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SLE Clinical Manifestation



  • MSK related
    • Arthritis and arthralgias
      • occur in over 90 percent of patients with SLE and are often one of the earliest manifestations
      • Arthritis, with demonstrable inflammation, occurs in 65 to 70 percent of patients and tends to be migratory, polyarticular, and symmetrical
    • AVN
    • Myositis : DDx: HCQ, Steroid, Colchicine, Statin, TSH, infectious, electrolyte abnormalities 
  • Cutaneous Lupus (Lupus Specific or Lupus Non-specific
    • Lupus Specific )
      • Acute cutaneous lupus erythematosus (ACLE)

        Localized ACLE (ie, malar rash, butterfly rash)

        Generalized ACLE

        Toxic epidermal necrolysis-like ACLE

        Subacute cutaneous lupus erythematosus (SCLE)

        Annular SCLE

        Papulosquamous SCLE

        Drug-induced SCLE

        Less common variants: VEEP erythrodermic, poikilodermatous, erythema multiforme-like (Rowell syndrome), and vesiculobullous annular SCLE

        Chronic cutaneous lupus erythematosus (CCLE)

        •Discoid lupus erythematosus (DLE)

        -Localized DLE

        -Generalized DLE

        -Hypertrophic DLE

      • 15 to 30 percent

      •  DLE have increased risk for photosensitivity and leukopenia but decreased risk for serositis and arthritis

        TPCL

        Lupus erythematosus tumidus (LE tumidus)

        •Lupus profundus (also known as lupus panniculitis)

        •Chilblain lupus erythematosus (chilblain LE)

        •Lichenoid cutaneous lupus erythematosus-lichen planus overlap syndrome (LE-LP overlap syndrome)

  • NPSLE Ref: Neurological Manifestations of Systemic Lupus Erythematosus in Children and Adults 2010
    • 12 Central Nervous System7 Peripheral Nervous System
      1. Aseptic meningitis

