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Dr Ashok Kumar, MD, FRCP (London)Director & Head
Department of RheumatologyFortis Flt. Lt. Rajan Dhall Hospital
Vasant Kunj, New Delhi
Best papers in SLE and CTDs
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Introduction
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Functions: Opsonization, clearance of apoptotic cells & CICs
CRP can sometimes dissociate into monomers (mCRP), exposing novel epitopes which trigger an immune response
Anti-CRP has been described in SLE and may consume CRP in SLE- this is a possible explanation why CRP does not rise in SLE
Authors believe that anti-CRP is involved in pathogenesis of LN
Hypothesis: Anti-CRP may predict the outcome of LN
Methods 57 patients with LN were recruited by Nephrology
Department of University Hospital, Prague, Czech Repub (2005-2010)
All biopsy-proven LN (29 new and 28 follow up cases)
119 serum samples from these patients at different time points
122 samples from age matched healthy controls
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Definitions Active LN: active urinary sediment, and/or
proteinuria ≥0.5 g/day, and/or worsened GFR >25 % above baseline, and/or C3 (At least two of the aforementioned criteria had to be met)
Complete response: inactive urinary sediment, decrease of proteinuria to ≤0.2 g/day, and normal/ stable renal function (<10% of normal GFR)
Partial response: inactive urinary sediment, proteinuria ≤0.5 g/day, and normal/stable renal function (<10% from baseline)
Favourable outcome: at least partial response in the first/second year of treatment
Unfavourable outcome: nonresponse, renal flare, or end-stage renal disease (ESRD)
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Anti-CRP antibody assay
Anti-CRP-Ab: measured by in-house ELISA (Sjowall et al)
Highest patient sample was taken as 100 arbitrary units (AU)/ml
The lower limit of detection of assay was 15 AU/ml
The cutoff for a positive test was 45.5 AU (95th percentile in 122 healthy individuals)
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Results Anti-CRP levels were significantly higher in LN patients
than controls [21.1 AU vs. <15.0 AU] (p = 0.012)
Anti-CRP-Ab was positive in 26% of patients
It was positive exclusively in patients with active LN 15/46 (33%); patients with inactive LN were all negative (0/11, p = 0.051)
Levels correlated with SLEDAI (rs = 0.41, p = 0.002) and anti-dsDNA
Negative correlation with C3 (not C4)
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Results: Time to response
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Results: Time to flare
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Results: Response to treatment
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Conclusions Anti-CRP-Ab levels correlate with lupus activity
Anti-CRP-Ab positivity is a strong predictor of unfavourable long-term therapeutic response
Moreover, response is delayed
Anti-CRP-Ab-positive patients, especially those not responding to standard therapy within 1 year, do not benefit from further continuation of same treatment
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Introduction Currently, the main ISDs for LN are CYC, MMF and
AZA
Many patients experience serious adverse effects with these
Leflunomide has been reported to be beneficial in LN
Authors present a meta-analysis of prospective clinical trials to assess the efficacy and safety profile of leflunomide in LN
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Inclusion and exclusion criteria
A systematic review of RCTs comparing LEF to CYC in adult LN
Inclusion criteria Diagnosis of LN based on the ACR criteria Leflunomide used as an induction therapy for LN Therapeutic efficacy and safety recorded over 24 weeks or more
Two authors independently evaluated the retrieved studies
Exclusions: Case series/reports, retrospective, and pediatric studies
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Outcome measures Three clinical outcomes were studied
Remission rate (including CR and PR) and change in SLEDAI score Renal function (24-hour proteinuria and serum creatinine) ADRs: LFT abnormality, GI dysfunction, rash, alopecia,
leucopenia, infection, menstrual abnormalities and herpes zoster infection
CR criteria: Normal serum creatinine and serum albumin, inactive urinary sediment, and 24-hour urinary protein <0.5 g
PR criteria: 50% improvement in all renal parameters without deterioration in any parameter
Quality evaluation: Jadad score 3 or more (scale: 1-5)
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Conclusions Leflunomide is a promising therapy for LN treatment
Comparable efficacy and better safety profile w.r.t CYC
A treatment option for CYC failures in LN
Results should be interpreted with caution because of the small sample size and high heterogeneity
Larger RCTs with longer duration needed to validate
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Introduction In primary SS (pSS), B cells are hyperactive and play a central
role
This concept is supported by reports of beneficial effect of RTX
Question is: how to predict response to RTX?
