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SLE Treatment


# Anti-CD19 Car T cell therapy in refractory SLE 
Mackensen, A 
Nat Med 2022 

Essentially, leads to CD19 depleted B cells. 
5 patients of were studied. 
All immunomodulatory studies stopped in 2 months
1 patient requires: Tocilizumab


3 phase 2 study 

#Phase 2 
Liftiflimab
-targets Blood Dendritic cells Antigen 2 (BDCA2)
NEJM: Cutaneous SLE, Other SLE 
-met primary end point

#Phase 2 Obinutizumab
B cell target (against CD20)
-met primary end points

#Phase 2 
Iberomide (decreases B cell activity y and type 1 IFN)


SLE treatment options 
    • Results of recent phase II clinical studies of anti‐IFNα antibodies have been mixed. Rontalizumab did not meet the primary or secondary end points in a recent study 15. However, a post hoc analysis suggested potential benefit in a small subset of patients with a low baseline IFN signature. In contrast, sifalimumab met primary and some secondary end points 16, but the treatment effects were modest. Both of these molecules have specificity only for IFNα, leaving other type I IFNs unaffected and able to bind IFNAR.
    • Ref:doi: 10.1002/art.39962
    • Monitoring:
  • B-cell targeted: 
  • Targeting T Cells
    • Inhibition of T-cell function: abatacept, ruplizumab, toralizumab, lupuzor
  • Cytokines
    • IL - 6: phase 2 study 
    • TNF - Alpha Inhibitors : See in RA 
    • Complement Inhibitors
    • Eculizumab 

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: DAD improved APLA, and  survival by CV (cholesterol and DM) and steroid use / flare 
      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.
Question: WHY DID MAINTAIN TRIAL 2010 failed to show benefit of MMF over AZA that ALMS maintain trial showed in 2011? To note: repeat bxp had no difference in MAINTAIN trial patients. Also, to note ALMS induction study came in 2009 JASN. 



Perhaps the most notable difference between the two studies concerns the demographics of the study populations ALMS was an international study that enrolled a significant proportion of non-Caucasian patients (with one-third of all patients identified as Hispanic ethnicity), whereas MAINTAIN was a European study predominantly comprised of Caucasians (79%). The prognostic importance of race and ethnicity in lupus nephritis outcomes has been well demonstrated [21, 22], and thus the superiority of MMF detected in the ALMS trial may be at least partially explained by the higher risk population enrolled. Indeed, differential responses to therapy based on race/ethnicity were also suggested in the induction phase of the ALMS trial: while MMF was not superior to IVC for induction therapy in the overall cohort, in subgroup analyses, patients grouped as ‘other’ (mostly black and mixed-race patients) and Hispanic patients had significantly better response rates with MMF.  

Another important difference between the ALMS and MAINTAIN trials were the different induction regimens employed and the timing of randomization. The ALMS patients received either high-dose ‘NIH protocol’ IVC or MMF, whereas the MAINTAIN patients uniformly received low-dose ‘Euro-Lupus’ IVC. Furthermore, the maintenance phase of ALMS included only the 227 patients who responded to induction therapy, and were subsequently re-randomized to a maintenance strategy, whereas MAINTAIN included all patients regardless of response to induction (indeed they were randomized only once, at study entry). It may therefore be possible that MMF is superior to AZA only if starting from an attained remission.

There were subtle but important differences in the endpoints and outcomes of the trials (Table 2). MAINTAIN, the negative study, was a smaller trial, with 105 patients compared with 227 in ALMS maintenance. In MAINTAIN, renal flares occurred in 19% of the MMF group and 25% of the AZA group, a non-significant difference. However, while the trial was designed to detect what the authors considered a ‘clinically meaningful’ difference of 10% in renal flares, both the groups had a much lower proportion of flares than anticipated in the power calculation (35% predicted in the AZA group). This left the trial underpowered, as shown by the wide CI for the hazard ratio (0.33–1.71). It is conceivable that a larger trial, similar to ALMS, might have found a significant and clinically meaningful difference.