      2. Cerebrovascular disease

      3. Demyelinating syndrome

      4. Headache

      5. Movement disorder

      6. Myelopathy

      7. Seizure

      8. Acute confusional state

      9. Anxiety disorder

      10. Cognitive dysfunction

      11. Mood disorder

      12. Psychosis

      1. Guillain-Barré syndrome

      2. Autonomic disorder

      3. Mononeuropathy, single/multiplex

      4. Myasthenia gravis

      5. Cranial neuropathy

      6. Plexopathy

      7. Polyneuropathy

  •                         Note: 
        • It is cognitive dysfunction (thinking, memory, and concentration) vs cognitive impairment 
        • Steroid-induced psychosis is dose-dependent and occurs in the first 2 weeks of treatment initiation
        • AION (painless, no improvement) vs Optic Neuritis (painful, waxing/waning) must be differentiated 
        • A combination of myelitis and ON can be seen in the setting of SLE, MS, NMO. APLA can mimic demyelinating disease. spinal involvement in MS is usually < 2 spine and  but in SLE is > 3, but there is identical findings of SLE and MS In brian
        • Positive ANA is noted in 27% of patients with MS 
        • PRES is a DDx as well - first described in 15 patients in 1996, 2 of those patients had SLE. PRES is a clinical-radiologic syndrome characterized by headache, decreased consciousness, visual changes, and seizures in the context of posterior cerebral white matter edema. It has been associated with a variety of conditions, including hypertension, eclampsia, renal disease, immunosuppressive therapies, post–solid organ transplantation, and autoimmune disease.
        • Prevalance of PN in SLE is 6 % in 2000 patients, of which 67% was attributed to SLE 
          • Sensory and SM axonal polyneuropathy is the most common forms; 17 % of biopsy sample had small fiber neuropathy not included in the NPSLE . Small fiber neuropathy - The diagnosis is confirmed by a skin biopsy that demonstrates decreased intraepidermal nerve fiber density
        • DDx of PN: When encountering a SLE patient with peripheral neuropathy, it is essential for the physician to consider and rule out non-SLE etiologies such as infections (e.g., HIV, syphilis, Lyme disease, leprosy), malignancy, endocrine disorders (e.g., diabetes mellitus, hypothyroidism), toxins (e.g., alcohol, heavy metals), vitamin deficiency (e.g., vitamins B12, B6), and drugs (e.g., hydroxychloroquinecolchicinevitamin B6 excess).
    • Mechanism of NPSLE
      • Primary Injury to Vasculature : 
        • Thromboembolic events to small and large vessels - often due to APLA 
        • bland vasculopathy to small vessels characterized by vascular hyalinization, perivascular inflammation, and endothelial proliferation
        • ASCVD 
        • True vasculitis is exceedingly rare 
      • Primary Injury to Parenchyma: due to 
        • ab - 
          • APLA may also bind directly to neuronal cells - explaining why there is diffuse cognitive impairment event in the absence of VTE  
          • Anti-ribosomal P - psychosis, mood disorders, depression (Note: Antiribosomal P ab is seen only in 14% of SLE but specificity is > 90%)
          • A subset of anti-DNA ab cross-react with NMDAR (N-methyl-D-aspartate) receptor - leads to non-inflammatory apoptosis of neuronal cells - associated with cognitive dysfunction 
        • cytokines
        • chemokines
        • infiltrating cells when there is a breach in BBB
      • DDx: PML 
    • Imaging: MRI: The most commonly noted abnormalities are small, hyperintense, T2-weighted, focal white matter lesions located in the periventricular and subcortical white matter of the frontoparietal regions of the brain (though these findings are nonspecific. Other various findings are noted. 
      • Normal MRI in 42 % of NPSLE
  • Ocular involvement 
    • KCS (most common)
    • Retinal abnormalities - corelates with LN, CNS involvement and APLA 
    • Episcleritis and Sclreritis 
    • Uveitis is extremely rare 
    • Medications: HCQ (very low risk at at or below 6.5 mg/kg of ideal body weight) and Steroids 
  • Pulmonary Manifestation
    1. Pleuritis
    2. Plerual effusion
    3. DAH
    4. Acute Pneumonitis
    5. CILD 
    6. PAH
    7. Shrinking Lung Syndrome
    8. Small airway disease 
    9. BOOP (rare case reports)
  • GI manifestion: 
    • Dysphagia (upper 1/3 of Esophagus)
    • Pancreatitis 
      •  Note: AZA and steroids can cause pancreatitis but are less common in SLE patients 
    • Peritonitis
    • Very rarely: Mesenteric vasculitis 
    • Mild LFT abnormalities in 60% of patients 
      • Lupus hepatitis is different than AI Hepatitis 
    • VTE in the setting of APLA 
    • Rarely: Protein losing enteropathy, Intestinal pseudoobstruction

  • Renal Manifestations: 90% in a biopsy, 50% clinically; evident mostly in first 36 months of illness 
    • IC mediated GN
    • TIN Disease : in up to 60% of renal biopsy 
    • Vasculopathy:  Lupus vasculopathy (Igb, and Complement containing thrombi), TMA (fibrin thrombi) is seen in 24% of biopsy often is associated with APLA, Vasculitis, Nonspecific vascular sclerosis 
    • 10% will end up with ESRD despite treatment 
    • Treatment of Lupus Nephritis:
      • J M Mid 20s: 
      • Lupus disease manifestations including pleuropericarditis, peritonitis, fever, positive ANA, positive dsDNA, positive Smith, positive RNP, hypocomplementemia, non-hemolytic anemia, arthritis, malar rash and later biopsy proven subacute cutaneous lupus.  Kidney biopsy result 2/2018  with identified lupus nephritis class V along with a thrombotic glomerulopathy/microangiopathy (patient started on aspirin but hematology felt findings represented a local phenomenon and not a manifestation of antiphospholipid disease).  
      • MMF stopped due to N/V
      • ER 1/2018 with dyspnea, fever and right side chest pain with right sided pleural effusion and lung infiltrates.  Hospital course includes introduction of MPA (Myfortic) for lupus nephritis and steroid sparing potential due to cytopenias and serositis.  
      • Nephritis proved refractory  to mycophenolate prompting change to cyclophosphamide infusions.  Despite cytoxan infusions patient's proteinuria worsened and patient received rituximab infusions x2 7/2019.  
      • Later stopped all meds and had skin flare up with malar rash and extremity rash.  resumed hydroxychloroquineRe-dose rituximab 1/2020 though rituximab infusion 1/28/2020 complicated by an infusion reaction.  
      • Did not want reintroduction of MMF and/or options including a re-challenge with slowly infused, highly pre-medicated rituximab plus/minus adding tacrolimus.   
      • Repeat kidney biopsy 3/2020 demonstrates significant scarring - Neph still felt reasonable to try immunosuppression.  
      • By mid-June 6/2020 presents with epigastric pain, patient hospitalized and hospital course includes hemodialysis initiation.  
      • Positive urine pregnancy test 11/9/2020 with pelvis US demonstrating a single live intrauterine pregnancy.   Course includes prolonged QTc interval and hydroxychloroquine held.  Coombs negative hemolytic anemia felt by inpatient Hematology team to be linked to turbulent fistula flow, mild degree of microangiography and related to dialysis and not representing an autoimmune etiology.  
      • After pregnancy, resumed hydroxychloroquine (checked ECG shortly afterward without change in QTc interval).  
      • Feels good, reports being off prednisone fully since 1/2021 and  intermittent compliance with hydroxychloroquine regularly.  
      • Later reportsmuch improved adherence with hydroxychloroquine.  Primary concern at last visit 9/2021 was weight loss.
      • "I haven't had a flare up since my baby was born."  
    • Induction therapy  story :
      • 1986: High dose steroid vs CYC . CYC better. 
      • EURO-LUPUS Nephritis 2002: low dose CYC by AZA just as good as high dose CYC 
      • ALMS 2009 : MMF was not superior over CYC but worked well
      • 2009 in LMN - induction with Cyclosporin > CYC > Prednisone but relapse was higher with cyclosporin as well 
    • Maintainance therapy story: 3-5 yr after remission (some centers do repeat biopsy to decide on the medication taper)
      • The MAINTAIN Trial 2010 (same group as EURO-LUPUS trial nephritis group)- fewer renal failure with MMF but not significant; fu biopsy was indifferent 
      • ALMS Nephritis trial - MMF may be better than AZA in the high-risk ethnic group 
      • Combination low dose MMF and tacrolimus 
    • Differences on Class 3/4 vs pure Class 5 Lupus Nephritis 
      • Treat Class 5 if > 1 gm of proteinuria/day despite ARB/ACEI
      • Treat if Cr rising 
      • Choice of treatment unclear: EULAR rec; MMF is preferred due to better toxicity profile, IV CYC or Calcineurin inhibitor as monotherapy or in combination with MMF 
    • Mycophenolate Mofetil

