Refractory Systemic Lupus Erythematosus .pptx

Refractory systemic lupus erythmatosus

1. Refractory Systemic Lupus Erythematosus Samar Tharwat Radwan Assistant Professor of Rheumatology and Immunology (Internal Medicine Department ) Musculoskeletal Ultrasound –EULAR Mansoura University

2. Agenda Introduction Selected severe refractory manifestations Neuropsychiatric Involvement Gastrointestinal Involvement Hematologic Involvement Renal Involvement Cutaneous Involvement Pulmonary Involvement Cardiac and Vascular Involvement Comorbidity and Complications in SLE Treatment Strategy of Severe Refractory SLE New developments in systemic lupus erythematosus

3. Introduction Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease Variable severity and course Tendency for flare Fanouriakis , Antonis, et al. "Update ο n the diagnosis and management of systemic lupus erythematosus." Annals of the rheumatic diseases 80.1 (2021): 14-25.

4. EPIDEMIOLOGY Incidence :0.3–31.5 cases per 100000 Increased in the last 40 years Prevalence 50–100 cases per 100000 adults Gergianaki I, Fanouriakis A, Repa A, et al. Epidemiology and burden of systemic lupus erythematosus in a southern European population: data from the community-based lupus Registry of Crete, Greece. Ann Rheum Dis 2017;76:1992–2000.

5. Clinical Manifestations Wallace, Daniel J., and Dafna D. Gladman. "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults." UpToDate. Waltham (2020).

6. Aringer , Martin, Nicolai Leuchten , and Sindhu R. Johnson. "New criteria for lupus." Current rheumatology reports 22 (2020): 1-8.

7. Aringer , Martin, Nicolai Leuchten , and Sindhu R. Johnson. "New criteria for lupus." Current rheumatology reports 22 (2020): 1-8.

8. Aringer, Martin. "EULAR/ACR classification criteria for SLE." Seminars in arthritis and rheumatism. Vol. 49. No. 3. WB Saunders, 2019. ANA positive

9. Early diagnosis and prompt personalized treatment strategies are crucial in preventing the development of undesired prognosis

10. Refractory SLE Do not respond to standard therapy OR Relapse after initial clinical remission

11. Disease activity Increasing signs and symptoms. Changes in serology. Absence of improvement that lead to increase therapy. Patterns of disease activity

12. Well designed RCTs with an enrollment of severe and refractory SLE are limited RCTs include SLE patients with a mild to moderate. Assessment indices are also challenging in terms of severe/ refractory SLE ( SLEDAI-2K) Clinical interventions are difficult to unify for severe/refractory SLE in RCTs

13. Selected Neuropsychiatric Involvement Transverse myelitis Posterior reversible encephalopathy syndrome (PRES) Diagnostic Biomarkers and Imaging in NPSLE Management of Severe Refractory NPSLE

14. Transverse myelitis Rare (1-3%) Severe Compared to controls, SLE-TM patients exhibited a high frequency of fever and positive anticardiolipin and lupus anticoagulant. Predictors of poor outcome: Initial severity of neurological impairment Extensive spinal cord lesions Delayed use of pulse intravenous methylprednisolone Zhang S, Wang Z, Zhao J, Wu DI, Li J, Wang Q, Su J, Xu D, Wang Y, Li M, Zeng X (2020) Clinical features of transverse myelitis associated with systemic lupus erythematosus. Lupus 29(4):389 – 397.

