Mixed connective tissue disorder

Mixed connective tissue disorder - MCTD Autoimmune SLE RA Sjogrens Dermatomyositis Polymyositis Systemic Lupus Rheumatoid Arthritis

1. MIXED CONNECTIVE TISSUE DISEASE Chair person: Dr. Kalinga . B E Student: Dr. Raghu. G

2. History 1972 Sharp and colleagues Identified a group of patients who have mixed clinical features of SLE , SYSTEMIC SCLEROSIS AND POLYMYOSITIS.

3. Mixed Connective Tissue Disease Autoimmune Disease. Features of: SLE Scleroderma Inflammatory Myositis ( Polymyositis ) Rheumatoid arthritis Serology: positive anti U1-RNP Ab

4. Terminology Mixed Connective Tissue disease Patient meets criteria for MCTD generally with antibody positivity (RNP Ab ) Undifferentiated Connective Tissue disease Patient does not meet criteria for any given autoimmune disease but has features suggesting the early features of an autoimmune disease. Overlap Syndrome features of two or more distinctly recognizable rheumatic diseases but lacks sufficient features to meet the criteria for any classification.

5. UCTD vs Overlap vs MCTD Undifferentiated Connective Tissue Disease Polymyositis-Scleroderma Overlap Mixed Connective Tissue Disease

6. Epidemiology of MCTD Prevalence 3-4 per 100,000 population Female to Male Ratio is 3:1 Present in all races Peak age of Onset: 15-25

7. MCTD In India Rare entity in india . 16 patients were MCTD out of 441 pateints studied during 13 years. ( Lawrence, Agarwala and Mishra ) 3/1000 ( A Sood , A Kumar. British society for rheumatology)

8. ETIOLOGY The fundamental cause of MCTD remains unknown. Autoimmunity to components of the U1-70 kd snRNP is a hallmark of disease .

9. U1nRNP is a subunit of spliceosomes . Two subunits of spliceosomes are antigenic targets in autoimmunity. These are: 1. Small nuclear ribonucleoprotein particles ( snRNPs ). 2. Heterogenous nuclear RNP ( hnRNP ).

10. These snRNAs contain a high content of uridine and are, therefore, called U RNAs. Five different types of URNAs are defined on the basis of immunoprecipitation (U1, U2, U4, U5, and U6). Antibodies directed exclusively against U1 subunit are known as antiU1RNP antibodies.

11. They precipitate three proteins with molecular weight of 68000, 33000, and 22000. The clinical correlates of MCTD appear to be most closely associated with antibodies to the 68 kD and the 33000 proteins of the U1 RNP complex.

12. IMMUNOPATHOLOGY

13. B oth adaptive immunity and innate immunity are believed to play a role in the pathogenesis of MCTD. The adaptive immune response included B cells with the hallmark feature of anti-RNP antibodies, as well as RNP- reactiveT cells. Innate immune signaling through Toll-like receptors 7 and 3 appear to be involved.

14. The loss of T-lymphocyte and B-lymphocyte tolerance, due to cryptic self-antigens or molecular mimicry by infectious agents, and driven by U1-RNA-induced innate immune responses, are proposed current theories of pathogenesis.

15. Dignostic criteria Features of SLE, systemic sclerosis, RA, and polymyositis Four different diagnostic criteria have been proposed Sharp Kasukawa Alarcon-Segovia Kahn Highest sensitivity (62%) and specificity (86%) with Alarcon-Segovia.

16. Alarcon-Segovia Clinical Criteria 3/5 (must have synovitis or myositis ) Edema of the hands Synovitis Myositis Raynaud’s phenomenon Acrosclerosis Serologic: high titers of anti-U1 RNP

17. The crux of the MCTD diagnosis is the presence of high titers of antibodies to U1-RNP .” A bsence of anti- Sm or anti- dsDNA .

