Objectives To assess the efficacy and the safety of biologics in a cohort of patients with relapsing polychondritis (RP).
Methods We conducted a French multicentre retrospective cohort study including patients treated with biologics for RP. Efficacy outcomes were clinical response (partial or complete) and complete response during the first 6 months of exposure, plus daily corticosteroid dose at 6 months. Other outcomes were adverse drug reactions (ADRs), persistence of biologics and factors associated with a response.
Results This study included 41 patients exposed to 105 biologics (tumour-necrosis factor (TNF) inhibitors, n=60; tocilizumab, n=17; anakinra, n=15; rituximab, n=7; abatacept, n=6). Overall response rate during the first 6 months of exposure was 62.9%. Complete response rate was 19.0%. Reduced corticosteroid doses were highly variable among patients. ADRs were mostly infections (n=42). Reasons for biologic withdrawal (73.3%) were insufficient efficacy (34.3%; ranging from 23.5% for tocilizumab to 72.7% for etanercept), loss of efficacy (18.1%) and ADRs (20.9%; mostly for anakinra: 46.7%). Persistence was comparable among biologic classes. Among TNF inhibitors, the highest persistence was observed with adalimumab. Differences in clinical response rates were observed depending on biologics and organ involvement. There were trends towards a lower response rate in cases with associated myelodysplastic syndrome and for a higher response rate for nasal/auricular chondritis, sternal chondritis and concomitant exposure to non-biologic disease-modifying antirheumatic drugs.
Conclusions This study describes the efficacy of biologics for refractory RP. However, the number of complete responses was low and there were concerns about the risk of ADRs, particularly infections.
- relapsing polychondritis
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Relapsing polychondritis (RP) is a rare autoimmune disease that affects cartilaginous tissues, with a risk of both cartilaginous (e.g., respiratory tract) or non-cartilaginous organ involvement.1 Its incidence has been estimated to be <5/million people/year.2–4 The main features are nasal and auricular chondritis, seronegative polyarthritis, sternal and costal cartilage inflammation, and laryngotracheal, ocular, cochlear and vestibular involvement. Other features (mainly cardiovascular and central nervous system inflammation) are rare.1 5 Patients with myelodysplastic syndrome associated with RP or laryngotracheal involvement may have a worse prognosis.5
The disease course is characterised by flares and remissions. To this day, corticosteroids are the first-line treatment for this disease. Because the usual course takes many years to evolve, severe involvement or an inadequate response to high-dose corticosteroids (≥1 mg/kg/day of prednisone equivalent),1 corticosteroid-sparing agents are often prescribed, such as immunosuppressive or immunomodulatory drugs (e.g., dapsone, methotrexate, azathioprine, cyclophosphamide, ciclosporin and mycophenolate).1
The pathophysiology of RP is poorly understood. The roles of both humoral and cellular immune responses have been described. Many cytokines may be also involved, like tumour necrosis factor (TNF)-α, interleukin-1 and interleukin-6.6 Consequently, the use of biologics in corticosteroid-dependent patients and in patients with an inadequate response to high doses of corticosteroids have been increasingly reported during the last decade.1 7 However, these have been mainly single case reports and, hence, are subject to potential publication bias (favouring positive outcomes). Few single-centre series have been reported until now: that is, nine refractory patients treated with rituximab,8 nine patients exposed to 22 biologics (mainly TNF inhibitors),9 and four and three patients treated with abatacept.10 11 Moreover, end points for the assessment of biologic efficacy have been highly variable across these reports; therefore, it was very difficult to estimate the efficacy of biologics to treat RP from a literature review.1
Thus, this study aimed to assess the efficacy and safety of biologics in a large cohort of patients with RP.
