1. Seronegative Spondyloarthropathies and Systemic Sclerosis Victor Politi, M.D., FACP Medical Director, SVCMC, School of Allied Health, Physician Assistant Program

6. HLA stands for Human Leukocyte Antigen this is a genetic region designated because these antigens were first detected on peripheral blood lymphocytes Includes HLA-A,B,C,DR each with many alleles Located on chromosome 6

7. HLA complex has been associated with a variety of diseases AS B27 RA DR4 SLE DR3 Reiter's B27

16. Reactive Arthritis HLA-B27 positive (50-80% of cases) Formerly called Reiter’s Syndrome Tetrad of urethritis,conjunctivitis/uveitis,mucocutane ous lesions (mouth ulcers) and aseptic arthritis (oligoarthritis) Most common in young men Often follows infection

17. Reactive Arthritis Most cases develop days - weeks following dysenteric infection (shigella, salmonella, yersinia, Campylobacter) or sexually transmitted disease (chlamydia trachomatis or Ureaplasma urealyticum) To be distinguished from GC arthritis(migratory polyarthralgias) and non GC acute bacterial (septic) arthritis ie staph.

18. Reactive Arthritis Arthritis - usually asymmetric - involving large weight bearing joints (knees, ankle) –In 20% of cases - sacroiliitis or ankylosing spondylitis present –systemic symptoms - fever & weight loss common at initial stage of disease –Other symptoms - mucocutaneous lesions carditis & aortic regurgitation may occur

19. Reactive Arthritis Most signs of the disease disappear within days to weeks –arthritis symptoms however may persist for months or years –common for recurrences - can involve any combination of clinical manifestations - can be followed by permanent sequelae (joints)

20. Reactive Arthritis- differential dx Gonococcal arthritis can mimic reactive arthritis –however, in gonococcal arthritis marked improvement 24-48 hrs after antibiotics culture results distinguish two disorders also must consider rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis no association between HIV and reactive arthritis

21. Reactive Arthritis - Tx NSAIDs tetracycline's sulfasalazine Anti-TNF agents (etanercept, infliximab)

22. Psoriatic Arthritis In 15-20% of psoriasis patients arthritis coexists There are several subsets of arthritis that may accompany psoriasis –joint disease resembles RA, polyarthritis - symmetric, fewer joints involved than in RA –oligoarticular form - considerable destruction of affected joints

23. Psoriatic Arthritis –disease pattern where distal interphalangeal joints primarily affected,pitting of nails, onycholysis frequent –arthritis mutilans (severe deforming- with marked osteolysis) pencil in cup deformity –spondylitic form (primary involvement - sacroiliitis, spinal involvement) 50% of cases HLA-B27 positive

24. Psoriatic Arthritis Psoriasis usually precedes arthritis in 80% –20% of cases it occurs simultaneously –patient may have a single patch of psoriasis and unaware of its connection to arthritis –psoriasis may not be present at time of exam (important to obtain personal history)

25. Psoriatic Arthritis- Radiographic findings –Help distinguish it from other forms of arthritis –marginal erosions of bone –irregular destruction of joint and bone –phalanx may appear - sharpened pencil –paravertebral ossification –fluffy periosteal new bone - @ insertion of muscles and ligaments into bone, shafts of metacarpals, metatarsals and phalanges

26. Psoriatic Arthritis- Treatment Symptomatic –NSAIDs –methotrexate –PUVA therapy for skin lesions Corticosteroids (less effective in psoriatic arthritis & may exacerbate psoriasis) antimalarials may also exacerbate psoriasis

27. Arthritis with GI symptoms 1/5 of patients with inflammatory bowel disease have arthritis 2/3 of patients with Whipple’s disease have arthralgia or arthritis (usually episodic/large joint polyarthritis) Arthritis usually precedes Whipple’s by years (fever,lymphadenopathy,arthralgias,malabs orption,infection w/tropheryma whippelii.)

28. Arthritis with GI symptoms Two forms of arthritis are seen in Crohn’s disease and ulcerative colitis –peripheral arthritis (non deforming asymmetric oligoarthritis of large joints) –spondylitis (indistinguishable by symptoms or x-ray from ankylosing spondylitis)50% of cases are HLA-B27-positive

29. In most cases arthritis improves with controlling intestinal inflammation.

30. Systemic Sclerosis Chronic disorder characterized by diffuse fibrosis/thickening of skin,telangiectasia and pigmentation changes Cause unknown 3rd - 5th decade onset Women affected –2 - 3 times more frequently than men

31. Systemic Sclerosis Two Forms –limited (80% of cases) CREST syndrome - scleroderma limited to face and hands –diffuse (20% of cases) trunk and proximal extremities also affected

32. Causes The cause of limited scleroderma is yet to be determined. Studies of genetic factors show only rare occasions of multicase families. Human leukocyte antigen associations are present but are not strong. Autoimmunity,fibroblast dysregulation, have been implicated.

33. Causes The predominance of cases occurring in women after their childbearing years and the similar clinical presentation of scleroderma to graft-versus-host disease has suggested the importance of fetal/maternal etiology of scleroderma. The possibility of fetal lymphocytes retained in the maternal circulation

34. Causes Environmental factors also are likely important. Some similarities in clinical presentation occur with silica, L-tryptophan (eosinophilia-myalgia syndrome) an over the counter remedy for insomnia and premenstrual symptoms.