18. “With serology superseding the clinical symptoms in the diagnosis, there is a risk of fitting the clinical symptoms to the antibody signs”

19. Clinical Features of MCTD Early Features Arthritis Raynaud’s Puffy Hands/sausage digits Esophageal reuflux Later features Can develop skin thickening typical of Scleroderma Can develop lupus manifestations Can develop organ involvement: lungs, kidneys, muscle.

20. SKIN MANIFESTATIONS The most common skin change is the Raynaud phenomenon. Raynauds phenomenon accompanied by sausage shaped fingers and swelling of dorsum of hand are typical. Rarely gangrene of hands also seen

21. Raynauds in Rheumatology

22. Rashes- occur in 50% of patients and include -Photosensitivity rash. - Malar rash. - Telangiectases . - Gottron papules or a heliotrope rash.

23. Oral ulcers similar to those found in lupus may occur.

24. ARTHRITIS More common and frequently more severe than in classic SLE. Approximately 60 percent of patients with MCTD develop an obvious arthritis, often with deformities .

25. Arthralgia ultimately occurred in more than 90%. I nflammatory arthritis developed in 50% of patients. Deformities can occur but joint erosions are uncommon.

26. Muscles Myalgia - 25% to 50%. M yositis - 25% to 75% of patients.

27. Muscle discomfort with elevated creatinine kinase levels in the absence of significant muscle weakness. This is typically an early feature of MCTD. Fibromyalgia has also been reported to occur in MCTD.

28. Hematologic abnormalities   • Approximately 75% of patients have a low-grade anemia.  • Leukopenia , mainly affecting the lymphocyte series, is a common finding.  •The majority have hypergammaglobulinemia . Less common problems include thrombocytopenia, hemolytic anemia.

29. Pulmonary About 85% of patients have pulmonary involvement, which is often asymptomatic.

30. Pleural Effusions Pulmonary Hypertension Pleuritic Pain Intersitial Lung Disease (30-50%) Thromboembolic Disease Obstructive Disease Pulmonary Vasculitis

31. Pulmonary hypertension is the most common disease-related cause of death in patients with MCTD. It accounted for death in 13% during the follow-up period

32. Gastrointestinal Gastrointestinal involvement is seen in about 70% patients. The most common manifestations are oesophageal dysmotility , lower oesophageal sphincter laxity, and gastrooesophageal reflux.

33. the next most common gastrointestinal features of MCTD are bacterial overgrowth syndromes and malabsorption . Pseudodiverticula along the antimesenteric border of colon can occur like in scleroderma.

34. Sicca Secondary Sjögren syndrome occurs in approximately 25% of all patients with MCTD Anti-SSA (Ro) antibodies. Patients may have salivary or submandibular gland enlargement.

35. Cardiac disease    All three layers of the heart may be involved in MCTD. Pericarditis is the commonest clinical manifestation of cardiac involvement being reported in 10 to 30% of patients;

36. Pericardial Disease Pericardial Involvement Scleroderma 59% SLE 44% MCTD 30% RA 24% MCTD At autopsy – 56% had pericardial disease Asymptomatic pericardial effusion – 24-38%

37. Cardiac pulmonary hypertension is among the most serious cardiac complication in MCTD. Less common- valvular abnormalities, septal hypertrophy, and myocarditis .

38. Pregnancy    40% prevalence of flares during pregnancy Small for gestational age infants occurred in 50% of pregnancies. The mechanism for pregnancy complications is probably an autoimmune reaction against placental tissues.

39. Nervous system Central nervous system (CNS) involvement is rare in MCTD. Most common are trigeminal neuralgia, which can be the initial feature of MCTD.

40. CNS Headache . Aseptic meningitis. Psychosis. Stroke. Seizures. Cauda equina syndrome and transverse myelitis . C erebral hemorrhage .

41. Renal The absence of severe renal disease is a hallmark of MCTD. Renal involvement occurs in about 25 percent of patients. Membranous nephropathy is the most common finding. Less common- MPGN, Interstital nephritis.

