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Dermatologic Therapy, Vol. 23, 2010, 123–136 © 2010 Wiley Periodicals, Inc. Printed in the United States · All rights reserved DERMATOLOGIC THERAPY ISSN 1396-0296

Psoriatic arthritisdth_1306 123..136

Uwe Wollina*, Leonore Unger†, Birgit Heinig‡ and Thomas Kittner§ *Department of Dermatology and Allergology, †Department of , ‡Centre for and Rehabilitation, and §Department of Radiology, Hospital Dresden-Friedrichstadt, Academic Teaching Hospital of the Technical University of Dresden, Dresden, Germany

ABSTRACT: Psoriatic (PSA) is an entity of inflammatory disease associated with psoria- sis. PSA belongs to the heterogeneous group of seronegative spondylarthropathies. Both peripheral and axial skeleton can be affected in a characteristic pattern. In addition to that, and are important extracutaneous manifestations. anterior is temporarily seen in about one quarter of PSA patients. There is a closer relationship of nail and joint disease. This review provides data on drug and physical treatment options. In particular DMARDS and inhibitors of a are established therapies with importance for quality of life and long term outcome. New drugs are tested in various trials.

KEYWORDS: biologics, dactylitis, DMARDS, enthesitis, , treatment, uveitis

History, definition, and classification Table 1. Classification criteria for psoriatic arthri- of psoriatic arthritis tis (CASPAR) 1. Criterion – inflammatory disease of joints, spine or The possible relationship between and /enthesis (2 points) inflammatory joint disease was recognized first by and French medicine since early 19th century (1,2). In 2. At least one of the following criteria (1 point each) 1973, Moll and Wright defined psoriatic arthritis 1. Psoriasis (skin, scalp) – now (PSA) as: inflammatory arthritis (peripheral) and/ 2. Psoriasis in patient’s history or or , with psoriasis but 3. Psoriasis in family history negative (3). Current under- 4. Psoriatic nail involvement (now) standing sees PSA as a seronegative inflammatory 5. Rheumatoid factor negative (ELISA) disease of joints, entheses and periarticular con- 6. Dactylitis (now) 7. Dactylitis in patient’s history nective tissue in association with any clinical type 8. Radiological signs of new bone formation of psoriasis (4). There is no particular laboratory adjacent to the joints (except ) parameter for diagnosis. Rheumatoid factors or PSA can be considered to be definite when at least 4 anti-cyclic citrullinated antibodies are seen in 4.7% criteria are fulfilled. and 7.6%, respectively (5). PSA can be classified according to the CASPAR criteria (Table 1) with a specificity of 98.7% and a sensitivity of 91.4% (5). A lower sensitivity of 77.3% was noted in early disease (6). Epidemiology

Address correspondence and reprint requests to: Uwe Wollina, Most PSA patients show skin manifestations first MD, Department of Dermatology and Allergology, Academic but 15% develop extracutaneous manifestations Teaching Hospital Dreseden-Friedrichstadt, Friedrichstrasse before onset of psoriasis (4,7). In a recent analysis of 41, 01067 Dresden, Germany, or email: [email protected]. 2009 psoriasis patients 19% had PSA. Another 7.7%