This national, multicentre, retrospective study included adult patients treated with biologics for RP between 2001 and July 2015 in France. Rheumatologists and internal medicine physicians were contacted by the French National Society of Internal Medicine (n=1200) and by the Club Rhumatisme et Inflammation (n=2500 rheumatologists and internal medicine practitioners) networks. Inclusion criteria were being an adult (≥18 years) patient with RP who satisfied the McAdam, Damiani and Levine as well as the Michet diagnosis criteria12–14 and exposed to at least one biologic, including TNF inhibitors, anakinra, abatacept, tocilizumab and rituximab. The exclusion criterion was a patient’s opposition to data being collected.
Demographic, clinical and biological data were recorded on a standardised form at the time of exposure to the biologic (T0), then at 3 and 6 months, and then every 6 months. The follow-up ended with discontinuation of the biologic or the last date when the patient was still receiving the biologic. For rituximab patients, we recorded data for up to 12 months after exposure.
Efficacy outcomes were the rates of complete response (CR, defined by no clinical activity) and of response (defined by at least a partial clinical decrease in disease activity, including CR) obtained in at least one assessment during the first 6 months of exposure. Due to the retrospective design and the subsequent unavailability of systematic paraclinical examinations, investigators were requested to categorise the clinical signs of disease activity at each visit compared with the signs of RP when the biologic was started: that is, as worsening, stable disease, partial improvement (ie, response) or no activity (ie, CR). The rates of response and CR during the first 6 months of exposure were presented according to the biologics in the overall population as a global measurement, but also according to organ involvement (ie, auricular/nasal, joint, ocular, cochleovestibular or respiratory involvement). In the analyses according to organ involvement, response was defined as partial or complete improvement in the clinical signs of disease activity in the given organ. To assess corticosteroid-sparing, we compared daily corticosteroid doses (prednisone equivalent) between T0 and month 6 for patients who had ≥6 months exposure to a biologic. Adverse drug reactions (ADRs) were described. We also compared the persistence (time under treatment) of biologics (excluding rituximab) and the reasons for discontinuing a biologic.
Descriptive analyses are presented using frequencies and percentages for qualitative variables, and medians or means (as appropriate) with ranges for continuous variables. We analysed the persistence of biologics using Kaplan-Meier curves. Comparisons were made using the log-rank test (α=5%).
We also assessed the factors associated with achieving a response during the first 6 months of exposure to a first-line biologic using a univariate logistic regression model. Odds ratios (ORs) and their 95% confidence intervals (CIs) were computed. The following variables were tested: age, gender, the presence of an associated disease (except myelodysplastic syndrome), the presence of a myelodysplastic syndrome, disease duration before exposure to a biologic, Charlson’s score,15 history of organ involvement due to RP, organ involvement due to RP at initiation of the biologic and concomitant exposure to a non-biologic disease-modifying antirheumatic drug (NBDMARD). From multiple testing, the alpha threshold value was 0.0024 (Bonferroni’s correction). This was an explanatory model. No multivariate model was conducted due to the low number of patients.
All statistical analyses were performed using SAS V.9.4 software.
Forty-one patients were included from 14 centres; the patients were exposed to 105 biologics in total. Baseline characteristics are detailed in table 1. The mean age was 46.9±12.5 years and 53.6% were women. Median time from RP diagnosis to first-line initiation of a biologic was 26.5 months. The most frequent involvements were nasal chondritis, arthralgia and auricular chondritis. All but two patients had an active disease at first exposure to a biologic, and all but three patients had previous exposure to NBDMARDs (mostly methotrexate, n=30).
Exposure to biologics
The reasons for initiating a biologic were corticosteroid dependence (n=28), an inadequate response to corticosteroids as judged by the prescriber (n=11) and ADRs to methotrexate (n=3: one hepatitis, one neutropaenia and one skin rash). First-line biologics were TNF inhibitors (n=30), tocilizumab (n=5), rituximab (n=4), and anakinra and abatacept (n=1 each). Twenty-eight patients were exposed to at least two lines of biologics (because of insufficient efficacy in 14, relapses in 8 and ADRs in 9).