42. Features of Diseases Feature MCTD SLE Scleroderma Polymyositis Renal Involvment Less Common Common Renal Crisis may occur Rare Pulmonary PAH/ILD Less common PAH/ILD ILD may occur Esophageal Dysmotility Common Rare Common Uncommon, but dysphagia Antiphospholipid Syndrome Less common Common Less common Less common Cytopenias Can Occur Common Rare Rare Sclerodactyly Common Rare Common Rare Neurological Less Common, (trigeminal) More Common Rare Rare

43. Laboratory Findings The diagnosis of MCTD depends on the demonstration of anti U1RNP antibody in high titres. Anti U1RNP antibodies by haemagglutination test titre > 1:1600 is characteristic feature of MCTD. The absence of anti- Sm antibodies and anti-DNA antibodies.

44. Antibody Findings Disease ANA RF dsDNA Sm Scl-70 RNP SLE 95-99 20 50-70 30 30-50 RA 15-35 85 <5 10 Diffuse SSc >90 30 40 30 MCTD 95-99 50 <5 100

45. Anti-RNP Ab IgG form is generally more associated with MCTD, while IgM form may often occur in Lupus. When found in isolation suggests MCTD. Sensitivity- 71 to 100%. Specificity- 84%.

46. Antinuclear antibody positivity is seen in 100% of patients in high titre with coarse speckled pattern.

47. Other lab features Leukopenia , anemia, thrombocytopenia. Elevated ESR. Very high serum immunoglobulins . Complement levels usually normal or high. Rheumatoid Factors increased in 50 % of patients.

48. IMAGING • Chest radiography : infiltrates, effusion, or cardiomegaly . • Echocardiography : effusion ,pulmonary hypertension.

49. Ultrasonography /CT scanning :abdominal pain (indicated for evidence of serositis , pancreatitis, or visceral perforation related to vasculitis ) MRI - Used to assess neuropsychiatric signs or symptoms

50. TREATMENT There is no specific treatment for MCTD. The overall goal of therapy is to control symptoms and to maintain function. Monitoring for development of complications, such as pulmonary hypertension or infection, is important.

51. General Appropriate vaccines for age and risk; Modify cardiovascular risk; promote healthy lifestyle, including exercise, diet, and risk avoidance. S upplementary calcium and vitamin D.

52. Arthralgia /arthritis Mild - antimalarial , NSAIDs. Moderate to severe - systemic corticosteroids. Methotrexate . azathioprine .

53. Avoiding Infliximab ( TNF- alpha inhibitor)-because of potential risk for disease flare.

54. Raynaud phenomenon Mild—protective measures. Moderate—calcium channel blockers may be of benefit. Severe—scleroderma-like management

55. Rash Mild—protective measures to avoid the sun, antimalarial , and topical corticosteroids Moderate to severe—systemic corticosteroids, immunosuppressant, including azathioprine .

56. Esophageal reflux Mild—avoidance measures Moderate to severe—proton pump inhibitor, endoscopy with screening for Barrett esophagus .

57. Myositis Mild— antimalarial , corticosteroids. Moderate to severe—corticosteroids, methotrexate , and IVIG .

58. Pulmonary involvement Yearly screening with pulmonary function testing and pulmonary imaging may be beneficial for the identification of early disease.

59. Moderate to severe— cyclophosphamide immunosuppression or treatment as for primary pulmonary hypertension may be beneficial

60. Cardiovascular Modify risk factors Yearly screening with ECG and echocardiography may be beneficial for the identification of early disease or as clinically indicated.

61. Pleurisy/ Pericarditis - NSAIDs, low dose Prednisone 10 to 30 mg/ day. Myocarditis - Steroids + monthly cyclophosphamide .

62. Pregnancy and contraception Monitor as for a high-risk pregnancy; SSA (Ro) and RNP have been associated with congenital heart block in neonates; pregnancy Counsel on risk for sexually transmitted diseases, contraceptive options, risk and potential teratogenicity of medications. Avoid estrogen -containing contraceptives.

63. Corticosteroids These agents are reserved for more active or severe disease. Corticosteroids are occasionally helpful during early stage of disease.

