Psoriatic arthropathy

classification

1. Tutorial presentation Psoriatic arthropathy Moderator:- Dr. Deepak K. Mathur

2. Introduction to Psoriatic Arthritis (PsA) Chronic progressive, inflammatory disorder of the joints and skin 1 Characterized by osteolysis and bony proliferation 1 Clinical manifestations include dactylitis , enthesitis , osteoperiostitis , large joint oligoarthritis , arthritis mutilans , sacroiliitis , spondylitis , and distal interphalangeal arthritis 1 PsA is one of a group of disorders known as the spondyloarthropathies 2 Males and females are equally affected 3 PsA can range from mild nondestructive disease to a severely rapid and destructive arthropathy 3 Usually Rheumatoid Factor negative 3 Radiographic damage can be noted in up to 47% of patients at a median interval of two years despite clinical improvement with standard DMARD therapy 4 1 Taylor WJ. Curr Opin Rheumatol. 2002;14:98 – 103. 2 Mease P. Curr Opin Rheumatol . 2004;16:366 – 370. 3 Brockbank J, et al. Exp Opin Invest Drugs. 2000;9:1511–1522. 4 Kane D, et al. Rheumatology. 2003;42:1460 – 1468. 1 Taylor WJ. Curr Opin Rheumatol . 2002;14:98 – 103. 2 Mease P. Curr Opin Rheumatol . 2004;16:366 – 370. 3 Brockbank J, et al. Exp Opin Invest Drugs. 2000;9:1511–1522. 4 Kane D, et al. Rheumatology. 2003;42:1460 – 1468.

3. Spondyloarthritis, Psoriasis and PsA Spondyloarthritis (SpA) The prevalence of SpA is comparable to that of RA (0.5–1.9%) 1,2 Psoriasis (Pso) Psoriasis affects 2% of population 7% to 42% of patients with Pso will develop arthritis 3 Psoriatic Arthritis A chronic and inflammatory arthritis in association with skin psoriasis 4 Usually rheumatoid factor (RF) negative and ACPA negative 5 Distinct from RA Psoriatic Arthritis is classified as one of the subtypes of spondyloarthropathies Characterized by synovitis , enthesitis , dactylitis , spondylitis , skin and nail psoriasis 4 1 Rudwaleit M et al. Ann Rheum Dis 2004;63:535-543; 2 Braun J et al. Scand J Rheumatol 2005;34:178-90; 3 Fitzgerald “Psoriatic Arthritis” in Kelley’s Textbook of Rheumatology, 2009; 4 Mease et al . Ann Rheum Dis 2011;70( Suppl 1):i77–i84. doi:10.1136/ard.2010.140582; 5 Pasquetti et al. Rheumatology 2009;48:315–325 Juvenile SpA Reactive arthritis Arthritis associated with IBD PsA Undifferentiated SpA ( uSpA ) Ankylosing spondylitis (AS) RA: Rheumatoid arthritis

4. Psoriatic Arthritis ACR Slide Collection on the Rheumatic Diseases; 3 rd edition. 1994. Data on file, Centocor , Inc.

5. Epidemiology of PsA Recent review undertaken to 2006 1,2 − Incidence Europe+North America: 3 to 23.1 cases/10 5 Japan 0.1 case/10 5 − Prevalence Europe+North America 20 and 420 cases/10 5 Japan 1 case/10 5 Population- based study /Minnesota (CASPAR criteria ) 2,3 − Incidence 7.2 cases/10 5 (men 9.1, female 5.4) − Prevalence 158 cases/10 5 The prevalence of PsA is assumed to be larger than expected, since enthesitis associated with PsA can develop without symptoms or signs that are recognizable by patients themselves or the physicians 4 1 Alamos et al. J Rheumatol 2008;35:1354-8; 2 Wilson F et al. J Rheumatol 2009;36:361-7; 3 Editorial by Chaudran . J Rheumatol 2009;36:213-5; 4 Takata et al. J Dermatol Sci. 2011 Nov;64(2):144-7

6. Etiology Genetic Factors Immunologic Mechanisms Environmental Trauma – Koebner phenomenon: psoriatic lesions arising at site of trauma (24-52%); development of PsA after trauma to joint. Bacterial infections - association between guttate psoriasis and streptococcal pharyngitis; up to 30% of PsA synovial tissue-derived T cells proliferate following exposure to group A strep

7. Genetic Factors Has been known to occur in families Up to 40% psoriasis or PsA have a family history in first degree relative The disease is 50 times more likely to occur in first degree relative than controls Tends to be concordant among monozygotic twins more commonly than dizygotic