In total, 105 exposures to biologics were recorded: TNF inhibitors, n=60 in 32 patients; tocilizumab, n=17 in 15 patients (2 patients had been re-exposed to tocilizumab after an intermediate biologic); anakinra, n=15 in 13 patients (2 patients had been re-exposed to anakinra after an intermediate biologic); rituximab, n=7 to 7 patients; abatacept, n=6 in 5 patients (2 patients had been re-exposed to abatacept after an intermediate biologic). The details of the biologic lines are shown in the online supplementary table 1. All biologics were used at the same dosage as given for rheumatoid arthritis. Abatacept and tocilizumab were given intravenously to all patients. At initiation of the biologics, corticosteroids were ongoing in 88 cases (83.8%; mean dose: 23.9 mg prednisone equivalent, range: 5–80) and NBDMARDs in 64 cases (60.9%), mostly methotrexate (42 cases, 40.0%; NBDMARDs used concomitantly to first-line biologics are detailed in table 1).
Supplementary file 1
Overall, only slight differences in the patients’ characteristics between biologics were observed (online supplementary table 2).
Overall response and CR rates
The outcomes considering the 105 exposures to biologics are presented in table 2. Rates of response and of CR achievement during the first 6 months were 62.9% and 19.0%, respectively. Response rates were the lowest for abatacept (50.0%) and anakinra (53.3%). They were 63.3%, 70.6% and 71.4% for TNF inhibitors, tocilizumab and rituximab, respectively. There were similar response rates across the TNF inhibitors. Analysis restricted to first-line biologics led to similar results for TNF inhibitors, with few patients exposed to other biologics (table 3).
Efficacy according to organ involvement
Achieving a response during the first 6 months with a biologic and according to organ involvement is shown in table 4. The efficacy of biologics for nasal/auricular chondritides were the highest with tocilizumab and the few patients treated with abatacept or rituximab. TNF inhibitors were the most effective biologic for joint inflammation, particularly adalimumab. Infliximab, tocilizumab and rituximab were more effective than anakinra for ocular involvement. Tocilizumab and TNF inhibitors were the most effective biologics for respiratory-tract involvement (along with abatacept, but only two observations were described with this biologic). No conclusion could be drawn for cochlea–vestibular involvement because almost all of these patients were exposed to TNF inhibitors.
Among the patients exposed to biologics for at least 6 months, there was only a modest reduction in median daily corticosteroid dose (5 mg of prednisone equivalent) between T0 and month 6. However, there was huge variability between individuals (tables 2 and 3, figure 1). Similar results were observed in analyses restricted to first-line biologics (figure not shown).
Adverse drug reactions
Overall, 20.9% of biologics were withdrawn due to ADRs. All ADRs associated with biologics are detailed in the online supplementary table 3. The most frequent ADRs were infections (n=42) and reactions at the site of injecting subcutaneous biologics (n=12). Three opportunistic infections were described: two recurrences of herpes occurred with anakinra and one zoster that occurred with tocilizumab. One case of cancer was observed: a lung carcinoma in a patient who smoked tobacco and after 19 months of exposure to anakinra. No deaths occurred during exposure to a biologic.
Persistence of biologics
Persistence was comparable among biologic classes (figure 2, panel A, p=0.77). Among the TNF inhibitors, the highest persistence was observed with adalimumab and the lowest with etanercept (figure 2, panel B: adalimumab vs etanercept: p=0.02).
Factors associated with achieving a response to first-line biologics during the first 6 months of treatment
No variable achieved significance (table 5). There was a non-significant trend towards a decreased rate of response in cases of associated myelodysplastic syndrome (OR, 0.14; 95% CI 0.01 to 1.51). Conversely, there was a significant trend towards an increased rate of response for cases of associated NBDMARDs (OR, 2.14; 95% CI 0.55 to 8.38), a history of sternal chondritis (OR, 5.00; 95% CI 1.22 to 20.45), nasal or auricular chondritis at biologic initiation (OR, 3.64; 95% CI 0.90 to 14.61) or sternal chondritis when the biologic was started (OR, 3.95; 95% CI 0.90 to 17.40).