123 Wollina et al. had intermittent but clinically unspecific joint Who is at risk for PSA? symptoms, which could not be clearly attributed to PSA (8). Figures are lower from Asian countries A prevalence study in Reykjavik (Iceland) demon- (1–9%) (9). There is reason to believe that PSA inci- strated that the relative risk for PSA in first degree dence is increasing. In Olmsted County, Minnesota relatives is 39, reflecting a strong genetic compo- in the United States, age- and sex-adjusted inci- nent (19). Psoriasis features associated with higher dence of PSA per 100,000 increased from 3.6 (1970 risk of PSA are scalp lesions (hazard ratio [HR] 3.89, to 1979) to 9.8 (1990 to 2000). Reasons for the 95% CI 2.18–6.94), nail dystrophy (HR 2.93, 95% CI increase are unknown, but greater physician aware- 1.68–5.12), and intergluteal/perianal lesions (HR ness of the diagnosis seems to be a possible factor 2.35, 95% CI 1.32–4.19) (20). Psoriasis patients with (10). asymptomatic enthesopathy seem to be at risk to In general, there is no relationship between develop PSA later (21). severity and extension of cutaneous manifesta- tions and articular manifestations but PSA patients in dermatological care tend to have a higher pso- Clinical findings and course riasis area and severity score (PASI) than rheuma- tologic PSA patients (11). PSA is seen mostly in adults but other age groups can also be affected. The natural course is charac- terized by flares and remissions (4). Primary Pathogenesis diagnosis is clinical. Joint affection can be monoar- thritic, oligoarthritic, or polyarthritic (Table 2) (22). The etiology of PSA although not completely under- (58.7%) is the most common manifes- stood genetic, environmental and immunologic- tation pattern, followed by (31.6%) factors. Genetic analyses suggest two genetic and (4.9%). Distal interpha- pathways in PSA, one is through human leukocyte langeal involvement is present in 41.0% and dac- (HLA) alleles B*27 and B*39, another is tylitis in 23.7% of patients (23). PSA specific is the through the function of haplotypes containing the distal arthritis of finger or (FIG. 1) whereas the HLA-allele Cw*0602 (12). PSA has a well-recognized knee is most commonly affected in PSA monoar- propensity for aggressive bone erosions. In some thritis (FIG. 2) (22). The spine can be involved in individuals, however, periarticular bone mineral- any part, but most often at lumbosacral transition ization is maintained, and there is often associated and the neck. Sacroiliacal joints are typically new bone formation with periostitis and frank affected asymmetrical with and stiffness suggesting a disorder of bone remodeling in the morning (FIG. 3). also far from the inflamed joints (13). T-cell driven immunopathology, pro-inflammatory cytokines in Table 2. Clinical types of psoriatic arthritis synovial tissue and the ability of peripheral mono- nuclear blood cells to produce osteoclasts in vitro Asymmetric mono- or most common type, most are hallmarks of the interaction of inflammation oligoarthritis affected are digits, knees, and and bone remodeling (14). Among the mechanisms ankle of abnormal bone remodeling mediators of osteo- Symmetric arthritis -like clastogenesis such as RANK ligand and molecular Mutilating arthritis rare type (<5% of patients) with signaling pathways including Dickkop-1 and bone marked deformities and morphogenetic proteins seem to be involved functional impairment Spondylarthritis mostly HLA B27-positive, with (15,16). spondylitis and sacroiliitis, Neuropeptides, nerve growth factor (NGF) and spondylitis ankylosans-like, its receptors (NGF-R) contribute to the inflamma- in later stages roentgenologic tory joint disease of PSA (4). Human synovial cells differences like the formation produce and release NGF and express high-affinity of para-syndesmophytes NGF-tyrosine kinase receptor TrkA/NGF. NGF Other types enhances the expression of TrkA and down- SAPHO syndrome sternoclavicular hyperostosis regulates IL-1 beta-induced TNF-alpha and iNOS and osteitis, palmoplantar production by synovial fibroblasts (17). NGF may pustular psoriasis to synovial cell proliferation, and thus could Psoriatic thickening of nail plates and/or influence the inflammatory and proliferative cas- pachydermo- , dactylitis, periostosis thickening of the bone cades of inflammatory arthritis (18).

124 Psoriatic arthritis

a

b FIG. 2. Goanarthritis – one of the more common sites for oligioarthritic PSA.

c

FIG. 1. Peripheral arthritis of small joints in PSA. (a) Distal FIG. 3. Axial involvement with characteristic parasyndes- joint affection and nail involvement. (b) Arthritis mutilans mophytes of the spine. with telescope joints. (c) X-ray findings of the same patient as in (b) demonstrating severe joint destructions and dislocations. both the immediately adjacent trabecular bone networks and in some cases deep fascia (25). The PSA characteristic “sausage” fingers or Enthesitis remains an elusive clinical feature: are caused by dactylitis (FIG. 4). By palpation both recent data confirmed the poor association dactylitis and peripheral arthritis in PSA cause a between clinical and ultrasonographic enthesitis in more tender sensation than in RA. Dactylitis PSA (26). appears to be a severity marker for the disease (24). The nail is functionally integrated with entheses A very characteristic and often painful manifes- associated with the distal phalanx that provides tation of PSA is enthesitis (FIG. 5). Collectively, the anchorage to the skin and joint (27). When the nail fibrocartilages, bursa, fat pad, and the enthesis organ is involved in nail psoriasis, a secondary itself constitute the enthesis organ. It also includes affection of the joint may develop as vice versa (28)