8. Genetics and HLA Antigens Concordance rate monozygotic twins of 35-70%, 12-20% for dizygotic twins. HLA-B27 in the presence of HLA-DR7, HLA-DQ3 in the absence of HLA-DR7, and HLA-B39 are predictors for disease progression, HLA-B22 is protective. HLAB27 less than AS or Reiter’s; some psoriasis and SpA are HLA B27 (-) PsA and HLA B27 who do not have SpA Some patients with HLA DR4: PsA with polyarthritis

9. Role of TNF Released predominantly by cells of the monocyte /macrophage lineage Accumulation of T-cells, infiltration of synovium: TNF-mediated production of factors that attract T-cells – monocyte chemoattractant protein-1 and macrophage inflammatory protein 3 alpha Induces lymphocyte and neutrophil migration into synovium

10. TNF in PsA High levels of TNF- α in PsA synovium Marked upregulation of TNF- α in PsA synovial membrane Inflammation of synovium, enthesis and bone TNF- α transgenic mice – bone destruction Promotes release of matrix-degrading metalloproteinases Enhances secretion of pro-inflammatory cytokines (IL-1, IL-6, IL-8) Potentiates osteoclastic bone resorption

11. Differential Diagnosis Rheumatoid Arthritis Symmetric PIP, MCP, not distal Ulnar deviation, swan neck deformities Rheumatoid nodules Ankylosing Spondylitis Strong HLA B27 association Male predominance Axial skeletal involvement – sacroilitis Bamboo spine Schober test demonstrating limited flexion Uptodate.com

12. Differential Diagnosis Reactive Arthritis LE arthritis 1-4 weeks after an infection Infectious agents: Shigella Salmonella Yersinia Campylobacter Chlamydia Triad: urethritis, conjunctivitis, arthritis Keratoderma Blennorhagicum Inflammatory Bowel Disease Associated Crohn’s LE distribution AAFP

13. Classification Criteria of PsA How to diagnose PsA?

14. Classical Description of PsA Using the Diagnostic Criteria of Moll and Wright Including 5 clinical patterns: Asymmetric mono-/ oligoarthritis (~30% [range 12-70%]) 1-4 Symmetric polyarthritis (~45% [range 15-65%]) 1-4 Distal interphalangeal (DIP) joint involvement (~5%) 1 Axial ( spondylitis and Sacroiliitis ) (HLA-B27) (~5%) 1,3 Arthritis Mutilans (<5%) 1,3 References see notes However patterns may change over time and are therefore not useful for classification 5 HLA: Human leucocytes antigen

15. Asymmetrical oligoarticular arthritis MC type (70%) Asymmetrical similar to low grade gout. Sausage like swelling of one or more digit ( dactylitis ). A large joint, such as the knee, is also commonly involved. Usually, <5 joints are affected at any one time. Enthesitis Flexor sheath synovitis

16. Hallmark Clinical Features in PsA Ritchlin C. J Rheumatol . 2006;33:1435–1438. Helliwell PS. J Rheumatol . 2006;33:1439–1441.

17. Dactylitis ACR Slide Collection on the Rheumatic Diseases; 3 rd edition. 1994. 1 Brockbank J, et al. Ann Rheum Dis . 2005;64:188 – 190. 2 Veale D, et al. Br J Rheumatol . 1994;33:133–38. Diffuse swelling of a digit may be acute, with painful inflammatory changes, or chronic wherein the digit remains swollen despite the disappearance of acute inflammation 1 Also referred to as “sausage digit” 1 Recognized as one of the cardinal features of PsA , occurring in up to 40% of patients 1,2 Feet most commonly affected 1 Dactylitis involved digits show more radiographic damage 1

18. Definition of Enthesitis Entheses are the regions at which a tendon, ligament, or joint capsule attaches to bone 1 Inflammation at the entheses is called enthesitis and is a hallmark feature of PsA 1,2 Pathogenesis of enthesitis has yet to be fully elucidated 2 Isolated peripheral enthesitis may be the only rheumatologic sign of PsA in a subset of patients 3 1 McGonagle D. Ann Rheum Dis. 2005;64( Suppl II):ii58 –ii60 . 2 Anandarajah AP, et al. Curr Opin Rheumatol . 2004;16:338–343. 3 Salvarani C. J Rheumatol . 1997;24:1106–1140.

