seen on plain X-rays.34 Bone edema which often precedes the development of overt erosions is also detected easily. MRI scans are also very useful in detecting active inflammation in the spine and MRI changes are usually evident much before any abnormality is visualized on X-rays.34 Thus, MRI evaluation is crucial in the diagnosis of early disease, especially affecting the spine.

Computerized Tomography

CT scans are most useful when joints or the spine need to be evaluated in detail, especially when an MRI is unavailable or contraindicated. CT scans also give a detailed view of the joints. Bones are viewed better than in MRIs. However, CT scans involve considerable exposure to radiation.

PsA has a variable course and prognosis. While some patients do well with small number of joints involved, and no significant damage, others progress very quickly, developed marked joint damage and disability.35 Over 10 years of follow-up, 55% of the patients had at least five clinically damaged joints.36 By the time patients present to a PsA clinic, 67% have at least one erosion.31 Even in early disease, of 129 patients seen within 5 months of onset of symptoms 47% developed erosions within the first 2 years.37 Factors associated with progression of joint damage include the number of actively inflamed and damaged joints at presentation, the ESR at presentation, and the number of actively inflamed joints at each visit.38–41 There are patients with PsA who achieve remission, defined as no actively inflamed joints for 12 months.42 In a longitudinal observation cohort 17.6% of the patients achieved remission, but only six patients had a complete remission with no actively inflamed joints, no damage, and off therapy. The period of remission lasted for 2.6 years, after which 52% of the patients flared. Thus, active disease must be treated aggressively, particularly in the presence of erosive changes. Quality of life and function of patients with PsA are reduced compared to the general population.43,44 PsA patients have worse quality of life and function than patients with psoriasis alone.45

Comorbidities

Patients with psoriasis and PsA have an increased prevalence of cardiovascular disease (CVD). In patients with PsA, the standardized prevalence ratio of hypertension, myocardial infarction, and angina is higher than the general population.46–48 For other comorbidities, see Chapter 18.

Mortality in PsA

Although population-based studies have shown that PsA is not associated with increased mortality, clinic-based studies have shown that patients with PsA have an elevated mortality risk, although the risk seems to have declined over the last decade.49 The four leading causes of death are diseases of the circulatory or respiratory system, malignancies, and injuries/poisoning. Evidence of previously active and severe disease, as manifested by the prior use of medications and by radiologic changes as well as an elevated ESR at presentation, are prognostic indicators for death.50

Early Diagnosis

PsA has an unpredictable clinical course. Radiographic damage can occur within 2 years of disease onset in almost half of patients with PsA, and the disease usually follows a chronic, progressive course.37,51 With the availability of effective therapy it is hoped that early diagnosis will help prevent damage. Since cutaneous psoriasis precedes or occurs simultaneously with joint disease in 85% of patients with PsA, screening patients with psoriasis for PsA has the potential to help detect PsA early.52

Several screening tools have been recently developed.53 The Psoriasis and Arthritis Questionnaire (PAQ) and its modification, Psoriatic Arthritis Screening and Evaluation (PASE) questionnaire, Psoriasis Epidemiology Screening Tool (PEST) questionnaire, and Psoriasis and Arthritis Screening Questionnaire (PASQ) were developed specifically to screen for PsA in patients with psoriasis, whereas the Toronto Psoriatic Arthritis Screen (ToPAS) was developed for use in the general population as well as in patients with psoriasis. The PASE, PEST, and ToPAS questionnaires have high sensitivity and specificity. Imaging studies using scintigraphy, MRI, and ultrasound have also shown abnormalities in subjects with psoriasis, who do not have overt PsA.19,54,55 Soluble biomarkers have also been evaluated as a marker for screening for PsA in patients with psoriasis; C-reactive protein and Matrix Metalloproteinase-3 have shown promise.56,57 Circulating osteoclast precursors are elevated in patients with PsA and psoriasis, and decrease with anti-TNF therapy.58 In prospective studies, clinical predictors for PsA in patients with psoriasis include presence of scalp or intergluteal/perianal psoriasis, ≥3 affected sites, and presence of nail dystrophy.59