125 Wollina et al.

FIG. 6. Pachydermoperiostitis of the great toe in PSA.

tion consists of plain-film X-rays of the peripheral skeleton focused on small joints of feet and hands. High resolution sonography is a useful tool to evaluate of joint disease (32). X-ray computed tomography (CT), today FIG. 4. Dactylitis digit II and II in combination with articular modified as multi-detector-/multi-row-CT (MD) involvement of distal and proximal interphalangeal joints. provides excellent spatial resolution down to tiny submillimeter structures based on isotropic volume elements (Voxel’s) for multiplanar image reformation. Because it is associated with a high radiation exposure, it should be avoided in younger patients with childbearing potential. Magnetic resonance imaging (MRI) provides an excellent soft tissue contrast. MRI can give clinically relevant additional information by spine and sacroiliacal joint examinations (33). MRI-based scoring systems are under investigation (34). MRI sensitivity can be further increased by the use of intraveneous contrast (e.g., gadolinium-chelates) for early stages of PSA (35). One should be aware that a negative X-ray and other imaging techniques do not exclude PSA. Typical PSA findings on X-ray images are bony erosions (lytic subchondral cysts, mutilations) FIG. 5. Enthesistis at the insertion of the Achilles . combined with proliferations (i.e. protuberances, periostal ossifications along diaphysial parts) (FIG. 7). Calcifications of joint capsules, periar- (FIG. 6). Therefore, nail involvement may be an ticular connective tissue and the insertion of indicator for PSA (29). The 20 MHz sonography is a tendons may occur in an irregular order. In useful tool for follow-up of nail disease (30). Like approximately 30%, the distal interphalangeal other spondylarthopathies, PSA has an increased (DIPs) joints of fingers and toes are involved risk for acute anterior uveitis with a prevalence of (transversal type) (4). 25.1% (31). The axial type with involvement of at all joints of a digit can be seen in 10% of all cases. In the major- ity of PSA cases asymmetric joint involvement Radiologic findings combining DIPs, proximal IPs, and the metacarpo- phalangeal joints built the radiological picture. Several radiological imaging techniques can be Arthritis of smaller joints is more frequent (50%) used to diagnose PSA. The typical initial examina- than those of the larger ones (10%). The sacro-iliac

126 Psoriatic arthritis

FIG. 7. Typical erosions and mutlitation with “pencil-in-cup” formation of distal interphalangeal joints.

joint space, and bony ankylosation. Erosive changes are localized predominantly in the iliacal part, not the sacral (4,34). In case of spine affection, typical paravertebral ossifications are found (parasyndesmophytes) (FIG. 3). They may occur isolated adjacent to the intervertebral space or can develop in a short dis- tance to the roof and basal plate of the vertebral bodies starting in a horizontal direction followed by a perpendicular growth. Syndesmophytes are rare in PSA (FIG. 9). Non-articular inflammatory changes (periostitis, tendinitis, enthesitis) may be seen in several regions (34).

Differential diagnosis

Because RA is the most common differential diag- nosis of PSA, major findings of both disorders are summarized in Table 3. Indeed, rheumatoid arthri- tis can occur in a patient with psoriasis. Gonarthri- tis, although a typical manifestation of PSA, can also be found in and . Activated is another . Distal joint affection of fingers and toes is often FIG. 8. Bilateral ankylosis of the sacro-iliacal joint. seen in PSA. The most common differential diagnosis in particular in females is Heberden’s arthrosis. For axial skeleton involvement other joints are affected in more the 50% of cases, usually spondylarthropathies including spondylitis anky- bilaterally but asymmetric (FIG. 8). Unilateral losans have to be considered. Radiological differ- involvement occurs in 20%. Isolated sacroiliitis ential diagnosis has to include disorders like without peripheral symptoms is rare. The combi- erosive osteoarthrosis (more elderly patients, more nation with spinal affection can be found more symmetric order), (parasyn- frequently (20% lumbar spine). The affected sacro- desmophytes are for PSA) and iliacal joint shows blurred contours, subchondral atypical manifestations of rheumatoid arthritis as erosions / sclerotic formations, widening of the well (22,34).