19. Symmetrical polyarthritis Rheumatoid like pattern. 15% Hands, wrists, ankles, and feet may be involved. D/D from RA by DIP joint involvement, Morning stiffness Fusiform deformity Wind swept deformity Relative asymmetry, Subcutaneous nodules absent. RF negative. Milder, with less deformity.

20. Distal interphalangeal arthropathy Classical form Less common 16% Involvement of the nail with significant inflammation of the paronychia and swelling of the digital tuft may be prominent, 30 pits with inflammatory arthritis of DIP joints considered diagnostic.

21. Psoriatic arthritis involving the distal phalangeal joint.

22. Arthritis mutilans Rare form 1-5% Some reports suggest up to 16% of patients. Resorption of bone ( osteolysis ), with dissolution of the joint, is observed as the "pencil-in-cup" radiographic finding and leads to redundant, overlying skin with a telescoping motion of the digit. This "opera-glass hand" is M>F and is more frequent in early-onset disease.

23. Arthritis mutilans , a typically psoriatic pattern of arthritis, which is associated with a characteristic "pencil-in-cup" radiographic appearance of digits. Arthritis mutilans ( ie , "pencil-in-cup" deformities).

24. Spondylitis with or without sacroiliitis Affect 5% of patients and has a male predominance. Can occur in conjunction with other subgroups of PA. Spondylitis may occur- Without radiologic evidence of sacroiliitis , which frequently tends to be asymmetrical, May appear radiologically without the classic symptoms of morning stiffness in the lower back. Thus, the correlation between symptoms and radiologic signs of sacroiliitis can be poor. Vertebral involvement differs from that observed in AS.

25. Vertebrae are affected asymmetrically, and the atlantoaxial joint may be involved with erosion of the odontoid and subluxation (with attendant neurologic complications). Therapy may limit subluxation -associated disability. Unusual radiologic feature nonmarginal asymmetrical syndesmophytes (characteristic), paravertebral ossification, and, less commonly, vertebral fusion with disk calcification. Lateral radiograph of the cervical spine shows syndesmophytes at the C2-3 and C6-7 levels, with zygapophyseal joint fusion.

26. Patterns may Change Over Time and are Therefore not Useful for Classification McHugh et al. Rheum 2003;42:778-783 Clinical subgroups at baseline and follow-up: Monoarthritis Monoarthritis Oligoarthritis Oligoarthritis DIP DIP Polyarthritis Polyarthritis Spondyloarthritis Spondyloarthritis Mutilans Mutilans No clinical evidence of joint disease

27. CASPAR Criteria for the Classification of PsA Inflammatory articular disease (joint, spine , or entheseal ) With 3 points from following categories: − Psoriasis : current (2), history (1), family history (1) − Nail dystrophy (1) − Negative rheumatoid factor (1) − Dactylitis : current (1), history (1) recorded by a rheumatologist − Radiographs: (hand/foot) evidence of juxta-articular new bone formation Specificity 98.7%, Sensitivity 91.4% Taylor et al. Arthritis & Rheum 2006;54: 2665-73

28. Signs and Symptoms Morning stiffness lasting >30 min in 50% of patients 1 Ridging, pitting of nails, onycholysis – up 90% of patients vs nail changes in only 40% of psoriasis cases 2,3 Patients may present with less joint tenderness than is usually seen in RA 1 Dactylitis may be noted in >40% of patients 2,4 Eye inflammation (conjunctivitis, iritis, or uveitis) — 7–33% of cases; uveitis shows a greater tendency to be bilateral and chronic when compared to AS 2 Distal extremity swelling with pitting edema has been reported in 20% of patients as the first isolated manifestation of PsA 5 1 Gladman DD. In: Up To Date. Available at: www.uptodate.com. Accessed December 3, 2004. 2 Taurog JD. In: Harrison's Online McGrawHill . Available at: http://www3.accessmedicine.com/popup.aspx?aID=94996&print=yes. Accessed January 2,2005. 3 Gladman DD. Rheum Dis Clin N Amer. 1998;24:829–844. 4 Veale D, et al. Br J Rheumatol . 1994;33:133–38. 5 Cantini F, et al. Clin Exp Rheumatol . 2001;19:291–296.