This study reports on the efficacy and safety of biologics to treat RP in the largest cohort assessed to date. In total, we described 60 exposures to TNF inhibitors, 17 to tocilizumab, 15 to anakinra, 7 to rituximab and 6 to abatacept in 41 patients.
The study population consisted of patients with severe RP, with 43.9%, 58.5%, 36.6% and 12.2% having experienced ophthalmological, respiratory tract, vestibular or cochlear, and cardiovascular involvements before initiating a biologic, respectively. Ninety-three per cent of patients had been exposed to NBDMARDs before receiving a biologic.
Overall, the biologics showed an overall response rate of 62.9%, but a low rate of CR (19.0%). The response was transient, leading to biologic withdrawal in 18.1% of cases. In contrast with previous case reports, the corticosteroid-sparing effect of biologics was highly variable between patients in our study, with only a mild effect overall.
Due to this study’s retrospective observational design, we cannot exclude that unmeasured factors related to the patients or physicians influenced treatment choice and the outcomes. However, the baseline characteristics of patients were relatively similar between the biologics. Hence, this study provides better understanding of the efficacy and safety of each biologic in a real-life setting and suggests some differences between biologics.
It is very difficult to compare these data with published case reports because of the differences in patients’ characteristics, outcome definitions and publication bias. Indeed, all biologics have been reported to be effective against RP, including for severe features such as respiratory and eye involvement.1 7
This study confirms the efficacy of TNF inhibitors with a low rate of withdrawal because of ADRs.1 7 However, etanercept did have a high rate of discontinuation due to insufficient efficacy. In conclusion, this study suggests that infliximab and adalimumab should be preferred among the TNF-α antagonists. Too few patients were exposed to golimumab and certolizumab pegol to draw any conclusions regarding their risk–benefit profiles. Adalimumab had the highest persistence rate, suggesting a good overall risk–benefit ratio.
This study confirms the low efficacy and high rate of withdrawal because of ADRs associated with anakinra,9 suggesting that this drug should not be preferred as a first-line biologic. In contrast, tocilizumab was highly effective for almost all features of RP, but with a 23.5% rate of withdrawal due to ADRs. This study also confirms the mild overall effectiveness of abatacept for RP, as suggested by the small open-label trial of four patients by Peng and Rodriguez.10 Two of our patients with tracheal symptoms responded to abatacept, but none of our six patients exposed to abatacept had parenchymal pulmonary or central nervous system involvement, which worsened with abatacept in the trial by Peng and Rodriguez.10
Conversely, our study showed the good efficacy of rituximab in contrast to the study by Leroux et al,8 but supports previous case reports.7 Of note, three patients in the present cohort had been previously included in Leroux’s analysis. Unfortunately, it was not possible to access the medical charts of all nine patients included in this series. In our study, the efficacy of rituximab was notable for nasal or auricular chondritis, sternal chondritis and eye involvement. Of note, in the study by Leroux et al, all nine patients were refractory to high-dose steroids and to at least two immunosuppressive drugs and, therefore, may have had a more resistant disease. Lastly, only two patients in the study by Leroux et al had eye involvement (including one also included in our study), but achieved stability by 6 months after starting rituximab.8
As previously suggested,9 the rotation of biologics is widely used in practice. The low number of patients and the heterogeneity of biologic exposures have prevented further analyses according to lines of treatments. We found no factor significantly associated with an achieved response at 6 months. As expected, there was a trend towards a lower response rate in cases of associated myelodysplastic syndrome, as suggested in a recent case-series.16 Interestingly, the concomitant use of NBDMARDs tended to be associated with an achieved response, as were nasal/auricular or sternal chondritis. None of these associations reached significance and we cannot exclude trends found by chance due to multiple testing. However, these associations are clinically relevant and the non-significance may be preferentially caused by a lack of statistical power.
