1. SJOGREN’S SYNDROME: Adult and Pediatric Manifestations Robert I. Fox, M.D., Ph.D. Carla M. Fox, RN Scripps Memorial Hospital Scripps/XiMED Medical Center La Jolla, California USA robertfoxmd@mac.com

2. Learning Objectives By the end of the session, the participant will be able to: the participants should be able to: 1) Recognize the criteria for diagnosis of Sjogren’s Syndrome (SS) in adults. 2)Describe clinical features and therapy of juvenile SS. 3) Identify other conditions that may mimic juvenile SS.

3. Sjogren's syndrome in adults Primary Sjogren's syndrome Objective dry eyes (keratoconjunctivits sicca) and Objective dry mouth (xerostomia) Evidence of a systemic immune cause (ANA+ with antibody to SS-A (Ro)

4. Exclusions for Adult SS HIV and hepatitis C Pre-existing lymphoma

5. Sjogren’s Syndrome is more than dry eyes and mouth) A systemic immune disorder in adults that occupies the interface of: –the innate and acquired immune system –lymphadenopathy and lymphoma –vasculitis and demyelinating disorders such as multiples –the autonomic and adrenal-axis

6. Sjogren's as part of Juvenile Polyarthritis Usually does not have dryness features Often presents with recurrent parotid swelling Poorly defined epidemiology since not common and lumped with juvenile SLE

7. All slides are available on my website robertfoxmd.com but may not be accessible on your iPhone (due to web security) 7

8. Background - 1 SS has “benign” and “systemic” manifestations.

9. SS-Related Health Care Costs in Adults -1: Dry or painful eyes are now the most common cause of visits to Ophthalmologists in the U.S. and Japan. Lost productivity (over $160 billion/year just for dry eyes (especially in computer users where decreased blink rate is 90%.

10. Sjogren’s Symptoms are so debilitating, that patients would: equate SS with impact similar to moderate angina. trade 2 years of “life expectancy” to not have SS symptoms.

11. Diagnosis of Sjogren’s Syndrome in the Adult

12. The European-American Consensus Criteria, 2002 Symptoms of dry eyes and dry mouth –Inability to eat a dry cracker without water. –Water needed at bedside at night. Objective signs of dry eyes and dry mouth (Schirmer’s test, tear break up) (Saliva flow)

13. Consensus Criteria, 2002 also called American-European Consensus Group Criteria (AECG) Evidence of a systemic autoimmune cause for the dryness-- –Positive anti-Ro (SS-A or SS-B antibody) –Positive minor salivary gland biopsy (focus score >1)

14. EYE DRYNESS results in the clinical appearance of keratoconjunctivitis sicca (KCS) characteristic of Sjogren’s Syndrome The upper lid literally sticks to the Epithelial surface and pulls surface mucin layers off. The Rose Bengal dye retention test is like “rain water pooling in a street pothole” This test can be done at bedside and allows “triage” and rapid referral of patients to Ophthalmology

15. Rash distinct from SLE (erythema annulare)

16. Arthritis distinct from RA (Jaccoud's arthropathy)

17. High Risk of Lymphoma

18. Differential Diagnosis of SS - 1 SLE-- many similarities to SS RA, Scleroderma, Dermatomyositis-- called secondary Sjogren’s Primary biliary cirrhosis Fibromyalgia with incidental positive ANA

19. Differential Diagnosis of SS - 2 Hepatitis C HIV (AIDS) Tuberculosis Leprosy Syphilis Lymphoma with positive ANA IgG4-Related Diseases-evolving spectrum

20. Differential Diagnosis of SS - 3 The antibody to Ro (SS-A) or La (SS-B) do not fulfill criteria for SLE. Many older patients labeled with mild SLE actually have SS. Many patients in Hematology clinic with mixed cryoglobulinemia, hemolytic anemia or ITP actually have SS.

21. Is Sjogren’s just SLE with 4/5 SLE Criteria? Different antibody profile Anti-SSA/B are not criteria for SLE; SS is more organ specific – (salivary/lacrimal gland) and more lymphoproliferative.