15. Posterior reversible encephalopathy syndrome (PRES) Rare (0.69 – 2.02%) Characterized by : Headaches Seizures Visual disorders Altered consciousness Predominant lesion Areas of posterior cerebral white matter Challenging (immunosuppressive (IS) drugs/hypertension) Underestimated variant of “ reversible neurological deficits ” Liu B, ZhangX , Zhang FC, Yao Y, Zhou RZ, XinMM,Wang LQ (2012) Posterior reversible encephalopathy syndrome could be an underestimated variant of “reversible neurological deficits” in systemic lupus erythematosus. BMC Neurol 12:152

16. Cerebral venous sinus thrombosis (CVST) Uncommon Potentially fatal Headache Symptoms secondary to raised intracranial pressure (vomiting, visual field defect, seizures, focal neurological deficits and altered consciousness) Acute / subacute / chronic. Vasculitis /Antiphospholipid/Thrombophilia (nephrotic syndrome)/chronic inflammatory status Oral contraceptive use/Pregnancy /Infection/Malignancy Magnetic resonance venography imaging/ cerebrospinal fluid (CSF) examinations Aggressive GC treatment/ anticoagulants Wang L, Chen H, Zhang Y, Liu W, ZhengW , Zhang X, Zhang F (2015) Clinical characteristics of cerebral venous sinus thrombosis in patients with systemic lupus erythematosus: a single- centre experience in China. J Immunol Res 2015:540738 – 540737.

17. Diagnostic Biomarkers and Imaging in NPSLE Autoantibodies: anti-ribosomal P autoantibodies, aPL , antineuronal antibodies (serum and CSF), CSF ubiquitin, CSF anti-ribosomal protein 2, anti-SSA. Magnetic resonance imaging (MRI) : not sensitive or specific Single-photon emission computed tomography (SPECT): sensitive FDG-PET/CT Niu N, Cui R (2017) Glucose hypermetabolism in contralateral basal ganglia demonstrated by serial FDG PET/CT scans in a patient with SLE chorea. Clin Nucl Med 42(1):64–65

18. Management of Severe Refractory NPSLE Challenging High-dose GC or pulse intravenous MP Cyclophosphamide (CYC) and rituximab Intrathecal injection with methotrexate (10 – 20 mg) plus dexamethasone (10 – 20 mg) per week for one to five consecutive weeks, in combination with conventional IS drugs Yang, Huaxia , et al. "Management of severe refractory systemic lupus erythematosus: Real-world experience and literature review." Clinical reviews in allergy & immunology 60.1 (2021): 17-30.

19. Gastrointestinal Involvement Lupus Mesenteric Vasculitis Protein-Losing Gastroenteropathy Acute Pancreatitis Acute Acalculous Cholecystitis Management of Severe Refractory GI Involvement in SLE

20. Gastrointestinal Involvement GI involvement are challenging Symptoms are nonspecific and difficult to differentiate from that of infections and side effects of therapeutic agents SLEDAI may underestimate lupus activity Tian XP, Zhang X (2010) Gastrointestinal involvement in systemic lupus erythematosus: insight into pathogenesis, diagnosis and treatment. World J Gastroenterol 16(24):2971 – 2977.

21. Lupus Mesenteric Vasculitis 2.2–9.7% Abdominal pain ( 29 – 65%) Inflammatory vasculitis/thrombosis Typical CT imaging : dilated bowel/ thickened bowel wall/ the target sign Ju, Ji Hyeon, et al. "Lupus mesenteric vasculitis can cause acute abdominal pain in patients with SLE." Nature Reviews Rheumatology 5.5 (2009): 273-281.

22. Intestinal Pseudo-Obstruction Ineffective intestinal propulsion without mechanical obstruction. Vasculitis causing ischemia / autoantibodies against intestinal smooth muscle cells. CT scanning : dilated fluid-filled bowel loops, thickened bowel walls, and multiple fluid levels without mechanical obstruction. Ohri , Alpana J., Chintan G. Shah, and Amish H. Udani . "Intestinal pseudo-obstruction–an under-recognized presentation of systemic lupus erythematosus." Indian Journal of Nephrology 32.5 (2022): 476-479.

23. Protein-Losing Gastroenteropathy Uncommon (1.9 – 3.2%) Intestinal lymphangiectasis / vasculitis . Diarrhea was the most common manifestation. Positive ANAs Exclusion of other common causes of hypoalbuminemia Tc-99m albumin scintigraphy is useful Peng, Liying , et al. "Characteristics and long-term outcomes of patients with lupus-related protein-losing Enteropathy: A retrospective study." Rheumatology and Immunology Research 1.1 (2020): 47-52.