29. Main Features of PsA Helliwell PS & Taylor WJ. Ann Rheum Dis 2005;64(2:ii)3-8 Fitzgerald “Psoriatic Arthritis” in Kelley’s Textbook of Rheumatology, 2009 *Low levels of RF and ACPA can be found in 5-16% of patients; **To a lesser degree than in RA ***Spinal disease occurs in 40-70% of PsA patients

30. Main Features and Their Frequency 1 Gladman D et al. Arth & Rheum 2007;56:840; 2 Kane. D et al. Rheum 2003;42:1460-1468 3 Gladman D et al. Ann Rheum Dis 2005; 64 :188–190; 4 Lawry M. Dermatol Ther 2007;20:60-67 5 Jiaravuthisan MM et al. JAAD 2007;57:1-27; 6 Yamamoto Eur J Dermatol 2011;21:660-6 Enthesopathy (38 %) 2 Dactyilitis (48 %) 3 DIP involvement (39 %) 2 Back involvement (50 %) 1 Nail psoriasis (80%) 4, 5 Skin Involvement In nearly 70% of patients, cutaneous lesions precede the onset of joint pain, in 20% arthropathy starts before skin manifestations, and in 10% both are concurrent. 6 DIP: Distal interphalangeal

31. Pso patients 6-8 Psychosocial burden Reactive depression Higher suicidal ideation Alcoholism  Metabolic Syndrome 3-5 Hyperlipidemia Hypertension Insulin resistent Diabetes Obesity  H igher risk of Cardiovascular disease (CVD) Ocular inflammation 1 (Iritis/Uveitis/ Episcleritis) IBD 2 Comorbidities in PsA Patients 1 Qieiro et al. Semin Arth Rheum 2002;31:264; 2 Scarpa et al. J Rheum 2000;27:1241; 3 Mallbris et al. Curr Rheum Rep 2006;8:355; 4 Neimann et al . J Am Acad Derm 2006;55:829; 5 Tam et al. 2008;47:718; 6 Kimball et al. Am J Clin Dermatol 2005;6:383-392; 7 Naldi et al. Br J Dermatol 1992;127:212-217; 8 Mrowietz U et al. Arch Dermatol Res 2006;298(7): 309-319 Nail pitting, transverse depressions, and subungual hyperkeratosis

32. Staging of psoriatic arthritis

33. Treatment of PsA Outcomes measurements

34. Dosing schedule, monitoring and side effects of disease modifying drugs

35. Generic Name Manufacturer U.S. Trade Name(s) * How Supplied Usual Adult Dose Methyl- prednisolone Multiple Medrol ® , Depo-Medrol ® , Solu-Medrol ® Acetate - Injectable IM—20, 40, and 80 mg/ml Sodium succinate - Injectable : IM—40, 125, and 500 mg, 1 and 2 g vials Oral: Tabs—2, 4, 8, 16, and 32 mg Acetate:IM—10 to 80 mg every 1 to 2 weeks Intra-articular, intralesional —4 to 80 mg every 1 to 5 weeks Sodium succinate:IM—10 to 80 mg daily IV—10 to 40 mg every 4 to 6 hours; up to 30 mg/kg every 4 to 6 hours Oral:2 to 60 mg in 1 to 4 divided doses to start, followed by gradual reduction Prednisone Multiple Deltasone ® , Sterapred ® , LiquiPred ® Oral Solution—1 and 5 mg/ml Tabs—1, 2.5, 5, 10, 20, and 50 mg Use lowest effective dose (5–60 mg/day) Prednisolone Multiple Orapred ® , Pediapred ® , Prelone ® , Delta- Cortef ® , Econopred ® Oral Solution/Syrup—5, 15, and 20 mg/5 ml Oral Tabs—5 and 15 mg Use lowest effective dose (5 to 7.5 mg/day) Pharmaceutical treatments for psoriatic arthritis: corticosteroids.

36. Efficacy of drugs in psoriatic arthritis

37. Indications for biologic agents in psoriatic arthritis

38. Mechanism of action, dosing schedule and major risks with the biologic therapies

39. Generic Name Manufacturer U.S. Trade Name(s) * Injectable Supply Usual Adult Dose Abatacept Bristol Myers Squibb Orencia ® 250 mg vial IV—Dosed according to body weight (<60 kg=500 mg; 60–100 kg=750 mg; >100 kg=1,000 mg); dose repeated at 2 weeks and 4 weeks after initial dose, and every 4 weeks thereafter SQ—may give weight-based IV loading dose, then 125 mg SQ once weekly Adalimumab Abbott Humira ® 40 mg/0.8 ml, 20 mg/0.4 ml prefilled syringe SQ—40 mg every other week alone or in combination with other DMARDs Anakinra Amgen Kineret ® 100 mg/0.67 ml syringe SQ—100 mg/day; dose should be decreased to 100 mg every other day in renal insufficiency CertolizumabPegol a UCB Cimzia ® 200 mg powder for reconstitution, 200 mg/ml solution SQ—initial dose of 400 mg (as 2 SQ injections of 200 mg), repeat dose 2 and 4 weeks after initial dose; Maintenance dose is 200 mg every other week (may consider maintenance dose of 400 every 4 weeks) Etanercept Amgen Pfizer Immunex Enbrel ® 50 mg/ml in 25 mg or 50 mg single use prefilled syringe SQ—50 mg once weekly with or without MTX