The ALMS trial was sponsored by Vifor Pharma (formerly Aspreva Pharmaceuticals), a Canadian pharmaceutical company that produces MMF under the brand name Cellcept, whereas the MAINTAIN trial was investigator-sponsored and did not receive industry funding. While the industry sponsorship undoubtedly demands a higher level of scrutiny of positive trials [23–25], ALMS employed a rigorous double-blind randomization strategy in which both groups received a placebo identical to the non-administered drug (a ‘double-dummy’ design). MAINTAIN, on the other hand, utilized a less-desirable open-label design. Overall, the raised skepticism warranted by ALMS' industry sponsorship may be alleviated by the scrupulousness of the study design.

Perhaps the most peculiar difference between ALMS and MAINTAIN was the disparate rates of and reasons for patient withdrawal. The overall withdrawal rate in the ALMS maintenance trial was almost double that observed in MAINTAIN: 44% versus 23%, respectively. In ALMS, withdrawals were more common in the AZA group (51% of patients versus 37% in the MMF group) and were mostly due to adverse events, which were more common with AZA. While analysis of specific adverse events is limited by concerns for statistical power and multiple hypothesis testing, leucopenia and non-nephritic systemic lupus erythematosus flares appeared significantly more common in the AZA group, whereas gastroenteritis was significantly more common in the MMF group. Pregnancy in ALMS was considered a serious adverse event and grounds for the cessation of the study drug. A numerically larger but statistically insignificant number of subjects in the AZA group became pregnant or had elective abortions compared with the MMF group (six pregnancies and three abortions in the AZA group, compared with three and two, respectively, in the MMF group), although it was not reported how many patients withdrew because of desired pregnancy. In MAINTAIN, on the other hand, withdrawals were much fewer and, in general, easier to explain. There were more withdrawals in the MMF group (28% versus 17% in the AZA group) and these were largely driven by pregnancy or desire for pregnancy. This is coherent with the better safety data for AZA in pregnancy compared with MMF, and so with the open-label design it is probable that subjects taking AZA would be less likely to quit the trial in order to pursue pregnancy.



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 2005 
      • 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
    • MOA:
      • A folate antimetabolite that inhibits DNA synthesis. 
      • Binds to dihydrofolate reductase, resulting in decreased purine synthesis and cell proliferation. 
      • Monitoring:
        • Monitoring: 
          • Clinical Evaluation for symptoms of 
            • Myelosuppression: Fever, and other manifestations of infection, easily bruisability, and bleeding, shortness of breath
            • Pulmonary Damage: Shortness of Breath; dry, non-productive cough. Acute Pneumonitis as against chronic ILDs
            • Hepatotoxicity: RUQ and pain, N, V
            • Lymphoproliferation: Lymph node swelling 
          • Laboratory / Imaging Evaluation: 
            • Myelosupression and Hepatotoxicity: 
              • CMP and CBC with diff 
                • Typically 2 wk, 4wk, 6wk, 8wk, 12 wk, 20 wk, 28 wk, then every 3 months; 
                • Frequency can be adjusted for each individual patients based on actual lab values and symptoms
            • Pulmonary Damage: Shortness of Breath 
          • Avoid Regular Alcohol Consumption 
      • Anti-inflammatory mechanisms of methotrexate in RA ARD 2001
      • Anti-inflammatory mechanisms of methotrexate in RA ARD 2001

      • Double blind, randomized, placebo controlled clinical trial of methotrexate in systemic lupus erythematosus J Rheumatology 1999
        • MTX 15 to 20 mg/week for 6 months was effective in controlling cutaneous and articular activity of SLE and permitted prednisone dose reduction. At these doses MTX presented frequent but mild side effects that did not result in drug discontinuation in the majority of patients.
      • Steroid-sparing effects of methotrexate in systemic lupus erythematosus: a double-blind, randomized, placebo-controlled trial Arthritis Rheum 2008
        • Sixty participants (27 methotrexate, 33 placebo) completed the study and 26 terminated early. Among participants who had the same baseline prednisone dose, those taking methotrexate received, on average, 1.33 mg/day less prednisone during the trial period (96% CI 0.06, 2.72 mg/day; a 22% reduction of their average-during-trial daily dose) compared with those in the placebo group. 
      • SubQ vs PO (25 mg weekly)
        • Prefer SubQ if patient agress
      • Split dose: either for tolerability (depending on the timing of Nausea next morning vs next evening) or efficacy (longer trough on splitting the dose)
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.