127 Wollina et al.

FIG. 9. Cervical spine involvement of PSA, in this case with syndesmophytes.

Table 3. Clinical findings and differential diagno- those with controlled polyarticular disease but one sis of rheumatoid arthritis (RA) and psoriatic or two persistently actively inflamed joints (37). arthritis (PSA) Disease modifying drugs (DMARDS). DMARDS Finding RA PSA remain the first choice for the treatment of periph- Morning stiffness > 1h +++ + eral arthritis despite scarce evidence of their effi- Arthritis > 3 joints +++ - cacy or ability to halt radiographic progression. Arthritis of the hand +++ + Effective DMARDS in PSA are (MTX), Symmetrical arthritis +++ +/- , A, and leflunomide Rheumatoid nodules +++ - (38). MTX is used once a week (15–50 mg) with a Rheumatoid factor ++ +/- Erosions and demineralization ++ (later) +/- good efficacy on skin disease, some effects on (wrist) joints, low costs, and mostly mild adverse effects on Dactylitis - +++ liver and blood. Bioavailability is better with sub- New bone formation (near - +++ (later) cutaneous injections than oral application (39,40). joints) Folic acid (5 mg) given 24 h later reduces potential Affection of distal finger/toe - +++ adverse effects (4). Some studies are in favor of an joints earlier treatment with higher dosages than previ- ously used. Response rates up to 68% could be achieved (41,42) associated with an improvement of health related quality of life (43). MTX increases Enthesiopathy is seen in reactive arthritides like drug survival and reduces drop-outs during treat- Yersinia-associated arthritis, in SAPHO syndrome, ment with biologics (44,45). ochronosis, acromegaly, diffuse idiopathic hyper- There are five randomized controlled trials ostosis, and fibromyalgia (4). (RCT) for sulfasalazine available that suggest some effect in milder forms of peripheral but not axial arthritis (38). Ciclosporin A is used at a Treatment dosage of 2.5–5 mg/kg body weight. RCTs have not been performed in PSA. Available data suggest 1. Drug therapy (Tables 5 & 6) some effect on arthritis, good response of skin disease and improvement of arthritis-related pain Symptomatic therapy. Peripheral mild mono- or (46). oligoarticular and axial PSA, dactylitis and enthesi- Leflunomide treatment is started with a “loading tis benefit from nonsteroidal anti-inflammatory dose” of 100 mg/d for three days, followed by drugs (NSAID) (36). of small joints 20 mg/d. The anti-inflammatory effect is in the can be treated by periarticular range of MTX but without any beneficial effect on injections (4). Periodic intra-articular injection of skin disease. The TOPAS study involved 190 PSA corticosteroid are of particular value in the man- patients treated with leflunomide for 6 months. agement of patients with oligoarticular disease or The American College of Rheumatology 20% crite-

128 Psoriatic arthritis

Table 4. Pharmacokinetics of tumor necrosis factor-a inhibitors infliximab, , and

Half-life Maximum concentr. Minimum concentr. Average concentr. AUC0-T (mg h/L) Drug (days) (mg/L) (mg/L) (mg/L) steady state Infliximab 7.6 165 Ϯ 42 8.3 Ϯ 11.9 37.1 120,000 Ϯ 37,000 i.v. (5 mg/kg) (5 mg/kg) (5 mg/kg) (5 mg/kg) (5 mg/kg) 10 299 7.11 58.2 (10 mg/kg) (10 mg/kg) (10 mg/kg) (10 mg/kg) Etanercept 2.8 Ϯ 0.8 2.5 Ϯ 0.5 at 53 Ϯ 35 h 1.5 Ϯ 0.6 1.9 Ϯ 0.5 321 Ϯ 83 s.c. (25 mg) (25 mg BIW) (25 mg BIW) (25 mg BIW) (25 mg BIW) 4.9 Ϯ 2.5 at 69 Ϯ 48 h 3.1 Ϯ 1.6 3.7 Ϯ 2 600 Ϯ 291 (50 mg BIW) (50 mg BIW) (50 mg BIW) (50 mg BIW) Adalimumab 10–20 7.7 Ϯ 3.4 at 90 Ϯ 48 h 3.8 Ϯ 2.1 5.5 Ϯ 2.5 1830 Ϯ 850 s.c. (40 mg) steady state steady state steady state