This study demonstrated the high drop-out rate from biologics in real-life practice because of insufficient efficacy, loss of efficacy or an ADR, ranging from 33.3% to 86.7% across the biologics. Overall, about three-quarters of the biologics were discontinued within a mean follow-up time of 6 months, including one-fifth for ADRs. Among these, infections (notably respiratory tract infection) were common. Of note, most patients were concomitantly exposed to corticosteroids and non-biologic immunosuppressive drugs. Unfortunately, due to the retrospective design of our study, no data could be recorded regarding vaccinations prior to exposure to biologics.
This study has some limitations, mostly because of its retrospective design. Fourteen University centres participated in the study; thus, case recording is incomplete and may not reflect all patients treated for RP with biologics in France. Assessment of disease activity was made according to clinical activity, with no standardised paraclinical examination available to improve documentation of organ involvement. As previously stated, the multiplicity of lines of biologics and of unmeasured factors that may have impacted on the choice of biologic or the outcomes prevent from making any definitive direct comparisons, the few patients included and the heterogeneity of biologics used limited interpretation of the risk–benefit ratio for each organ and for each biologic. Similarly, 41.5% of the patients were concomitantly exposed to various NBDMARDs. Due to the heterogeneity of NBDARDs, no comparison could be made. Of note, no patient was concomitantly exposed to oral cyclophosphamide because, in France, cyclophosphamide is almost exclusively given intravenously for severe flares.
As stated above, the assessment of factors associated with a response in univariate analyses should be considered as exploratory; the lack of statistical power led to suggesting trends only. Altogether, this study suggests the need for registries on patients with RP, in particular to compare biologics with NBDMARDs, which is an important question that was not addressed in this study. Indeed, despite the findings on various cytokine expressions,6 the pathophysiology of this disease is widely unknown and, thus, the rationale for using biologics as a first-line treatment is insufficient.
In conclusion, this retrospective study showed the efficacy of biologics to treat patients with RP who were resistant to NBDMARDs. It also suggested differences in efficacies depending on the biologic and organ involvement, as well as differences in safety profiles. Prospective studies with head-to-head comparisons of biologics for RP are needed to confirm these results.
The authors thank the Société Nationale Française de Médecine Interne and the Club Rhumatisme et inflammation for having informed the physicians about this study. This work has been presented at the 2016 American College of Rheumatology meeting (11–16 November 2016, Washington, DC, USA).
Handling editor Josef S Smolen
Contributors GM, GP, ML-M and LS designed the study. All other authors included patients into the study. GM and AP conducted the statistical analyses. GM, GP, ML-M and LS interpreted the results and drafted the manuscript. All authors reviewed the manuscript and gave their approval for submission.
Funding This study was funded by Toulouse University Hospital.
Competing interests GM received a travel grant from Abbvie in 2013 and Amgen in 2017 and received research grants from Novartis, CSL Behring and the Institut Servier in 2016 and 2017. GP received travel support and lecture fees from Abbvie. DW received speaking fees and membership on the advisory boards of the following societies: AbbVie, BMS, MSD, Pfizer, Roche Chugai, Amgen, Nordic Pharma, UCB, SOBI, Sanofi Aventis, Novartis, Janssen, Celgene, Hospira, Lilly and Sandoz; he received grants/hospitality from Abbvie, Pfizer, Roche Chugai, MSD and UCB. BT received travel support from Roche and LFB, and received consulting fees from Roche, GSK, LFB and Grifols. PC received consulting and lecturing fees from Abbvie, Astra Zeneca, Bristol-Myers Squibb, Gilead, Glaxo Smith Kline, Janssen, Merck Sharp Dohme, Roche, Servier and Vifor.
Patient consent Not required.
Ethics approval This study received approval from the Toulouse University Ethics Committee in 2013, and according to French law from the Comité Consultatif du Traitement de l’Information et de la Recherche en Santé (n°13.251) in 2013 and then authorisation from the Commission Nationale de l’Informatique et des Libertés (n°DR-2013-378) in 2013.
Provenance and peer review Not commissioned; externally peer reviewed.
Correction notice This article has been corrected since it published Online First. Author Arsène Mékinian’s name has been corrected.
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