Aims of present study were as follows: To assess the effect of RTX treatment in patients with pSS based on
sequential parotid biopsies obtained in a placebo-controlled, randomised clinical trial
To assess the relationship between parotid gland histology and response to RTX
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Methods 30 patients with pSS (American-European criteria) were
treated in a randomised double-blind placebo-controlled trial on day 1 and day 15 with either 1000 mg intravenous RTX or placebo
Parotid gland biopsy done before and 12 weeks after RTX therapy
2 `blinded’ assessors documented disease activity
(ESSDAI) before and after RTX
Clinical Response: Fall in ESSDAI by 3 or more points
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Histopathological analysis Focus score, Germinal Centre (GC) score and
Lymphoepithelial lesions (LEL) were assessed carefully
LEL is cross section of a striated duct with 2 features: -CD20+ B cell infiltration (within basement membrane) -Hyperplasia of the epithelium
Immunohistochemical analysis was also done
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Results 20 patients were assigned to RTX and 10 to placebo group
5 out of 30 patients were excluded 1 due to serum sickness, 3 due to inadequate biopsy in RTX-group 1 dropped out of placebo group
16 RTX-treated patients and 9 placebo-treated patients could undergo complete histopathological evaluation
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At an α level of 5%, the number of responders and non- responders would give us a power of 94.2%
to assume that the baseline number of CD20+ cells/mm2 could serve as a potentially prognostic
factor with regards to response to RTX treatment
Conclusions In pSS, RTX leads to major reduction of B cells, GCs
and LELs
Reduction in the LELs may result in regeneration of striated ducts
The baseline number of CD20+ B cells/mm2 of parenchyma may serve as a predictor of response to RTX
Thus baseline parotid biopsy may strongly contribute to a more personalised treatment approach to patients with pSS
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Introduction Cancer risk in myositis patients is exceptionally high
Myositis-cancer interval of 3 yrs defines `cancer-associated myositis’
A more stringent definition considers only 1-year interval
What about cases where cancer and myositis are separated widely?
Hypothesis: Only those with temporal overlap of cancer and myositis are true CAM cases; others are not
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Methods 281 patients (PM 89, DM 192) diagnosed at Seoul National
University Hospital, according to Bohan and Peter criteria
Seven cases had active cancer at myositis diagnosis
Routine cancer screening done for others at myositis diagnosis:
Head and neck inspections CT chest & abdomen Upper and lower GI endoscopy Tumour markers- CA-125 (W), PSA (M), CA 19-9, CEA
A total of 52 cancer cases (PM 15, DM 37) were identified
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Classification of cancer cases in patients with myositis (n=52) Two categories
CAM: Cancer concurrent with active myositis CNM: Cancer non-concurrent with active myositis
CAM (n=30) Cancer & myositis diagnosed concurrently (within 3 months) [n=17] Cancer detected during Rx of myositis [n=8] Myositis detected during progression/recurrence of cancer [n=5]
CNM (n=22) Cancer detected with myositis in remission without any relapse
[n=16] Myositis detected with cancer in remission without any relapse
[n=6]
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Assessment of cancer risks and stages
SIRs were estimated by dividing the observed number of either CAM or CNM by the expected number of cancers in myositis cohort
Expected number was obtained by applying the calendar-year-specific cancer incidence of the age and sex matched Korean population to the corresponding person-year of 281 myositis patients
Combined SIR of CAM and CNM corresponded to the total cancer SIR in 281 patients
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Results
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Timing of myositis development One stage 1 small lymphocytic lymphoma for 21 months:
myositis developed when it transformed into stage 4 DLBC lymphoma
1 case of Ca Stomach: Myositis developed when distant metastasis occurred after 37 months of cancer free period
A case of Ca Breast behaved similarly after 155 months of a cancer-free period
Two had oesophageal cancer of stage 3, but developed myositis when their cancers progressed to stage 4 despite treatment
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Conclusions CAM and CNM represent 2 different subpopulations
CAM is likely to represent true cancer-associated myositis: Certain tumour antigens expressed in advanced stages could trigger cross-reactive immune responses against muscle
This study confirms that CAM temporal interval is ~3 years