22. Why is Sjogren’s not just SLE with 4/5 Criteria? 1.Interstitial pneumonitis (not pleurisy), interstitial nephritis (not glomerulonephritis) 2.Higher frequency of lymphoma 3.Genome Screens support this with Homing receptors found in SS but not SLE (CXCR5)

23. Treatment of DRY EYE Benign Symptoms -1 can demonstrate increased Cost-Benefit/Productivity Artificial tears and lubricants Punctal occlusion Do not use preserved tears more than 4x/day Topical cyclosporin (Restasis) Recognize and treat blepharitis

24. DRY EYE Therapy - 2 Special needs in operating room (where there is low humidity and high risk for corneal abrasion). Avoid Lasik eye surgery. Look for “lid lag” and exposure zone keratopathy, espeically if there is a history of Graves.

25. Systemic Manifestations Steroids work but have side effects. DMARDs to taper or replace steroids. Hydroxychloroquine Methotrexate, Azathioprine Mycophenolic acid mofetil We are interested in Sirolimus (rapamycin)

26. Biologics Previously Studied in SS Anti-CD20 (rituximab)* –glandular swelling, extraglandular renal and lung, mixed cryoglobulinemia BAFF (Blys)-ACR 2012 abstracts has been disappointing Abatacept (CD40 L)-ACR 2012

27. Rituximab Most widely used biologic in SS (ACR 2013 abstracts). Used in response to extraglandular manifestations such as persistent glandular swelling, pneumonitis, mixed cryoglobulinemia. Not approved by FDA.

28. Sjogren’s in Pregnancy - 1 In mothers with positive SS-A antibody, there is increased risk for neonatal heart block. This is due to the expression of an altered splice variant of the SS-A protein by the fetal heart between 12-18 weeks pregnancy. If evidence on fetal monitor, use decadron rather than prednisone—as it does not need to be activated by the placenta.

29. Sjogren’s in Pregnancy - 2 Watch for flare of symptoms after delivery. We give mother: –prednisone 15 mg on call to delivery room and then -- –prednisone 10 mg per day for 1 week post- partum to prevent flare. We prefer to not have long hours of labor and planned induction if possible. Watch for eclampsia and thrombosis if evidence of Cardiolipin syndrome.

30. Mothers with neo-natal lupus infants … Frequently show no symptoms of SS; Almost always have antibodies to SS-A; Only 18% will later develop clinical SS with a 20-year follow-up. The issues of prevention of heart block in neo-natal lupus refer to a subsequent pregnancy.

31. Sjogren’s in Children - 1 (part of spectrum of JIA) You can reassure mother with SS that there is only a slightly increased risk that the child may develop Sjogren’s. Rather than 5/1000 incidence, the risk is only increased to 15/1000—so 985/1000 kids will be fine.

32. Sjogren’s in Children - 2 Usually presents with parotid swelling or as “recurrent mumps,” “Mono” or “CMV” as an initial diagnosis that does not resolve. Rarely do children present with symptoms of dryness. The spectrum of rashes and extraglandular manifestations is similar to adults.

33. Sjogren’s in Children - 3 If parotid swelling persists for 8 weeks, then a needle biopsy is indicated to rule out low-grade lymphoma. Remember than children can develop HIV related complex as well as Hepatitis C that mimics Sjogren’s. Rule out infections such as TBC or Actinomycosis. Juvenile SS can also present like “Stills.”

34. Usual cause of parotid swelling Mumps

35. Recurrent Parotid Swelling as part of JIA--juvenile SS

36. In boys and teenagers, we find higher incidence of IgG4 (Mikuculiz) or Lymphoma

37. Adolescent with HIV (AIDS-related Complex)

38. Epidemiology in Children (from University of California San Diego registry) 4 cases per 100,000 for whites 31 cases per 100,000 for asians 13 cases per 100,000 for hispanics

39. Pathogenesis Onset before menses indicates that other genes that predispose (HLA-DR, C4 null) are probably present. Serology of SS-A+/SS-B+ distinguishes from Juvenile SLE. Role of viruses such as EBV likely, as they have normal latency in the nasopharynx.