Table 5. Overview about randomized controlled trials in PSA with documented ACR response

ACR20 (verum versus Drug No. Pts. Rx placebo/control) Reference Leflunomide 190 20 m/d, orally 36.6 vs. 20% (week 12) (47) Infliximab 104 5 mg/kg bwa, iv 65% vs. 10% (week 16) (53) Infliximab 200 5 mg/kg bwa, iv 54% vs. 16% (week 98) (55) Etanercept 60 25 mg tawc, sc 25% vs. 13% (week 12) (57) Etanercept 752 50 mg weekly versus eawb, sc 66% or 77% (week 12) (61) Adalimumab 313 40 mg eaw, sc 58% vs. 14% (week 24) (63) 405 50/100 mg sc 1¥ mo, sc 48% vs. 9% (week 12) (74) Alefacept 185 15 mg weekly + MTX, im versus MTX alone 54% vs. 23% (MTX alone) (57) 146 90/63 mg sc 42% vs. 19% (week 12) (74)

abw, body weight; beaw, every other week; ctaw, twice weekly. iv, intravenous; im, intramuscular; mo, month. ria for improvement in rheumatoid arthritis (ACR constant = 0.908 Ϯ 0.121 per day (51). Association 20) response was 36.6% in the leflunomide group and dissociation rates of binding to soluble and 20% in the placebo group (p = 0.0138) (47). TNF were found to be similar for adalimumab, Leflunomide is approved for PSA in Europe. infliximab, and etanercept, as were their calculated Combinations of DMARDS have not systemati- binding affinities. Avidity of binding to soluble TNF cally been studied. In a single 12 months RCT was 10- to 20-fold greater for soluble etanercept comparing MTX with MTX plus ciclosporin A (n = (K(D) = 0.4 picomolars [pM]) than for soluble adali- 72) both the tender joint score and the PASI score mumab or infliximab (K(D) = 8.6 and 4.2 pM, were significantly lower with the combined respectively) (52). treatment (48). Infliximab. More than 300 patients with PSA were Tumor necrosis factor-a inhibitors (TNFaI). The proof recruited into the IMPACT and IMPACT 2 trials. of concept of use of TNFaI in PSA was done in an Patients received infusions of infliximab (5 mg/kg) open MRI-controlled study with 10 PSA patients or placebo at weeks 0, 2, 6, and 14. After week 16, with polyarticular affection and infliximab for 10 patients initially assigned to receive placebo weeks (49). The first symptom that responds to crossed over to receive infliximab 5 mg/kg every 8 intravenous infliximab is arthritis-related pain weeks through week 50, while patients initially ran- (50). There is now a range of TNFaI available for domized to infliximab continued to receive active PSA patients. Pharmacokinetics of the infliximab treatment at the same dose through week 50. etanercept and adalimumab are summarized in Sixty-five percent of infliximab-treated patients Table 4. Available data for a patient of standard achieved an ACR20 response at week 16 (65%), but weight (70 kg) with golimumab are: apparent clear- only 10% with placebo (53). Infliximab significantly ance = 1.38 Ϯ 0.04 L/d, apparent volume of distri- inhibited radiographic progression in patients with bution = 24.9 Ϯ 1.04 L, and absorption rate PSA as early as 6 months after starting treatment,

129 Wollina et al.

Table 6. Treatment algorithm for PSA modified according to Ritchlin et al. (99)