35. Systemic Sclerosis In diffuse scleroderma - tendon friction rubs (especially over the wrist, ankles and knees) In general, patients with CREST syndrome have better outcomes than those with diffuse disease (patients w/limited disease rarely develop renal failure or interstitial lung disease)

37. CREST Syndrome  Calcinosis  In scleroderma, calcific deposits are found predominantly in the extremities, around joints, and around bony prominences.  Deposits typically are found in the flexor surfaces of the hands and the extensor surfaces of the forearms and knees.  The deposits rest in the dermis but can be found in deeper periarticular tissues.

38. CREST Syndrome  Raynaud phenomenon  Triphasic color changes of pallor, cyanosis, and erythema represent phases of vasoconstriction, slow blood flow, and reperfusion, respectively.  Color changes extend proximally from the tips of digits to various levels, with a well-demarcated border.

39. CREST Syndrome  Esophageal dysmotility  The earliest change in the distal esophagus (primarily smooth muscle) is an uncoordinated disorganized pattern of contractions resulting in low amplitude or absent peristalsis.  Lower esophageal sphincter (LES) pressure typically is lower than in healthy controls, and incomplete relaxation of the LES occurs, according to Sjögren.

40. CREST Syndrome  Sclerodactyly  The process typically begins in the distal fingers and advances proximally.  The process also may occur on the face, over the forehead, and around the mouth. Facial involvement can lead to a mauskopf (mouse head) appearance. Lips become thinner, and radial furrowing develops around the mouth. The oral aperture is reduced in size (microstomia). Wrinkles over the forehead diminish.

41. CREST Syndrome Telangiectases are flat and nonpulsatile and typically have a rectangular or elongated shape. The vessels are so close together that they appear as discrete mats.

42. Systemic Sclerosis- symptoms/signs Most frequently first sign in cutaneous features (visceral involvement may precede) 90% of patients early manifestations - polyarthralgia and Raynaud’s phenomenon Subcutaneous edema, fever and malaise common symptoms

43. Systemic Sclerosis- symptoms/signs Skin becomes thickened with loss of normal folds Telangiectasia, pigmentation and depigmentation ulceration of the fingertips, subcutaneous calcification dysphagia due to esophageal dismotility

44. Systemic Sclerosis- symptoms/signs Diffuse pulmonary fibrosis GI tract symptoms caused by fibrosis and atrophy –hypomotility –malabsorption from bacterial overgrowth –diverticular develop

45. Systemic Sclerosis- symptoms/signs Renal crisis (usually indicative of poor prognosis - though many cases treated successfully w/angiotensin- converting enzyme inhibitors) Cardiac symptoms –pericarditis –heart block –myocardial fibrosis –right heart failure secondary to pulmonary HTN

46. Systemic Sclerosis- Lab findings Mild anemia often present Antinuclear antibody tests - positive Scleroderma antibody (SCL-70) directed against topoisomerase III –1/3 of patients w/diffuse systemic sclerosis –20% of patients w/CREST syndrome (anticentromere ab seen in 50% crest but 1% of syst. Scler.

47. Sclerodermalike disorders

48. Systemic Sclerosis-Diagnosis Eosinophilic fascitis - rare disorder that presents with skin changes resembling diffuse systemic sclerosis –inflammatory abnormalities limited to the fascia rather than the dermis and epidermis –presence of peripheral blood eosinophilia –absence of Raynaud’s phenomenon –good response to prednisone –have increased risk of aplastic anemia

49. Systemic Sclerosis-Diagnosis Eosinophilia-myalgia syndrome –first noted in patients that ingested tryptophan (essential amino acid- was sold over the counter until banned by FDA) –weeks-months after ingesting symptoms appeared syndrome of severe generalized myalgias, cutaneous abnormalities, pulmonary symptoms, fever, myopathy, lymphadenopathy Patients presenting with systemic sclerosis or eosinophilic fascitis-like syndrome should be asked about tryptophan use

50. Systemic Sclerosis - Treatment Symptomatic and supportive Intervention for management of specific organ manifestations (ie., Raynaud's syndrome - calcium channel blockers, esophageal disease - H2 blockers, etc.)

51. Systemic Sclerosis- Outcome Cases that do not develop severe internal organ involvement in the first 3 years do better with 72% surviving at least 9 years 40% - 9 year survival rate in scleroderma

52. Systemic Sclerosis- Outcome prognosis worse in diffuse scleroderma cases, in blacks, in males, and in older patients In most cases death results from renal, cardiac or pulmonary failure Patients may be at increased risk of breast and lung cancer

53. Systemic Sclerosis- Outcome Limited disease is associated with better survival rates than diffuse disease (50% at 12 y compared to 15% for diffuse scleroderma).

54. Systemic Sclerosis- Outcome Renal involvement was responsible for one half of scleroderma-related deaths in patients with widespread skin changes, while patients with sclerodactyly alone did not tend to have renal disease at all.

55. Systemic Sclerosis- Outcome Mortality in patients with limited skin involvement is a result of cardiac, pulmonary, and GI causes.

56. Questions ??