24. Acute Pancreatitis Rare but severe Antiphospholipid/vasculitis/immune complex/complement activation E levated serum amylase or lipase Dima, Alina, et al. "Systemic lupus erythematosus-related acute pancreatitis." Lupus 30.1 (2021): 5-14.

25. Acute Acalculous Cholecystitis Severe gallbladder inflammation and the absence of gallstones 0.15% Arterial occlusion (deposition of immune complexes and thrombi mediated) Imaging : distended gallbladder , thickened wall , pericholecystic fluid, and absence of gallstones Higher morbidity (up to 50%) Aggressive GC. Lee, Jeonghun , Young Joo Lee, and Youngsun Kim. "Acute acalculous cholecystitis as the initial manifestation of systemic lupus erythematous: a case report." Medicine 100.22 (2021): e26238.

26. Management of Severe Refractory GI Involvement in SLE Early diagnosis Aggressive immunosuppressive therapy (help avoid surgical intervention) High-dose GC and IS drugs (CYC, calcineurin inhibitors (CNI), mycophenolate mofetil (MMF), and AZA)/Pulse intravenous MP Infection/antibiotics/parenteral nutrition/prokinetic agents Yang, Huaxia , et al. "Management of severe refractory systemic lupus erythematosus: Real-world experience and literature review."  Clinical reviews in allergy & immunology  60.1 (2021): 17-30.

27. Hematologic Involvement Severe Refractory Thrombocytopenia

28. Severe Refractory Thrombocytopenia 5% of lupus thrombocytopenia H igh-dose GC combined with AZA, MMF, or CNI Pulse intravenous MP (1 g/day, 1 – 3 days) High-dose intravenous immunoglobulins (20 g/day, for 3 – 5 consecutive days) Rituximab:100 mg once weekly for 4 weeks Thrombopoietin receptor agonists such as romiplostim and eltrombopag Jiang, Ying, et al. "Systemic lupus erythematosus-complicating immune thrombocytopenia: from pathogenesis to treatment."  Journal of autoimmunity  132 (2022): 102887.

29. Renal Involvement Refractory Lupus Nephritis

30. Refractory Lupus Nephritis No change in (or worsening of) proteinuria and/or estimated glomerular filtration rate in response to 2 different standard-of-care induction regimens after 4–6 months in patients who are adherent to treatment.

31. Refractory Lupus Nephritis Despite prompt diagnosis and treatment with aggressive immunosuppression, a significant proportion of LN patients do not respond to treatment Several factors: drug resistance nonadherence to treatment undertreatment accumulated chronic damage

32. Arora, Swati, and Brad H. Rovin . "Expert perspective: an approach to refractory lupus nephritis."  Arthritis & Rheumatology  74.6 (2022): 915-926.

33. Cutaneous Involvement

34. 1.Acute/Subacute Cutaneous Lupus

35. 2.Chronic Cutaneous Lupus

36. Azathioprine cyclosporine cyclophosphamide

37. Pulmonary Involvement Diffuse Alveolar Hemorrhage Pulmonary Arterial Hypertension

38. Diffuse Alveolar Hemorrhage Mortality rate of 50–90% Symptoms are usually nonspecific Hypoxemia (74.5–100%), dyspnea (77.7–90%), cough (75.5–79%), and fever (61.7–72%) rather than hemoptysis (66–69.1%). Elevated C-reactive protein (CRP) Increase DLCO Sharp drop in hemoglobin CT/ bronchoalveolar lavage Rule out infections (pneumocystis carinii) GC / CYC / rituximab Al- Adhoubi , Nasra K., and Jonas Bystrom . "Systemic lupus erythematosus and diffuse alveolar hemorrhage, etiology and novel treatment strategies." Lupus 29.4 (2020): 355-363.

