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SLE Treatment


Steroids
NSAIDs
    • Inhibit cyclooxygenase, types 1 and 2. 
    • Used for fever, serositis, and arthritis. 
HCQ
    • MOA: Lancet 2013
      • Immunomodulative properties without immunosuppression.
      • Increases lysosomal pH and interferes with antigen processing and possibly modulation of the immune response mediated by TLR 9 and TLR . Thus inhibits mostly the innate immune system -  antigen Processing and Co-stimulation activation. 
    • Used for arthritis, skin rashes, and fatigue. Might have a useful role in nephritis
    • Advantages: 
      1. Decrease damage accrual 
      2. Improve survival 
      3. have antithrombotic properties, and shows improved outcome in APLA patient 
      4. reduce cholesterol concentrations.
      5. Reduce DM 
      6. Reduce flare up and reduce GC dosing 
      • Results: Overall, mean [HCQ] was 918±451 ng/ml. Active SLE was less prevalent in patients with higher [HCQ]. A total of 171 patients were randomised and followed for 7 months. SLE flare rates were similar in the two groups (25% in group 1 vs 27.6% in group 2; p=0.7), but a significant spontaneous increase in [HCQ] in both groups between inclusion and randomisation strongly suggested improved treatment adherence. Patients at the therapeutic target throughout follow-up tended to have fewer flares than those with low [HCQ] (20.5% vs 35.1%, p=0.12)
      • Conclusions: Although low [HCQ] is associated with higher SLE activity, adapting the HCQ dose did not reduce SLE flares over a 7-month follow-up.


Azathioprine
    • MOA:
      • Purine analogue that suppresses DNA synthesis by inhibiting synthesis of xanthylic and adenylic acids. 

      • Monitoring: 
        • Metabolised by metabolism involves the enzyme thiopurine methyltransferase (TPMT). Consider testing for TPMT activity prior to initiation of Azathioprine. 
        • Metabolites cleared by Xanthine Oxidase. Hence, Xanthine Oxidase inhibitors (i.e Allopurinol, Fuboxostat) are relatively contraindicated when using Azathiopurine.
      • Long-term follow-up of a randomised controlled trial of azathioprine/methylprednisolone versus cyclophosphamide in patients with proliferative lupus nephritis Ann Rheum Dis 2011
        • Conclusion: Induction treatment with ivCY was superior to AZA/MP in preventing renal relapses, but other parameters for renal function did not differ. AZA/MP can therefore serve as an alternative in patients with proliferative LN who wish to avoid gonadal toxicity of CY
        • Renal relapses occurred more often in the AZA/MP group (n=14 (38%) vs n=5 (10%); p=0.002, HR: 4.5).
      • The MAINTAIN Trial
      • The Aspreva Lupus Management Study (ALMS)
        • Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis NEJM 2011 Mary Anne Dooley et al. 
        • Methods: 36-month, RCT, double-blind, double-dummy, phase 3 study comparing oral mycophenolate mofetil (2 g per day) and oral azathioprine (2 mg per kilogram of body weight per day), plus placebo in each group, in patients who met response criteria during a 6-month induction trial. The study group underwent repeat randomization in a 1:1 ratio. Up to 10 mg of prednisone per day or its equivalent was permitted. The primary efficacy end point was the time to treatment failure, which was defined as death, end-stage renal disease, doubling of the serum creatinine level, renal flare, or rescue therapy for lupus nephritis. Secondary assessments included the time to the individual components of treatment failure and adverse events.
        • Results: A total of 227 patients were randomly assigned to maintenance treatment (116 to mycophenolate mofetil and 111 to azathioprine). Mycophenolate mofetil was superior to azathioprine with respect to the primary end point, time to treatment failure (hazard ratio, 0.44; 95% confidence interval, 0.25 to 0.77; P = 0.003), and with respect to time to renal flare and time to rescue therapy (hazard ratio, <1.00; P < 0.05). Observed rates of treatment failure were 16.4% (19 of 116 patients) in the mycophenolate mofetil group and 32.4% (36 of 111) in the azathioprine group. Adverse events, most commonly minor infections and gastrointestinal disorders, occurred in more than 95% of the patients in both groups (P = 0.68). Serious adverse events occurred in 33.3% of patients in the azathioprine group and in 23.5% of those in the mycophenolate mofetil group (P = 0.11), and the rate of withdrawal due to adverse events was higher with azathioprine than with mycophenolate mofetil (39.6% vs. 25.2%, P = 0.02).
        • Conclusions: Mycophenolate mofetil was superior to azathioprine in maintaining a renal response to treatment and in preventing relapse in patients with lupus nephritis who had a response to induction therapy.


