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Abstract
Objective To determine whether serial ANA testing predicts biological disease modifying antirheumatic drugs (bDMARD)-associated ANA/dsDNA production in patients with rheumatoid arthritis (RA).
Methods Serial autoantibody profiles, bDMARD treatment sequences and clinical data were collected from patients identified from our database that since 2005 received (i) a first bDMARD (tumour necrosis factor inhibitor (TNFi)) and (ii) tocilizumab and/or abatacept.
Results Of over 1000 patients, 454 RA patients received a first TNFi. Infliximab group demonstrated higher ANA seroconversion rates (31.2%) compared with etanercept (11.8%) and adalimumab (16.1%) (p<0.001). Median (range) treatment duration prior to ANA seroconversion was 10.9 (1.3–80.0) months. Positive anti-dsDNA titres of IgG class (median (range) of 77 IU/mL (65–109)) were noted in six (7.2%) patients, within a median (range) of 2.0 (0.8–4.2) years. Three patients developed classifiable lupus. 4 of 74 (5.4%) primary non-responders and 24 of 111 (21.6%) secondary non-responders developed positive ANA antibodies after TNFi initiation (p=0.003). Seven (9.5%) tocilizumab-treated patients changed to positive ANA; five (8.6%) abatacept-treated patients changed to positive ANA status.
Conclusions This study demonstrates no utility of serial ANA/dsDNA testing that could be used to predict onset of seroconversion and therefore the development of lupus/vasculitis. An association however between seroconversion and the development of a secondary non-response to bDMARD therapy is suggested.
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Introduction
Tumour necrosis factor inhibitor (TNFi) therapies and other targeted agents in the treatment of rheumatoid arthritis (RA) have all been associated with the induction of other autoimmune pathology.1 ,2 Following a pooled analysis of the initial clinical trials that evaluated infliximab and reported an increase in autoantibody induction with one patient developing lupus-like syndrome,3–6 there have been several reports confirming the association of TNFi with autoantibody production with or without development of lupus/vasculitis.7–15 There is minimal guidance however on whether monitoring for the development of new autoimmune disease is worthwhile, and if so, how this may be implemented in clinical practice.
The Leeds Teaching Hospitals NHS Trust is the largest tertiary biological disease modifying antirheumatic drugs (bDMARD) centre for RA in the UK. Patients with RA and treated with TNFi have historically had regular ANA testing on therapy. We evaluated our single-centre bDMARD cohort to determine in patients with RA (i) the incidence of ANA/dsDNA antibodies, (ii) whether differences exist between the different bDMARDs, (iii) the clinical significance of such seroconversion and (iv) whether routine ANA testing could predict the development of lupus/vasculitis. We used routine data collected as part of our standard practice that is aligned with local hospital and ethics guidance.
Patients and methods
Patients
The prospective Leeds bDMARD database was established in 2000 in line with local ethics committee guidance. All patients have a diagnosis of RA based on the 1987 American College of Rheumatology (ACR) criteria ±2010 ACR/European League Against Rheumatism (EULAR) classification criteria for RA.16 ,17 We reviewed patients with RA who received a first TNFi between January 2005 and December 2012 and abatacept and tocilizumab (8 mg/kg 4-weekly) (mainly received following TNFi therapy). Patients that received certolizumab-pegol or golimumab were not included due to the relatively small numbers.
Methods
Serial autoantibody profiles (ANA, anti-dsDNA antibodies, antineutrophil cytoplasmic antibody with myeloperoxidase and proteinase-3 (PR3)) historically requested every 3 months, treatment sequences and clinical data were collected and evaluated. ANA levels were determined at the St. James’ University Hospital Immunology laboratory by indirect immunofluorescence with HEp-2 cells and anti-dsDNA antibody titres for IgG class were measured by ELISA (normal <50 IU/mL). EULAR responses were determined,18 and the reasons for discontinuation of therapy were recorded. Primary non-response was defined as failing to improve DAS28 by equal to or greater than 1.2 or failing to achieve DAS28 equal to or less than 3.2 within the first 3–6 months of starting the initial TNFi. Secondary non-response was determined by clinical judgement with loss of an initial response and evidence of flare.
Drug-induced lupus was defined as the patients who meet 4 out of 11 ACR diagnostic criteria for lupus while exposed to TNFi.
Statistical analysis
Descriptive summary statistics are provided for all continuous variables with parametric or non-parametric data as appropriate. T-tests and one-way analysis of variance test were used to compare ANA and dsDNA levels and mean values between the different treatment groups, and χ2 testing was used to analyse categorical data. A p value of <0.05 was considered as statistically significant. Statistical analyses were performed on SPSS V.18.