Therapeutic target Initial therapy Second line therapy Peripheral arthritis NSAIDs, intraarticular , Combined treatment DMARDs, in severe cases: TNFaIs Axial arthritis NSAIDs, physiotherapy, pain management, TNFaIs alone or in combination with MTX in moderate to severe cases: TNFaIs Enthesitis NSAIDs, physiotherapy, corticosteroids, TNFaIs (infliximab, etanercept) in severe cases: TNFaIs Dactylitis NSAIDs, corticosteroids, DMARDs TNFaIs (infliximab)

and the beneficial effect continues through one period followed by another 12-week open label year of infliximab therapy (54). period with 50-mg etanercept every week. The In the 2-year follow-up of IMPACT, 62% (48/78) ACR20 and PSARC at week 12 were 66% and 77% of infliximab-treated patients achieved an ACR20 (biweekly etanercept), and 61% and 76% (weekly response, while 45% and 35% of patients achieved etanercept), respectively. ACR50 and ACR70 were ACR50 and ACR70 responses, respectively. The 45% and 41%, and 35% and 37%, respectively (61). average estimated annual radiographic progres- At week 24 ACR20 was 69% and 72%, PSARC was sion with infliximab treatment was significantly 82% and 80%, respectively. Both treatment modali- reduced versus the estimated baseline rate of ties obtained comparable results for improvement progression. No new safety issues were observed of enthesitis, DLQI and C-reactive protein (62). during the second year of the study (55). Safety considerations: The US FDA does not Safety considerations: Screening for latent TB require any monitoring but this might be different (through a PPD and/or chest x-ray) should be done in other states. It is recommended that the follow- at baseline. Other optional tests conducted at base- ing tests be undertaken at baseline: PPD and line include: BUN, creatinine, SGOT, SGPT, hepati- or/chest x-ray, BUN, creatinine, SGOT, SGPT, hepa- tis C serology, and b-HCG (to exclude gravity). titis C serology, and b-HCG. Consider three peri- Consider periodic CBC and clinical follow up every odic CBC, ESR, and clinical follow up every 3 three months (56). months (56).

Etanercept. In an RCT with 60 patients with Adalimumab. In the ADEPT trial patients with either PSA or psoriasis over 12 weeks, efficacy and moderately to severely active PSA and a history of safety of etanercept (25 mg twice-weekly subcuta- inadequate response to NSAIDs were randomized neous injections) or placebo was assessed. The to receive 40 mg adalimumab or placebo subcuta- ARC20 was achieved by 22 (73%) of etanercept- neously every other week for 24 weeks. At week 12, treated patients compared with four (13%) of 58% of the adalimumab-treated patients (87 of 151) placebo-treated patients. Etanercept was well tol- achieved an ACR20 response, compared with 14% erated (57). A total of 1122 patients who had of the placebo-treated patients (23 of 162) (p < active PSA were enrolled in a Phase 4, non- 0.001). At week 24, similar ACR20 response rates randomized, open-label, single-arm, 24-week were maintained and the mean change in the study. They received etanercept therapy 50 mg modified total Sharp score was –0.2 in patients subcutaneously once weekly for 24 weeks. After 24 receiving adalimumab and 1.0 in those receiving weeks of treatment, 865 patients (77.1%) achieved placebo (p < 0.001). Disability and quality of life a “mild or better” score on the physician global measures were significantly improved with adali- assessment of psoriasis and were improved from mumab treatment compared with placebo. Adali- baseline. Patient global assessment of joint pain mumab was generally safe and well tolerated (63). and joint disease scores were improved by means Patients who completed ADEPT could elect to of 2.7 and 1.5, respectively (58). A sustained receive open-label adalimumab, 40 mg subcutane- benefit of treatment, including inhibition of radio- ously every other week after week 24. At week 48, graphic progression, was observed during 3 years patients from the adalimumab arm of ADEPT (n = of treatment (59,60). 151) had achieved ACR20, ACR50, and ACR70 The PRESTA trial for adult PSA patients (n = 752) response rates of 56%, 44%, and 30%, respectively. compared 50 mg etanecerpt biweekly with 50-mg Improvements in disability were sustained from etanercept every week in a 12-week double-blinded week 24 to week 48. Adalimumab demonstrated