      Cyclophosphomide
            • Methods: In this multicenter, prospective study randomly assigned 90 SLE patients with proliferative glomerulonephritis to a high-dose IV CYC regimen (6 monthly pulses and 2 quarterly pulses; doses increased according to the white blood cell count nadir) or a low-dose IV CYC regimen (6 fortnightly pulses at a fixed dose of 500 mg), each of which was followed by AZA. Intent-to-treat analyses were performed.
            • Results: Follow-up continued for a median of 41.3 months in the low-dose group and 41 months in the high-dose group. Sixteen percent of those in the low-dose group and 20% of those in the high-dose group experienced treatment failure (not statistically significant by Kaplan-Meier analysis). Levels of serum creatinine, albumin, C3, 24-hour urinary protein, and the disease activity scores significantly improved in both groups during the first year of follow-up. Renal remission was achieved in 71% of the low-dose group and 54% of the high-dose group (not statistically significant). Renal flares were noted in 27% of the low-dose group and 29% of the high-dose group. Although episodes of severe infection were more than twice as frequent in the high-dose group, the difference was not statistically significant
            • Conclusion: European SLE patients with proliferative lupus nephritis, a remission-inducing regimen of low-dose IV CYC (cumulative dose 3 gm) followed by AZA achieves clinical results comparable to those obtained with a high-dose regimen.
        • Austin et al. (NIH) 
          • prednisone, cyclophosphamide, and cyclosporine in LMN 2009
          • Forty-two patients with LMN participated in a randomized, controlled trial to compare adjunctive immunosuppressive drugs with prednisone alone. Adjunctive regimens included either cyclosporine (CsA) for 11 mo or alternate-month intravenous pulse cyclophosphamide (IVCY) for six doses; the control group received alternate-day prednisone alone. Median proteinuria was 5.4 g/d (range 2.7 to 15.4 g/d). 
          • Primary outcome, time to remission of proteinuria during the 12-mo protocol, by univariate survival analysis was assessed. At 1 yr, the cumulative probability of remission was 27% with prednisone, 60% with IVCY, and 83% with CsA. Although both IVCY and CsA were more effective than prednisone in inducing remissions of proteinuria, relapse of nephrotic syndrome occurred significantly more often after completion of CsA than after IVCY. By multivariate survival analysis, treatment with prednisone and high-grade proteinuria (>5 g/d) but not race or ethnicity were independently associated with a decreased probability of remission. 
          • Adverse effects during the 12-mo protocol included insulin-requiring diabetes (one with prednisone and two with CsA), pneumonia (one with prednisone and two with CsA), and localized herpes zoster (two with IVCY). 
          • In conclusion, regimens containing CsA or IVCY are each more effective than prednisone alone in inducing remission of proteinuria among patients with LMN.






11 Clinical Criteria and 6 Immunological Criteria
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