Results
Data on the tocilizumab and abatacept-treated cohorts are included in the online supplementary file.
Demographics and baseline characteristics
Over 1000 patients with RA treated with one or more bDMARDs were identified from the database of which a total of 454 patients (78.6% female, age 18–85 years) receiving a first TNFi were included: 254 etanercept, 138 infliximab and 62 adalimumab. The baseline characteristics of the cohort (table 1) revealed no significant differences among the three treatment groups except for concomitant methotrexate (MTX) use in almost all patients commenced on infliximab compared with etanercept and adalimumab (p<0.001). Only one patient was on concomitant leflunomide (10 mg daily) instead of MTX.
Baseline characteristics of patients initiated on TNFi agent
ANA status before and during therapy
Median (range) follow-up of this cohort was 4.8 (0.6–8.0) years. Following TNFi commencement, ANA positivity increased significantly in the infliximab group only (37.0–63.8%; p<0.001), with higher ANA seroconversion rates (31.2%; 38.5 cases per 100 patient-years) compared with etanercept (11.8%; 11.3 cases per 100 patient-years) and adalimumab (16.1%; 16.1 cases per 100-patient years) (p<0.001) (table 2). Median (range) duration of therapy prior to ANA seroconversion was 10.9 (1.3–80.0) months with no significant difference between the three TNFi. Eighty-six percent of cases of seroconversion occurred within 2 years of initiation of TNFi agent. No association with clinical characteristics was observed, including between combination and the monotherapy groups or effect of concomitant oral corticosteroid. Proportion of patients ANA positive at onset is included in table 2; additional information on change in status of these patients is detailed in the online supplementary figure S1, as are data on ANA patterns at onset and during therapy for all patients.
ANA/dsDNA seroconversion and discontinuation rates of initial TNFi therapy
Correlation between ANA seroconversion and drug discontinuation
Two hundred and eighty-three (62.3%) patients discontinued an initial TNFi agent for any reason during the observation period (table 2).
Discontinuation due to inefficacy
One hundred and eighty-five (65.4%) patients discontinued initial TNFi due to inefficacy; 74 primary non-responders (defined as demonstrating no clinical evidence of improvement (lack of disease activity assessment 28 (DAS28) reduction) at first response assessment of 12 weeks) and 111 secondary non-responders (defined as loss of a clearly definable response status (with increase in DAS28)). Also, 4 of 74 (5.4%) primary non-responders and 24 of 111 (21.6%) secondary non-responders developed positive ANA antibodies after TNFi initiation (p=0.003). A higher positive conversion rate was observed in the infliximab secondary non-response group (34.2%) compared with the etanercept secondary non-responders (13.1%). The median (range) time to ANA positivity prior to initial TNFi discontinuation for the 24 secondary non-responders was 10.9 months (16.9–71.2). There were no significant differences in discontinuation rates among patients that were ANA positive and negative at treatment onset (p=0.14), or in primary and secondary non-response rates in those with ANA positive at anti-TNF onset (refer to the online supplementary file for further details).
Discontinuation due to adverse events
A total of 87 patients discontinued initial TNFi due to an AE; 51 (33.3%) in the etanercept group, 24 (26.1%) in the infliximab group and 12 (31.6%) in the adalimumab group (p=0.489). Median (range) treatment duration to discontinuation was 6.7 (0.4–63.9) months: etanercept 5.3 (0.4–57.6) months, infliximab 7.1 (0.4–63.9) months and adalimumab 7.9 (0.5–36.5) months, respectively (p=0.302). Eighteen patients showed positive ANA conversion (neurological symptom, n=5; rash, n=3; ischaemic heart disease, n=3; malignancy, n=2; infection, n=2; neutropenia, n=1; comminuted fracture, n=1; drug-induced lupus, n=1).
TNFi -associated lupus
Of 83 patients that seroconverted to positive ANA, 6 (7.2%) patients developed positive anti-dsDNA titres (median (range) of 77 IU/mL (65–109)). Median (range) treatment duration to positive dsDNA test was 2.0 (0.8–4.2) years (table 2). One patient developed drug-induced lupus on their first TNFi; ANA positivity was present 2.6 years before but anti-dsDNA antibodies were detected at lupus onset 3 weeks prior. Another two cases of drug-induced lupus were recorded in this study with clinical characteristics and symptoms detailed in table 3. Drug-induced lupus was defined as the patients who met 4 out of 11 ACR classification criteria for lupus while exposed to TNFi.
Summary of TNFi agent-associated lupus
Development of vasculitis
Data are included in the online supplementary file.
Comparison of tocilizumab and abatacept with TNFi agents
Minimal seroconversion was observed. Complete data can be found in the online supplementary file.