40. Golimumab Centocor Ortho Biotech Simponi ® 50 mg/0.5 ml syringe SQ—50 mg once per month, alone or in combination with MTX Infliximab Centocor Ortho Biotech Remicade ® 100 mg in a 20 ml vial IV—5 mg/kg at 0, 2 and 6 weeks followed by maintenance every 8 weeks thereafter; may be given with or without MTX Rituximab Biogen Idec / Genentech Rituxan ® 100 mg/10 ml and 500 mg/50 ml vial IV—1,000 mg IV infusion separated by 2 weeks (one course) every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks Tocilizumab Genentech / Roche Actemra ® , RoActemra ® 80 mg/4 ml, 200 mg/10 ml, 400 mg/20 ml vial IV—4 mg/kg every 4 weeks; increase to 8 mg/kg every 4 weeks based on clinical response

41. Other agents Several other agents have been tried, including vitamin-D3,  bromocriptine , peptide T, and fish oils, but their efficacy remains to be proven. Antimalarials , particularly  hydroxychloroquine ( Plaquenil ), are usually avoided in patients with psoriasis for fear of precipitating exfoliative dermatitis or exacerbating psoriasis. However, 2 studies showed that these reactions did not occur in patients who were treated with hydroxychloroquine ; therefore, this drug is occasionally used to treat PA. Systemic corticosteroids are usually avoided because of possible rebound of the skin disease upon withdrawal.

42. Surgical Care in Psoriatic Arthritis Arthroscopic synovectomy has been effective in treating severe, chronic, monoarticular synovitis . Joint replacement and forms of reconstructive therapy are occasionally necessary. Patients in severe pain or with significant contractures may be referred for possible surgical intervention; however, high rates of recurrence of joint contractures have been noted after surgical release, especially in the hand.

43. Hip and knee joint replacements have been successful. Arthrodesis and arthroplasty have also been used on joints, such as the thumb PIP joint. The wrist often spontaneously fuses, and this may relieve the patient's pain without surgical intervention. For arthritis mutilans , surgical intervention is usually directed toward salvage of the hand; combinations of arthrodesis , arthroplasty , and bone grafts to lengthen the digits may be used .

44. Consultations and Monitoring in Psoriatic Arthritis If the patient's physiatrist feels uncomfortable with prescribing medications for PA, referral to a rheumatologist with more experience with these agents may be advisable. The physiatrist may then concentrate on functional restoration of the patient. Referral to a surgeon should be considered for appropriate patients. Children with juvenile PA should be examined by an ophthalmologist annually to check for the several forms of eye inflammation usually associated with various forms of juvenile arthritis. In addition, consultation with an orthopedic surgeon is warranted for individuals who may benefit from joint replacement, arthrodesis , or contracture release.

45. Dietary Considerations For people who have morning stiffness, the optimal time for taking an NSAID may be after the evening meal and again upon awakening. Taking NSAIDs with food can reduce stomach discomfort. Any NSAID can damage the mucous layer and cause ulcers and GI bleeding when taken for long periods. Cyclooxygenase (COX)–2 selective inhibitors are associated with a lower prevalence of gastric ulcer formation.

46. Physical Therapy in Psoriatic Arthritis The rehabilitation treatment program should be individualized and should be started early in the disease process. Such a program should consider the use of the following: Rest - Local and systemic Exercise - Passive, active, stretching, strengthening, and endurance Modalities - Heat, cold Orthotics - Upper and lower extremities, spinal

47. Deterrence and Prevention Lithium and withdrawal from systemic corticosteroids are well known to cause disease flare-ups. Other drugs that have been implicated include beta blockers, antimalarials (although, as previously mentioned, evidence suggests that hydroxychloroquine does not exacerbate skin lesions), and NSAIDs. If skin lesions worsen with an NSAID, switch to a different family of NSAID. Prevention includes rest and exercise. Joint protection, including splints, braces, and other supports, may be helpful. No definitive prevention exists, because this is a chronic disease that can wax and wane.

48. Thanks