130 Psoriatic arthritis clinical and radiographic efficacy regardless of weeks, etanercept 50 mg weekly, or adalimumab whether patients were receiving methotrexate 40 mg every other week. ACR20 response rates after (MTX) at baseline (64). The clinical and radio- 12 weeks were 75%, 72%, and 70%, respectively. graphic efficacy of adalimumab demonstrated Two drug-related adverse reactions were seen in during short-term treatment was sustained during patients with infliximab, none with the other long-term treatment (120 weeks) with a favorable TNFaIs. Etanercept showed the greatest improve- risk-benefit profile (65). ment of tender joints count, whereas infliximab Safety considerations: The FDA requires that and adalimumab achieved the greatest reduction patients be screened for latent TB (PPD and/or in PASI score (70). chest x-ray), routine CBC/chemistries at baseline, An observational study in the UK analyzed effi- and anti-dsDNA antibodies if -like symptoms cacy and safety of TNFaIs in 596 PSA patients. are present. In addition b-HCG, liver function tests, Disease activity was measured by the EULAR and RFT, can be considered at baseline (56). response. The study found that 75.8, 70.3 and 68.2% of the PSA cohort were EULAR responders at Golimumab. In the recent GOREVEAL trial adult 6, 12 and 18 months, respectively. After 18 months patients with PSA who had at least three swollen a good EULAR response was achieved 52% (etan- and three tender joints and active psoriasis were ercept), 53% (infliximab), and 58% (adalimumab) randomly assigned to receive subcutaneous injec- of those remaining on initial therapy. The inci- tions of placebo (n = 113), golimumab 50 mg (n = dence rate of severe adverse reactions (0.9) was 146), or golimumab 100 mg (n = 146) every 4 weeks not increased compared with a control group of through week 20. At week 14, 48% of all patients seronegative RA patients on DMARDs (71). receiving golimumab achieved an ACR20 response compared with 9% of patients receiving placebo (p Other biologics < 0.001 for all comparisons). Significant improve- ment was observed for quality of life scores (SF-36; Alefacept. Alefacept is a bioengineered fusion HAQ), the nail disease, and enthesitis. This efficacy protein of soluble lymphocyte function was maintained through week 24. Golimumab was (LFA-3) with Fc fragments of IgG1. A single course generally well tolerated (66). of alefacept intramuscularly in combination with methotrexate (MTX) was effective in treating both Certozilumab pegol. Cetrozilumab pegol is the psoriasis and psoriatic arthritis (PSA). ACR20 was recombinant antibody Fab’ fragment of a human- achieved in 54% of patients of the verum group ized TNFa inhibitory monoclonal antibody. A compared to 23% with MTX alone (72). phase II trial in psoriasis demonstrated superiority In an open-label extension study, patients with of 200 mg and 400 mg s.c. injections given every PSA on stable doses of MTX were treated with an other week over placebo (67). Adverse effects are additional 12 weekly intramuscular injections of comparable to other TNFaIs. alefacept followed by 12 weeks of observation. At the end 86 of 160 (54%) patients achieved ACR20, General safety considerations. All TNFaIs can of which 28 of 55 had received placebo plus MTX induce psoriasis in PSA patients, mostly of the pus- and 58 of 105 received alefacept plus MTX in the tular palmoplantar type. Usually this side effect can prior double-blind phase. Those patients achiev- be controlled by switching the treatment to ing ACR50 and ACR70 increased from 17% and another compound and topical therapy or PUVA 7%, respectively, in the double-blind phase to 32% therapy for palmoplantar lesions. The pathogen- and 12%, respectively, in the open-label extension esis, however, is not fully understood (68). Other phase. No additional toxicity was observed (73). possible adverse effects are infusion reactions Alefacept has been approved in the United States. (only for infliximab), lupus-like disorders, vasculi- Safety considerations: The FDA requires that a tis, granulomatous reactions, infections, neoplasia, CD4 level be taken at baseline and then weekly. and central nervous system-related adverse effects Alefacept should be held if the CD4 drops <250 (69). cells/mL. Other possible tests to undertake include a PPD and chest x-ray, b-HCG, CBC with differen- Comparative trials of TNFaIs. Atteno et al. (2010) tial, liver function test, and RFTs at baseline (56). investigated the effectiveness and safety of three in 100 consecutive PSA patients with inadequate Ustekinumab. Ustekinumab is a fully human response to DMARDs. After enrolment, all patients monoclonal antibody that binds with high specific- were randomly given infliximab 5 mg/kg every 6–8 ity and affinity to the cytokines interleukin (IL)-12