Discussion
There is minimal literature on the temporal association of bDMARD initiation and associated autoantibody development and a change in clinical phenotype. Our report from a large, single-centre bDMARD cohort adds to existing literature by illustrating, first, serial testing for ANA/dsDNA was not able to accurately predict onset of seroconversion with change in clinical phenotype, and second, seroconversion was observed with greater frequency in TNFi secondary non-response compared with primary non-response (despite high concomitant MTX use).
Consistent with previous studies, infliximab was associated with the highest seroconversion rate. An underlying mechanism might be attenuation of the usual negative feedback effect TNF has on type 1 interferons and subsequent development of Th2 pathology. Infliximab, with its effect on membrane-bound TNF, induction of apoptosis, antibodydependent and complementdependent cell lysis, may lead to a more profound dampening of this negative feedback loop. In contrast, antietanercept antibodies have not been clearly associated with reduced response, suggesting lower avidity antibodies (false-positive ADA). Only a very small number of patients however in our cohort developed clinical signs and symptoms consistent with lupus and vasculitis. This is in contrast to our earlier experience,9 but of note, our initial report comprised patients treated with infliximab and leflunomide, a combination likely to be potentiating autoantibody conversion and associated pathology further. Five additional patients in this current report however discontinued initial TNFi due to neurological symptoms (seizures, transient ischaemic attack, imbalance, arm weakness and mononeuritis multiplex), which may also have reflected drug-induced autoimmune pathology. Development of (cutaneous) vasculitis in our cohort was associated with seropositive RA (high titre RF), suggesting these cases were RA-associated vasculitis rather than drug-induced pathology.
Where ANA/dsDNA developed, we found no clear association between its onset and change in clinical features. ANA-induction on TNFi was observed as soon as after 1 month, with a median (range) onset of 10.9 (1.3–80.0) months and 85.5% of cases occurring within 2 years of initiation of TNFi agent, with a decent length of observation (median 4.8 years). A previous study suggested a gradual increase until 30 weeks in patients treated with infliximab.19 Where development of lupus pathology was observed however, dsDNA production occurred just prior. ANA titration was not routinely done, although the inherent weaknesses associated with serial dilution and titration would perhaps have limited robust interpretation of any trends that may have been observed.
While somewhat unexpected, we observed greater ANA seroconversion in TNFi secondary non-responders. Correlation of ANA/anti-dsDNA antibodies with clinical response to infliximab in patients with RA has been reported previously but in a smaller cohort20 in which ANA appearance seemed to predict late cessation of treatment. Insufficient time for primary non-responders to develop ANA may be relevant, although we detected ANA as early as 4 weeks. Furthermore, the basis for primary non-response is multifactorial with bioavailability and immunogenicity (that can develop after first dose exposure21) also identified as relevant factors. The development of ANA may be reflecting a general state of activation leading to additional antibody, including likely induction of specific antidrug antibody underlying the associated antidrug antibody and secondary non-response. A recent study reported an association with ANAs and anti-dsDNA antibodies in patients with psoriasis and loss of clinical response and HACAs.22
In summary, our cohort of patients with RA treated with bDMARDs and routine ANA/dsDNA monitoring at regular time points did not reveal an obvious pattern to be able to predict the development of autoantibodies (with evolution to lupus and vasculitis uncommonly seen), suggesting minimal clinical utility and a resource burden of this approach. A bDMARD-specific effect on ANA seroconversion (infliximab with highest rate although not exclusive effect) as well as an association between the development of seroconversion and secondary non-response to the TNFi was observed. A lack of accuracy in the definition of primary and secondary non-response might be contributing to the challenges in interpreting findings from different reports. Nevertheless, if loss of TNFi response due to drug immunogenicity is truly associated with ANA seroconversion, there may be value in investigating its use in combination with antidrug antibodies that have emerged as promising clinical tools to detect secondary failure to a bDMARD.23–25
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Files in this Data Supplement:
- Data supplement 1 - Online supplement
Footnotes
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Handling editor Tore K Kvien
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Funding KT was supported by ‘JCR-EULAR Young Rheumatologist Training Program’ Clinical Research Fellowship. MHB is funded by a NIHR Clinician Scientist Award (CS/08/08/04). MHB has received honoraria and attended advisory board meetings for Abbott, BMS, Pfizer, Roche and UCB. PE has received honoraria and attended advisory board meetings for Abbott, BMS, MSD, Pfizer, Roche and UCB.
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Competing interests MHB has received honoraria and attended advisory board meetings for Abbott, BMS, Pfizer, Roche and UCB. PE has received honoraria and attended advisory board meetings for Abbott, BMS, MSD, Pfizer, Roche and UCB.
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Provenance and peer review Not commissioned; externally peer reviewed.