Differential Diagnosis

A number of arthritic conditions may occur in patients with psoriasis and these must be differentiated from PsA (Table 19-1). Since psoriasis is a common condition, occurring in 2%–3% of the population, and rheumatoid arthritis, the most common form of inflammatory arthritis, may occur in 1% of the population, the co-occurrence of rheumatoid arthritis and psoriasis would be expected by chance alone in 2 in 10,000 people. Since RA, like PsA is inflammatory in nature, the differentiation may be difficult. Osteoarthritis, which is the commonest form of arthritis, occurs in about 5% of the population and it may coexist with psoriasis. While osteoarthritis is not usually an inflammatory form of arthritis, it affects the DIP joints, a site commonly affected in patients with PsA. Patients with PsA also have increased prevalence of hyperuricemia and gout, and occasionally gouty arthritis may mimic PsA. PsA also has to be distinguished from other SpA.60

The diagnosis of PsA is considered when a patient presents with inflammatory musculoskeletal disease. This may be in the form of arthritis, dactylitis, enthesitis, or spondylitis. The presence of cutaneous psoriasis is an important clue and this should be looked for carefully, especially in hidden regions such as the scalp, umbilicus, below breasts, or in the natal cleft. Nails should be carefully inspected for changes of nail psoriasis as the evidence of psoriasis may be present in the nail only. The pattern of involvement in PsA is often asymmetric. This is not usually the case in RA, which tends to be symmetric. A characteristic pattern of PsA is the “ray” pattern—involvement of all joints in a particular finger or toe, as opposed to joints beside one another. The “ray” distribution is typical for PsA, and is not usually seen in either RA or OA. The presence of dactylitis is an important feature. It is a typical feature for PsA and is not seen in RA. The only other arthritic condition that may manifest with dactylitis is reactive arthritis, which is not associated with psoriasis but where psoriasis-like lesions can occur (see Chapter 20). Spinal involvement presenting as inflammatory neck or back pain with or without restriction of mobility is present in about half of the patients with PsA, especially in well-established disease. It is not a feature of RA. The presence of spinal and peripheral arthritis makes the diagnosis of PsA very likely, and virtually rules out RA.

The diagnosis of PsA may sometimes be made even in the absence of psoriasis. If the above characteristic features are present even without cutaneous psoriasis, the diagnosis may be considered. The diagnosis is especially likely if there is a family history of psoriasis or PsA. The diagnosis may also be made if characteristic radiographic features such as “pencil-in-cup” changes, bony ankylosis, new bone formation close to sites of erosions, and nonmarginal syndesmophytes are present.

Laboratory tests have only a minor role to play in making the diagnosis of PsA. Characteristically, rheumatoid factor test is negative, although a positive test does not rule out the diagnosis. Elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) is present only in about half of the patients. However, these are markers of severity. ESR is a predictor of progression of joint damage and mortality, and CRP is a predictor of progression of radiological damage.38,41,50 Other tests usually done are routine tests such as blood counts, and liver and kidney function tests. Although these tests are not important in making a diagnosis, they give important information on the presence of comorbid conditions and are important in monitoring treatment. If synovial fluid can be aspirated from the joint, it can be tested to confirm inflammation and to rule out other causes of inflammation like infection and crystals. Synovial biopsies, usually done using an arthroscope, show evidence of chronic inflammation, and are sometimes required to rule out chronic infection. As outlined above, imaging is most important in making a diagnosis of PsA.

Standardized Assessment in PSA

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 psoriatic arthritis may be classified as in Box 19-3.

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, methylprednisolone) 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.66 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, glucocorticosteroids 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

There is a paucity of clinical trials with traditional disease modifying agents (DMARDs) in PsA.67 A recently published systematic review and meta-analysis of efficacy and toxicity of DMARDs and biological agents for PsA showed that treatment was more effective than placebo (RR = 0.35; 95% CI 0.25, 0.49) but caused more toxicity (RR = 2.33; 95% CI 1.61, 3.37).67