CAM Group: Ca oesophagus, ACUP, NHL, Ca lung and Ca ovary
No cancer types emerged as a significant risk in CNM
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Introduction Anti-Jo1 syndrome comprises myositis, ILD,
arthritis, Raynaud’s, mechanic’s hands and anti-histidyl tRNA synthetase
Anti-Ro52 co-exists in 40-72% cases of Anti-Jo1 syndrome and correlates with severe myositis and ILD, and poor response to Rx
Authors evaluated the effect of RTX in severe anti-Jo1 syndrome and studied the predictive factors for response
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Methods Case recruitment occurred in 2 German Centres from 2006
to 2014
Jo1 and Ro52 antibodies were measured with the immunoblotting assay ANA Profile 3 EUROLINE (Euroimmun)
Other lab data and clinical data from the patients’ medical records
Periodic screening for new organ involvement by clinical and laboratory examination (every 3 to 6 mos) and PFT (every 6 to 12m)
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Treatment regimen Patients received RTX if they had severe ILD or PM
refractory to immunosuppressive drugs (ISD)
RTX protocol: 2 × 1 g intravenously (I.V. days 0 and 14)
RTX was combined with corticosteroid and an ISD in all patients
Choice of co-medication, steroid dose, and tapering were individual physician’s decisions
RTX cycles were repeated every 6 months
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Outcome measures
Complete response: I. Resolution of muscle pain and weakness (subjective & objective) together with the normalization of CPK; II. Resolution of lung symptoms, disappearance of radiographic alveolitis, and normalization of standard PFT in the case of ILD; III. Resolution of joint symptoms, mechanic hands or Gottron papules/heliotrope rash each for at least 6 months
Improvement: Improvement of organ symptoms, and the physician’s and patient’s VAS of at least 30% plus 30% improvement in CPK levels in case of myositis, 20% improvement of radiographic signs or PFT values in the case of ILD, and improvement of skin manifestations
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Results
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Results (Contd.)
ISD given before RTX, partly in combination, were AZA(n=14), MTX(n=11), CSA(n=6), CYC(n=6), LEF(n=3), MMF(n=2), etanercept(n=2), HCQ (n=2), and INF/TAC/IVIG (1 each)
Patients received on average 4.6 cycles of RTX (1–13) in a mean interval of 6.4 months, and in 16/18, combined with an ISD
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Response to RTX Myositis: CR in 16/16; ILD: CR in 1/10, improvement in 9/10
Mechanic’s hands: CR in 2/3; DM: CR in 1/1 in skin features
Mean CPK level fell from 663 U/l to 92 U/l (p < 0.01) and prednisolone doses from 30.4 mg to 6.0 mg/day (p < 0.001)
Mean VC increased from 61% at the start of RTX to 86% at the last followup (p < 0.05), DLCO from 33.1% to 55.7% (p < 0.05)
CT scans were repeated in 6/10 patients with ILD, 6-12 months after the start of RTX; alveolitis completely disappeared in all
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Adverse events One patient died of pneumonia after the second cycle of
RTX
He had severe ILD with fibrosis for 7 yrs and PAH at the start of RTX, (mean prednisolone doses of 20 mg/day for many years)
One patient had UTI 3 days after starting RTX
IgG levels were found below normal in 5/12 tested without any consequences
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Anti-Ro52 Positive in 43% and significantly associated with acute-
onset ILD (p = 0.016) with high anti-Ro52 concentrations (+++, in 20%) showing the highest risk (p = 0.0005)
There was no association between the concentrations of anti-Ro52 antibodies and Jo1 antibodies (p = 0.41)
Patients with high anti-Ro52 antibodies showed response to RTX (7 out of 7 = 100%), but no response to any given ISD
The 4 patients with high anti-Ro52 concentrations who did not receive RTX had a poor outcome
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Conclusions The study confirms that patients with anti-Jo1
syndrome and coincident anti-Ro52 antibodies do not respond to various ISDs
High level of anti-Ro52 antibody predicts severe disease and response to treatment
Patients with severe Jo1 antisynthetase syndrome should be stratified by anti-Ro52 antibodies and treatment with RTX should be considered early in patients with high anti-Ro52 concentrations, even before the use of CYC or calcineurin inhibitors
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Question Which of the following statements is correct?
A. In SLE, CRP does not rise but mCRP levels are elevated
B. Liver dysfunction occurs more often with cyclophosphamide than with leflunomide
C. Large number of LELs in parotid gland biopsy predict good response to Rituximab in Primary Sjogren’s syndrome
D. In anti-Jo1 syndrome, the levels of anti-Jo1 and anti-Ro52 run parallel
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