The EXPLORER trial was designed to enroll a heterogeneous population of patients with significant SLE disease activity that was inadequately controlled by background immunosuppressants. The purpose of the design was to avoid the pitfalls observed in previous lupus trials in which insufficient lupus disease activity at entry might have impeded identification of differences between a test treatment and background therapy.

The EXPLORER population was maintained on the background treatment throughout the trial, and both arms were given a steroid initiation and taper to control immediate disease activity. Therefore, sicker patients could be enrolled, treated with an appropriate standard of care, and a novel definition of response could be investigated. 

CAVEATS of the STUDY: The stringency of the standards for re- sponse in this study is illuminated by the fact that if any patient had 1 new BILAG B score during the second half of the study, that patient would be considered a treat- ment failure. Seventeen patients in the rituximab group and 4 patients in the placebo group were categorized as having no clinical response solely on the basis of achiev- ing 1 new BILAG B score after 6 months.A BILAG B score signifies a range of moderate disease activity at any time in a 4-week period, and the minimal cutoff points can be reached through relatively mild and transient disease flares. This was confirmed by a study in which only 41% of patients with BILAG B disease flares were treated (43). Thus, in all cases, 1 relatively minor disease flare would count as a treatment failure.

the primary end point definition of response at week 52 was achieved in .30% of patients in either group 

A major clinical response was defined as achieving BILAG C scores or better in all organs at week 24 without experiencing a severe flare (1 new domain with a BILAG A score or 2 new domains with a BILAG B score) from day 1 to week 24, and maintaining this response without a moderate or severe flare (.1 new domains with a BILAG A or B score) to week 52. A partial clinical response was defined as 1) achieving BILAG C scores or better at week 24 and maintaining this response without a new BILAG A or B score for 16 consecu- tive weeks, 2) achieving no more than 1 organ with a BILAG B score at week 24 without achieving .1 new BILAG A or B score to week 52, or 3) achieving a maximum of 2 BILAG B scores at week 24 without developing BILAG A or B scores in new domains until week 52 if the baseline BILAG score for the patient was 1 A score plus .2 B scores, .2 A scores, or .4 B scores. No clinical response was defined as failure to meet the definition of a major clinical response or a partial clinical response. Patients who terminated the study early were scored as having no clinical response.


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. 

 

Volcosporin
  • MMF + tapering steroid + placebo vs MMF + tapering steroid + volcosporin 
  • Volcoscporin itself can cause decreased proteinuria independent of immunological response
  • Phase 2 trial had mortality in Bangladesh and Srilanka but was not conducted in these countries in phase 3 trial 





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:
PIPELINE DRUGS for LN
  • Anifrolumab LN study 
  • Belimumab + Rituximab: Rituximab limitations include increases BAAF and also acts only on circulating B cells. 
    • ELUNAR study - RTX + MMF vs Placebo + MMF had failed the study. Felt like failure in trial design 