Methotrexate

Although methotrexate is used most commonly to treat PsA, oral methotrexate (MTX) has been evaluated in only one RCT.68 This 12-week placebo-controlled trial of low-dose oral MTX given at a dose of 2.5–5.0 mg every 12 hours in three consecutive doses per week was terminated early after recruiting only 37 patients. MTX significantly improved physician global assessment, but there were no significant effects on tender and swollen joint scores, patient global assessment, and ESR. However, a retrospective analysis of PsA patients treated with MTX for 24 months therapy compared to a matched cohort not thus treated did not show any difference in radiographic progression scores in the two groups.69 A reappraisal from the same cohort showed that in the last decade treatment with MTX has changed to include patients with shorter disease duration and less damage, at increased dose, and that there may be better response with less progression of damage.70 In spite of lack of evidence from RCTs, based on efficacy in RA and psoriasis, rheumatologists have been using MTX as a first-line DMARD. Patients on MTX require regular monitoring of blood counts, liver function tests, and creatinine. Significant test abnormalities require adjustment of dose or treatment cessation. Although liver toxicity can occur in the absence of abnormal serum liver function tests, regular liver biopsies are not typically ordered by rheumatologists as they may be by dermatologists. The occurrence of liver fibrosis and cirrhosis seem to be higher in patients with psoriasis when compared to patients with RA, reflected in the differing guidelines in rheumatology and dermatology. There is increased prevalence of obesity, metabolic syndrome and type-2 diabetes in patients with psoriasis. Patients with psoriasis treated with MTX and having risk factors for liver disease, especially diabetes type 2 or obesity, are at higher risk of developing severe liver fibrosis compared to those without such risk factors, even when lower cumulative methotrexate doses are given.71 These risk factors are important for nonalcoholic steatohepatitis even when there is no exposure to MTX. Thus it is unclear whether weekly low-dose MTX independently increases risk for cirrhosis. In clinical practice, it will thus be prudent to get serial liver biopsies after a cumulative MTX dose of 1.5 g especially in those patients who have risk factors for fibrosis and cirrhosis such as obesity, metabolic syndrome, type 2 diabetes, viral hepatitis, and significant alcohol use.

Sulfasalazine

Five RCTs have evaluated sulfasalazine (SSZ) in the treatment of PsA; its benefits were moderate.67 In the largest of these, 221 PsA patients were treated with SSZ, 2 g/day, for 36 weeks.72 The psoriatic arthritis response criteria (PsARC) developed specifically for this study showed statistically significant improvement in the treatment group (57.8% for SSZ compared with 44.6% for placebo, P = 0.05). But, the only individual measure within the responder index to do so was the patient global assessment, and longitudinal analysis revealed only a trend favoring SSZ treatment. A systematic review revealed that the effect size for SSZ was less than 0.2, the level required to confirm response.73 SSZ has not been shown to prevent progression of joint damage.74

Leflunomide

Cyclosporine A

Cyclosporine A (CsA) is effective in controlling psoriasis. A three-arm RCT comparing CsA 3 mg/kg/day added to standard therapy, SSZ 2 g/day added to standard therapy, and standard therapy alone, showed that CsA was well tolerated and was more efficacious that standard therapy and SSZ.76 In the most recently published RCT, CsA was compared to placebo as an add-on treatment, in patients with PsA demonstrating an incomplete response to MTX monotherapy. There was significant improvement at 12 months in the swollen joint count, C-reactive protein, PASI, and synovitis detected by high-resolution ultrasound. There was no improvement in the Health Assessment Questionnaire or pain scores.77 Thus, CsA has a role in the management of PsA either on its own or as an add-on treatment to MTX. However, it is not well tolerated. Its effect on joint damage has not been assessed.

Gold

Although not shown to protect from progression of joint damage, Gold has been used in the treatment of PsA, with intramuscular gold being more efficacious.78 With significant concern about toxicity, slow mode of action, problems with availability, and availability of more effective drugs, it is seldom used nowadays.

Apremilast

Anti-TNF Agents

(See also Chapter 234.) Anti-TNF agents have revolutionized the management of PsA. There are currently four agents marketed for the treatment of PsA. In the placebo-controlled portion of the phase 3 Etanercept trial in PsA (n = 205), ACR 20 response was achieved by 59% of Etanercept treated patients versus 15% in the placebo group (P < 0.0001).81 Skin response, as measured by the PASI score in patients with body surface area (BSA) involvement at least 3% showed a 75% improvement in 23% and 3%, respectively at 24 weeks (P = 0.001). Measures of function and quality of life significantly improved. Significant inhibition of progression of joint space narrowing and erosions was shown. In the open label extension of this study, at 2 years, effectiveness was maintained. The drug was well tolerated. A more recent trial compared Etanercept 50 mg twice weekly for 12 weeks, followed by 50 mg weekly, compared with 50 mg weekly throughout in 752 patients with psoriasis affecting >10% of body surface area and at least two swollen and tender joints.82 There was no difference in the response to arthritis at week 12 or 24, although the skin response was better at week 12. No difference in skin response was evident at week 24. Dactylitis and enthesitis also showed improvement from baseline.

