1

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

2

Introduction

3

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

4

5

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)

6

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)

7

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)

8

Results: Time to response

9

Results: Time to flare

10

Results: Response to treatment

11

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

12

13

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

14

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

15

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)

16

17

18

19

20

21

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

22

23

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

24

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

25

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

26

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

27

28

29

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

30

31

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

32

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

33

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]

34

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

35

Results

36

37

38

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

39

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

40

41

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

42

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)

43

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

44

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

45

Results

46

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

47

48

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

49

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

50

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

51

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

52

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

53