Mycophenolate Mofetil
    • MOA:
      • Mycophenolate (mycophenolic acid as active metabolite) inhibits monophosphate dehydrogenase and blocks synthesis of guanosine nucleotides and proliferation of T and B cells.  
        • Thus, preferentially inhibits T and B cells 


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: Followup 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 followup. 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.
    • Extra-renal Lupus 
      • IV cyclophosphamide versus IV methylprednisolone in severe neurological manifestations in SLE
      • Patients and methods: The study was a controlled clinical trial at two tertiary care centres of patients with SLE according to the ACR criteria, with incident (no more than 15 days) onset of severe NP manifestations such as seizures, optic neuritis, peripheral or cranial neuropathy, coma, brainstem disease, or transverse myelitis. Induction treatment with 3 g of IV methylprednisolone (MP) followed by either IV monthly cyclophosphamide (Cy) versus IV MP bimonthly every 4 months for 1 year and then IV Cy or IV MP every 3 months for another year. The primary end point was response to treatment: at least 20% improvement from basal conditions on clinical, laboratory, or specific neurological testing variables.
      • Results: Overall, a response rate of 75% was observed. Of the 32 patients studied, 18/19 receiving Cy and 7/13 receiving MP responded to treatment (p<0.03).

MTX
Cyclosporin
    • MOA: 
      • Forms complex with cyclophylin that disrupts the activation of calcineurin (complex of pho sphatases). 
      • Inhibits production of interleukin 2 and arrests T-cell cycle between G0 and G1.
        • Thus, preferentially, inhibits T cells
      • Clinica Use:
        • RA
        • Lupus
        • Inflammatory myositis
        • Psoriasis
        • Pyoderma Gangrenosum 
        • IBD
      • Monitoring:
        • Toxic medications. Hence, used as 3rd line agents in most illness. 
      • PLN 
        • The CYCLOFA-LUNE trial - PLN
        • Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: the Cyclofa-Lune study (Prague)
        • Forty patients with clinically active proliferative lupus nephritis were randomly assigned to one of two sequential induction and maintenance treatment regimens based either on cyclophosphamide or Cyclosporine A. The primary outcomes were remission (defined as normal urinary sediment, proteinuria <0.3 g/24 h, and stable s-creatinine) and response to therapy (defined as stable s-creatinine, 50% reduction in proteinuria, and either normalization of urinary sediment or significant improvement in C3) at the end of induction and maintenance phase. Secondary outcomes were incidence of adverse events, and relapse-free survival. At the end of the induction phase, 24% of the 21 patients treated by cyclophosphamide achieved remission, and 52% achieved response, as compared with 26% and 43%, respectively of the 19 patients treated by the Cyclosporine A. At the end of the maintenance phase, 14% of patients in cyclophosphamide group, and 37% in Cyclosporine A group had remission, and 38% and 58% respectively response. Treatment with Cyclosporine A was associated with transient increase in blood pressure and reversible decrease in glomerular filtration rate. There was no significant difference in median relapse-free survival. In conclusion, Cyclosporine A was as effective as cyclophosphamide in the trial of sequential induction and maintenance treatment in patients with proliferative lupus nephritis and preserved renal function.
      • MLN (as noted above in Cyclophosphamide) 
        • 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.
      • Extrarenal Lupus 
Tacrolimus 
    • MOA: Calcineurin inhibitor  
      • Monitoring:
Leflunomide
    • Inhibits dihydroorotate dehydrogenase necessary for pyrimidine and cellular protein kinases synthesis. 
    • Has immunosuppressive and antiviral effects. 
    • Monitoring:
      • Extremely long half-life; needs to be stopped 3 months prior to pregnancy
      • Cholestyramine will help in rapid excreation by inhibiting the enter-hepatic circulation (Three times a day for 8 days)
        • Measure medication twice before conception after cholestyramine used
Biologics

Targeting B Cells: B-cell depleting therapy: Rituximab

the Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial
active moderate to severe extrarenal SLE were randomly assigned to receive RTX (two biweekly infusions of 1000 mg at baseline and at 6 months) or placebo, in combination with background immunosuppression (AZA, MMF, MTX) and prednisone (0.5 to 1 mg/kg/day)
At week 52, no difference was observed between patients treated with RTX and placebo in major or partial clinical responses. However, high background therapies could have masked RTX effects.

Although rituximab therapy led to more responders and greater reductions in anti-dsDNA and C3/C4 levels, it did not improve clinical outcomes after 1 year of treatment. 





B-cell modulating therapy: epratuzumab


Targeting B Cells: Inhibition of B-cell survival: belimumab, atacicept
  • Other potential B-cell (plasma cell) targeting strategies:bortezomib 
  • Monitoring:
Targeting T Cells
      • Inhibition of T-cell function: abatacept, ruplizumab, toralizumab, lupuzor 
      • Monitoring:
IL - 6: phase 2 study 

TNF - Alpha Inhibitors : See in RA 

Type 1 IFN Inhibitors
      • Sifalimumab 
      • anifrolumab (anti–IFN-α receptor subunit 1 mAb) 
      • Rontalizumab 
        • Monitoring:
Complement Inhibitors
      • Eculizumab 
        • Otheruses: 
        • Monitoring:
General Points on Biologics
      • Monitor for opportunistic infections or infectious complications
      • Hold these agents during intercurrent infections
      • PPD or IFN-Gamma release assay prior to starting all biologics
        • Consider CXR in patient at risk of latent TB
        • Subsequent periodic surveillance is needed
      • Avoid Live Vaccines 
      • Response to vaccines is suboptimal in Rituximab, and Abatacept. Use of all vaccines prior to initiation of these agents is suggested. 
  1. IV IG
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