131 Wollina et al. and IL-23, thereby suppressing IL-12- and IL-23- presenting cells that must interface with the T-cell mediated inflammation associated with psoriasis CD28 receptor to activate T cells (75). Rituximab is (67). a monoclonal anti-CD20 antibody leading to B-cell In a phase II double-blind, randomized, depletion (67). Sipiluzimab is a humanized mono- placebo-controlled, crossover study patients with clonal IgG1 antibody against CD2 selectively inhib- active PSA were randomly allocated either usteki- iting activation and proliferation of T-memory numab (90 mg or 63 mg) every week for 4 weeks cells. Antipsoriatic activity has been shown (76). (weeks 0–3) followed by placebo at weeks 12 and Orthoclone is a humanized antihuman CD4 IgG4 16 (n = 76; Group 1) or placebo (weeks 0–3) and antibody preventing T-cell activation via MHC ustekinumab (63 mg) at weeks 12 and 16 (n = 70; receptor binding (77). Two anti-CD25 antibodies, Group 2). At week 12, 32 (42%) patients in Group 1 i.e. basiliximab and daclizumab, have been shown and ten (14%) in Group 2 achieved an ACR20 anti-psoriatic activity (78,79). Galiximab is a pri- (difference 28% [95% CI 14.0–41.6]; p = 0.0002). matized monoclonal antibody that binds to CD80 Ustekinumab significantly reduced signs and found on certain T-cells and antigen-presenting symptoms of PSA and diminished skin lesions cells (80). compared with placebo, and the drug was well tolerated (74). 2. Physical therapy Other new treatment options. is a In addition to the use of drugs, physical therapy of the cytotoxic T-lymphocyte and ergotherapy are regarded as definite parts of antigen (CTLA) molecule and IgG1 that blocks the multimodal therapy concept for PSA. An over- CD80 and CD86 ligands on the surface of antigen- view is given in table 7.

Table 7. Physical therapies in PSA

Treatment Mechanisms and techniques References Kinesiotherapy passive methods include positioning, mobilization, stretching, tractions, (81–83) Maitland’s oscillatory mobilization, active kinesiotherapy deals with isometric tensing, exercises, complex or axial movements, movements, against low level resistance, movements in water bath, kinesiotherapy with devices and gait analysis Manual therapy frictions at the muscle and tendon regions, “deep frictions” by Cyriax (81,84) applied diagonally to the fiber, lines of muscles and tendons Thermotherapy mainly practiced in chronic stages (85) Cryotherapy local cryotherapy often used in acute arthritis, cryotherapy (15°C to (86–88) –180°C) for 1–3 min, for pain relief, normalization of muscular tonus, and active hyperemia, longer application (3–30 min) reduces pain, , and inflammation Therapeutic ultrasound/ therapeutic ultrasound is analgetic, anti-inflammatory, muscular (89,90) phonophoresis relaxing, phonophoresis = combination of ultrasound, antiphlogistic lipophilic drugs, higher efficacy Electrical stimulation galvanization, i.e., application with a frequency of 0 Hz, constant current (91–95) (CC)-wiring and constant voltage (CV)-wiring are known; electrical flow, two- or four-chamber bath, iontophoresis = galvanization for directed drug transport, transcutaneous electrical nervous stimulation (TENS; f = 20–100 Hz), interferential electrical stimulation (100 Hz, carrier frequency 4000 Hz), short-wave therapy (27 MHz) = high-frequency electrical stimulation with a condenser field method Massage therapy classic massage, reflex zone massage; gadget massage (e.g., (96,97) hydromassage), and lymphatic drainage Balneotherapy application of natural and specific local healing remedies during (98,99) complex rehabilitation, often in combination with climatotherapy; thermal salts therapy (26–28% saturated salt brine with pH 5.6), sulfurated bath (alkaline-muriatic sulfur springs), or radon baths Ergotherapy functional orientated kinesiotherapy of the extremities for preserving (79,99) personal independence

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