40. If early age of onset— below age 5 Look for “accelerating” factors such as C2 deficiency. Rule out HIV. Parotid swelling, may mimic: –Prolidase deficiency –Lyseine protein intolerance

41. Prolidase Deficiency (autosomal recessive mutation in peptidase D gene) It is more common in certain areas in northern Israel, both among members of a religious minority called the Druze and in nearby Arab Muslim populations. Cases I have seen are in Southern India (Tamil), where there is tremendous inbreeding. The disorder typically becomes apparent during infancy. Affected individuals may have enlargement of the parotids, and hepatosplenomegaly. Diarrhea, vomiting, and dehydration may also occur.

42. Lysinuric protein intolerance (LPI), hyperdibasic aminoaciduria type 2, cationic aminoaciduria, or familial protein intolerance About 140 SS patients have been reported, almost half of them of Finnish origin. Pediatric SS patients from Japan, Italy, Morocco and North Africa have also been reported. Infants with LPI are usually symptom-free when breastfed because of the low protein concentration in human milk, but develop vomiting and diarrhea after weaning. The infants may show enlarged parotids as well as hepatosplenomegaly and mental retardation.

43. Epidemiology in Children Our youngest juvenile SS was 4 years old. but increasingly prevalent after age 10. High female predominance-- 10:1 EBV nasopharygeal carcinoma among Chinese children indicates virus plus peanut aflo-toxin as co-factors. Lack of concordance in identical twins suggests importance of epi-genetic factors.

44. Clinical Presentation - 1 Hematologic-anemia, leukopenia, thrombocytopenia Cutaneous-rash ranging from E. annulare to lupus-like vasculitis. Need to distinguish HSP and TTP. Renal— distal RTA-may present with periodic paralysis and profound hypokalemia. –(suspect herbal medications)

45. Clinical Presentation - 2 POTS-postural orthostatic hypotension Autonomic neuropathy— including GI and bladder (possibly due to anti-M3 muscarinic and nicotinic receptor antibodies) Lymphadenopathy (especially cervical) and persistent parotid swelling that have high risk of non-Hodgkin’s lymphoma

46. Clinical Presentation - 3 Neurologic may be most difficult diagnosis May include aseptic meningitis, encephalitis, or neuro-psychiatric Seizures, stroke, or coma Periodic paralysis (due to low K)

47. Clinical Presentation - 4 Pleurisy and pericarditis Rarely pulmonary hypertension Heart block— not previously recognized Pulmonary-shrinking lung including pneumonitis similar NSIP or “shrinking lung”

48. Clinical Features in Juvenile SS Hematologic-anemia, leukopenia, thrombocytopenia Cutaneous-rash ranging from E. annulare to vasculitis. Need to distinguish from HSP. Renal—distal RTA—suspect herbal medications especially if low Vitamin K, and may even have periodic paralysis.

49. Auto-Antibodies in Kids ANA—less frequent SS-A/SS-B than adults Anti-Cardiolipin- (PT and PTT with 1:1 mix) High ESR and CRP Check Vitamin D levels Hyperglobulinemia Positive RF— especially monoclonal and type II mixed cryoglob

50. Therapy in Kids - 1 Overall similar to adults We avoid TNF inhibitors DMARDS are used in doses similar to JRA (mg/kg dosing)

51. Hydroxychloroquine, steroids, mycophenolic acid, Methotrexate Rituximab can now be used in children. Avoid TNF inhibitors. Therapy in Kids - 2

52. Summary - 1 The American European Consensus criteria: Subjective symptoms of dryness Objective evidence of autoimmune process such as a positive antibody to SS-A or RF Positive minor salivary gland biopsy

53. Summary - 2 Differential Diagnosis Although SLE is closely related to SS, there are distinct clinical and genetic factors. Think of SLE as immune complex-mediated and SS as aggressive lymphocytic infiltrates (including high risk of lymphoma).

54. Thank you for inviting us to your beautiful city Спасибо за приглашение на ваш красивый город

55. Supplemental Tables From my new chapter in UpToDate.com

56. Figures from new UpToDate

57. Differential Diagnosis - 1

58. Differential Diagnosis - 2

59. Differential Diagnosis - 3

60. Salivary Gland Enlargement

61. SS Diagnosis Algorithym

64. Thank you for inviting me. Robert I. Fox, M.D., Ph.D. Website: http://www.robertfoxmd.com Email: RobertFoxMD@mac.com