64. Cortiocsteroids Aseptic meningitis . Myositis . Pleurisy. Pericarditis and myocarditis . Interstitial lung disease.

65. Pulse therapy: - IV methyl predinsolone 1gm for 3 to 5 days. - Followed by oral predinsolone 0.5 to 1mg/kg for 4 to 6 wks. Maitaince therapy: Oral predinsolone 5 to 10mg. And try Taper once symptoms disappear.

66. Cytotoxic agents Major organ involvement may require moderate-to-high divided daily doses of cytotoxic agents. Pulmonary hypertension may respond well to aggressive immunosuppression with cytotoxic agents.

67. Immunosuppressive drugs may be useful for induction of remission. The commonly used agents are Azathioprine Cyclophosphamide Methotrexate .

68. NIH PROTOCOL FOR PULSE CYCLOPHOSPHAMIDE THERAPY Calculate body surface area (BSA) (m2): BSA = Height (cm) × weight (kg)/3600.

69. ■ Initial dose 0.5 to 0.75 g/m2 - Administer CYC in 150 ml normal saline intravenously over 30 to 60 minutes. - Alternative : equivalent dose of pulse CYC may be taken orally in highly motivated and compliant patients .

70. Obtain WBC count at days 14 after each CYC treatment ( delay prednisone dose)

71. Adjust subsequent doses of CYC to maximum dosage of 1.0 g/m2 to keep WBC count above 1500/ mL . If WBC count falls below 1500/ mL , decrease next dose by 25%.

72. Repeat IV CYC pulses monthly (every 3 weeks in extremely aggressive disease) for another 6 months (seven pulses). T hen quarterly for 1 year after remission is achieved.

73. Protect bladder against CYC-induced hemorrhagic cystitis: Diuresis with 5% dextrose and 0.45% saline (2 L at 250 mL /hr) high-dose oral fluids for 24 hours.

74. Mesna : (each dose is 20% of total CYC dose) intravenously or orally at 0, 2, 4, and 6 hours after CYC dosing. Mesna is especially important to use if sustained diuresis may be difficult to achieve or if pulse CYC is administered in outpatient setting.

75. Antiemetics Dexamethasone (10-mg single dose) plus Serotonin receptor antagonists: granisetron 1 mg with CYC dose ( usually repeat dose in 12 hours); ondansetron 8 mg three times a day for 1 to 2 days.

76. Complications of pulse CYC: Nausea and vomiting. Infection H erpes zoster Infertility (male and female ). Amenorrhea.

77. Induction therapy Steroid plus - Cyclophhasmide . - Mycophenolate moeftil - Azathioprine .

78. Maitance therapy Mycophenolate moeftil - 2 to 3 gm per day Azathioprine - 2 to 3 mg/kg/day

79. Follow-up 39 MCTD patients at 10 year follow-up 64% “differentiated” into another syndrome 11 systemic sclerosis, 10 SLE, 2 RA, 2 overlap syndrome Other studies have found similar results About 40% of patients with anti-U1RNP antibodies retain the diagnosis of MCTD and others are “reclassified” within 5 years of presentation

80. Prognosis in MCTD Survival Rates 5 yrs: 98% 10 yrs: 96% 15 yrs: 88% Major causes of death Pulmonary hypertension: 9/280 patients Cardiovascular events: 7/280 TTP: 3/280 Infections 3/280 J Rheumatol. 2013 Jul;40(7):1134-42

81. PROGNOSIS The prognosis is worse for people with features of systemic sclerosis and/or polymyositis .  The most severe clinical manifestation is pulmonary hypertension which contributes to premature death Scleroderma renal crisis , myocarditis are other causes of death

82. Summary Defintion . Intially presents with overlaping features. No specific treatment. Monitor for complications.

83. References Harrison’s principles of internal medicine 19 th edition. MARC C. HOCHBERG Rheumatology. kelly ’s textbook of Rheumatology. Uptodate .

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