In the IMPACT II phase 3 study, Infliximab in 200 PsA patients showed significant benefit. At week 14, 58% of Infliximab-treated patients and 11% of placebo patients achieved an ACR 20 response (P < 0.001). Presence of dactylitis and enthesitis decreased significantly in the Infliximab group. At 24 weeks, PASI 75 was achieved by 64% of the evaluable treatment group and 2% of the placebo group (P < 0.001).83 Infliximab also significantly inhibits radiographic progression, and improves function and quality of life.83,84

In the phase 3 Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT), 313 subjects were studied.85 At 12 weeks, 58% of patients receiving Adalimumab 40 mg every other week achieved ACR 20 response compared with 14% of patients receiving placebo (P < 0.001). PASI 75 was achieved by 59% in the Adalimumab-treated group and 1% in the placebo group (P < 0.001) in those 69 patients in each group who were evaluable for PASI scoring. Radiographic progression of disease was significantly inhibited, and there was improvement in disability and quality of life scores.85

The latest anti-TNF agent to be approved for PsA is Golimumab. In the GO-REVEAL trial, 405 patients active PsA were randomly assigned to receive subcutaneous injections of placebo (Golimumab 50 mg or Golimumab 100 mg every 4 weeks.86 At week 14, 51% of patients receiving Golimumab 50 mg and 45% of patients receiving Golimumab 100 mg achieved an ACR 20 response, compared with 9% of patients receiving placebo (P < 0.001 for all comparisons). Among the 74% of patients in whom at least 3% of the body surface area was affected by psoriasis at baseline, 40% of those in the Golimumab 50 mg group and 58% of those in the Golimumab 100 mg group had at least 75% improvement in the PASI at week 14, compared with 3% of placebo-treated patients (P < 0.001 for both doses). Improvement was also demonstrated in the HAQ score, SF-36, NAPSI, and enthesitis. There was no difference in the arthritis outcomes between the two doses of Golimumab and it is marked only for PsA at a monthly dose of 50 mg. Significant improvement in dactylitis was seen only in the 100 mg dose, although a trend was evident with the 50 mg dose.86 Golimumab was also shown to inhibit progression of radiographic damage.87

Thus, the anti-TNF agents have shown the greatest efficacy of any treatment to date in the various clinical aspects of PsA. Their efficacy in joint disease activity, inhibition of structural damage, function, and quality of life are similar, and they are well tolerated, with injection site reactions being the most significant. On comparing with traditional DMARDs, anti-TNF agents had the best efficacy/toxicity ratio (number needed to harm/number needed to treat = 0.25); tolerability was least with gold and leflunomide, and poor with SSZ.67 There are no direct head-to-head trials comparing the efficacy of various anti-TNF agents in PsA. However, a meta-analysis of anti-TNF RCTs showed that the three anti-TNF agents [(1) Infliximab, (2) Etanercept, and (3) Adalimumab] were significantly more effective than placebo.88 There were no significant differences between anti-TNF agents and placebo in the proportions of patients experiencing withdrawal for any reason, due to adverse events, serious adverse or upper respiratory tract infections. Pooled rates for injection site reactions were significantly higher for Adalimumab and Etanercept than for placebo, but there was no significant difference in the proportion of patients experiencing infusion reactions with Infliximab compared against placebo. Indirect analysis did not demonstrate any significant differences between the anti-TNF agents.88

Data from biologics registries that have been maintained in Europe suggest that drug survival (the length of time a patient continues to take a particular drug) of anti-TNF agents is significantly higher in SpA compared to RA.89,90 Concomitant MTX was associated with better drug survival in RA and PsA, but not for AS.90,91 There is a tendency toward shorter persistence with treatment for Infliximab when compared with Etanercept and Adalimumab.91,92 Risk factors for drug discontinuation include female sex, comorbidity, using Infliximab rather than Etanercept, and absence of concomitant therapy with MTX.91,92

Ustekinumab

(See also Chapter 234.) Ustekinumab is 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.93 A phase 2 trial in 146 subjects with PsA showed that at week 12, 42% of patients in active arm and 14% in the placebo arm achieved an ACR 20 response (p = 0.0002).94 Of 124 participants with psoriasis affecting 3% or more body surface area, 52% in the active arm and three of 5% in the placebo arm had a PASI 75 response (p < 0.0001). The drug was well tolerated.94 A larger phase 3 trial is underway.