Type 1 IFN Inhibitors:  Rontalizumab , Sifalimumab , anifrolumab,
    • Type I interferons (IFNs) represent the largest of the three families of IFNs and are composed of five subgroups (IFN-α, IFN-β, IFN-ω, IFN-ε, IFN-κ). All subgroups bind to a common type I IFN receptor, resulting in expression of a cascade of genes, known as the type I IFN gene signature (IFNGS).1 This signalling contributes to the activation of a variety of immune cells, providing defence against viral and other infections.2 The type I IFN system is known to play a central role in the pathogenesis of SLE.3–6 Patients with SLE have increased serum concentrations of type I IFNs,7 and an active IFNGS is observed in 50%–60% of adult patients with SLE.8 9 Most children with SLE, who usually display a more severe disease phenotype compared with adult patients,10 demonstrate increased expression of the active IFNGS.11 In addition, activation of the type I IFN system has been shown to correlate with SLE disease activity in adults. Expression of the IFNGS is more common in patients with severe clinical phenotypes, such as renal disease, haematological disorders and/or involvement of the central nervous system.12 Mounting evidence for a key role of the type I IFN system in the pathogenesis of SLE has prompted the development of several therapies aimed at downregulating type I IFN signalling. 
    • Ref: http://dx.doi.org/10.1136/lupus-2018-000284
  • Results of recent phase II clinical studies of anti‐IFNα antibodies have been mixed. Rontalizumab did not meet the primary or secondary end points in a recent study 15. However, a post hoc analysis suggested potential benefit in a small subset of patients with a low baseline IFN signature. In contrast, sifalimumab met primary and some secondary end points 16, but the treatment effects were modest. Both of these molecules have specificity only for IFNα, leaving other type I IFNs unaffected and able to bind IFNAR.
  • Ref:doi: 10.1002/art.39962
  • Monitoring:

Additional references to understand IFN biology

IFNs are cytokines involved in immune defense. Defects in IFNs affect the innate immune response and can also result in autoimmunity.

Three families of IFNs are recognized (figure 1) [2-4]:

●Type I IFNs (SLE) – The type I IFNs are IFN-alpha (13 isoforms), IFN-beta, IFN-epsilon, IFN-kappa, and IFN-omega. Cytokines in this large family are produced by almost all nucleated cells as a key element of antiviral defense. They bind the IFN-alpha receptor (IFNAR; a dimer of the proteins IFNAR1 and IFNAR2). IFN-beta can also signal though IFNAR1 alone. IFNAR is expressed broadly and transduces signals via the intracellular tyrosine kinases Janus kinase (JAK) 1 and tyrosine kinase (TYK) 2 to modulate gene transcription via a transcription factor complex consisting of signal transducer and activator of transcription (STAT) 1, STAT2, and IFN regulatory factor (IRF) 9. Type I IFNs also signal via STAT3 and through STAT-independent pathways [3]. Type I IFNs induce fever by stimulating prostaglandin production in the hypothalamus, though they are weaker pyrogens than interleukin (IL) 1 [5].

●Type II IFNs (GCA) – The type II IFNs are limited to IFN-gamma. This cytokine is produced by T cells (T helper type 1 [Th1] CD4 cells and CD8 cells), natural killer (NK) cells, natural killer T (NKT) cells, and some innate lymphoid cells. It binds the widely expressed receptor IFN-gamma receptor (IFNGR; a dimer of IFNGR1 and IFNGR2). IFN-gamma activates multiple effector functions in macrophages, including antigen presentation via class I and class II major histocompatibility complex (MHC) molecules, and promotes Th1 differentiation in CD4 T cells, among many other effects [4]. IFNGR signals via JAK1 and JAK2, generating a STAT1 dimer as its downstream transcription factor.

●Type III IFNs – The type III IFNs are the four isoforms of IFN-lambda. These cytokines can be produced by both stromal and immune cells and are less well understood than type I and II IFNs. They bind a receptor formed from the heterodimer of IL-10 receptor 2 (IL10R2) and IFN-lambda receptor 1 (IFNLR1), expressed predominantly by epithelial cells and neutrophils. Downstream signaling is shared with type I IFNs, JAK1, and TYK2, leading to formation of the STAT1/STAT2/IRF9 transcription factor complex. Compared with type I IFN, signals from type III IFN are less explosive but more sustained and play a role in host protection at skin and mucosal barriers and in the central nervous system (CNS


anifrolumab (anti–IFN-α receptor subunit 1 mAb) - TULIP 1 and TULIP 2 





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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