39. Pulmonary Arterial Hypertension 0.5 to 43% One of the leading causes of death Vasculopathy, vasculitis , and thrombosis associated with aPL Positive anti-RNP antibody and anti-SSA antibody Reduction in DLCO RT ventricular catheterization greater than 25 mmHg TTT: immunosuppressive therapy (CYC,GC) , PAH-targeted therapy (endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, guanylate cyclase stimulators, and prostacyclin analogs) Huang C, Li M, Liu Y, Wang Q, Guo X, Zhao J, Lai J, Tian Z, Zhao Y, Zeng X (2016) Baseline characteristics and risk factors of pulmonary arterial hypertension in systemic lupus erythematosus patients. Medicine (Baltimore) 95(10):e2761.

40. Cardiac and Vascular Involvement Lupus Myocarditis Digital Gangrene

41. Lupus Myocarditis Uncommon but severe Unexplained heart failure, cardiomegaly, tachycardia, impaired left ventricular ejection fractions (LVEF), and wall motion abnormalities Vasculitis Echocardiography and cardiac MRI Biopsy is the gold standard At the early stages, the cardiac functions of LM patients are compensated (impaired strain and twist of the left ventricle) Prompt aggressive GC therapy and early IS drugs Du Toit, Riette, et al. "Lupus myocarditis: review of current diagnostic modalities and their application in clinical practice." Rheumatology 62.2 (2023): 523-534.

42. Digital Gangrene Rare (0.67%) Ischemic necrosis and amputation and secondary infections leading to life-threatening consequences Risk factors : Raynaud ’ s phenomenon, elevated serum CRP, and long disease duration Vasculitis , thromboembolism, atherosclerosis, and hypercoagulability GC , CYC, antilipemic agents, and anticoagulation therapies Liu A, Zhang W, Tian X, Zhang X, Zhang F, Zeng X (2009) Prevalence, risk factors and outcome of digital gangrene in 2684 lupus patients. Lupus 18(12):1112–1118.

43. Comorbidity and Complications in SLE Rhupus Syndrome Sjögren’s Syndrome-Onset SLE Infections

44. Rhupus Syndrome Fulfill the criteria for both SLE and RA (ESR, CRP, and the positive rate of anti-cyclic citrullinated peptide antibody and rheumatoid factor were significantly higher in rhupus patients) 1.3 – 9.7% More significant arthritis Milder SLE complications Low-to-moderate dose of GC combined with disease modifying antirheumatic drugs (DMARDs). Rituximab Ahsan, Haseeb. " Rhupus : dual rheumatic disease." Journal of Immunoassay and Immunochemistry 43.2 (2022): 119-128.

45. Sjögren’s Syndrome-Onset SLE (SS/SLE) 8 to 25% Benign prognosis , elder in age, have more insidious disease Xerostomia, xerophthalmia, and renal tubular acidosis are higher Positive for RF, anti-SSA, and anti- SSB. Most SS/SLE patients remained stable at low-dose GC during follow-up Xu D, Tian X, Zhang W, Zhang X, Liu B, Zhang F (2010) Sjogren ’ s syndrome-onset lupus patients have distinctive clinical manifestations and benign prognosis: a case-control study. Lupus 19(2):197 – 200.

46. Infections Opportunistic Infections

47. Infections The most common causes of morbidity and mortality in patients with SLE. Opportunistic infections Viral and fungal pathogens, tuberculosis (TB), and CNS infections could be the most challenging comorbidities in SLE management.

48. Opportunistic Infections Cytomegalovirus (CMV): Hemocytopenia, fever, and liver dysfunction Pneumocystis carinii Fungal infections such as Aspergillus fumigatus , Cryptococcus , and Candida TB infections : anti-TB medications may induce lupus-like manifestations Central Nervous System Infections

49. Treatment Strategy of Severe Refractory SLE

50. Parra Sánchez, Agner R., Alexandre E. Voskuyl , and Ronald F. van Vollenhoven. "Treat-to-target in systemic lupus erythematosus: advancing towards its implementation." Nature reviews Rheumatology 18.3 (2022): 146-157.