Anti T Cell Agents

(See also Chapter 234.) Alefacept is a fully human lymphocyte function associated antigen-3/immunoglobulin G1 fusion protein that targets memory-effector T cells is an effective therapy for psoriasis.95 In combination with MTX, Alefacept is efficacious in PsA. In a phase 3 trial with 185 patients, 54% of patients in the Alefacept plus MTX group achieved an ACR 20 response, compared with 23% of patients in the placebo plus MTX group (P ≤ 0.001) at week 24.96 In patients with psoriasis involving ≥3% BSA (n = 87), a PASI 50 response at week 14 was achieved by 53% of patients receiving Alefacept plus MTX compared with 17% of those receiving placebo plus MTX (P < 0.001).96 Alefacept in combination with MTX is thus a treatment option in patients failing standard therapy.

Abatacept (CTLA4-Ig) is a recombinant human fusion protein that binds to the CD80/86 receptor on an antigen-presenting cell, thus blocking the second signal activation of the CD28 receptor on the T-cell. It is approved for use in RA.97 Results from a phase 2 study using Abatacept in PsA show that Abatacept at 10 mg/kg significantly improved ACR 20 and physical function in PsA patients. Abatacept treatment also resulted in less joint damage by MRI evaluation.98

Surgical Procedures

There are few studies addressing surgery in patients with PsA. It has been reported that about 7% of the patients with PsA require surgery and that the likelihood of surgery increased with disease duration.99 The average disease duration at the time of surgery was 13 years. The most common surgical procedure was total hip replacement followed by total knee replacement. Joint replacement in the metacarpophalangeal joints was also performed, followed by fusion surgery for the fingers, wrists, and ankles. Few patients had synovectomies, including knee, wrist, and elbow. The majority of the patients had only one procedure, but in 28% several procedure were performed. The upper and lower extremities were involved in a similar number of patients with few patients having both upper and lower extremity surgery. Surgery was predicted by the number of actively inflamed joints and the extent of X-ray damage at presentation to the clinic. Patients with the highest number of severely affected joints both clinically and on radiographs were more likely to have surgery. Although patients who had surgery had more severe disease, their health outcomes were not worse than those who did not have surgery.99 In another study of the type and outcome of reconstructive surgery for different patterns of psoriatic arthritis over a 10-year period was studied.100 The patients were divided into three groups: (1) distal joint involvement, (2) oligoarticular, and (3) polyarticular. It was shown that the majority of patients had polyarticular disease. The majority of the operations done in this group of patients included complex hand and foot reconstruction, followed by hip replacements, and surgical fusion of different joints. In the oligoarticular group most of the procedures involved joint replacement, usually the hip or knee. Patients with distal arthritis had fusions in the distal joints. Patients with polyarticular disease had lower level of physical functioning according to the scores on the physical function domain of a quality of life questionnaire. Patients with severe axial arthritis may develop marked deformity of the spine and on occasion require surgery to correct this deformity. While there are no reported studies specifically describing spinal surgery in patients with PsA, the procedures are similar to those performed in patients with AS.

Recommendations from GRAPPA

Based on formal literature reviews of therapies for peripheral joints, spine, skin and nails, enthesitis, and dactylitis, the GRAPPA group has developed a treatment grid categorizing each domain as mild, moderate, or severe based on measures of disease severity and impact on function and quality of life in order to help clinicians with treatment decisions.101 GRAPPA recommends that all domains of the disease be considered to define severity of “psoriatic disease.” The worst individual domain should guide the management of all domains of PsA. Thus, if the skin domain is severe, but the peripheral arthritis is mild, the patient is classified as heaving severe disease and treated for severe psoriasis as appropriate. GRAPPA has also suggested treatment strategies applicable to patients worldwide.