Biologics in Relapsing Polychondritis

Relapsing polychondritis is a rare, often severe, and untreated fatal connective tissue disease. The inflammation of the ear cartilage is often the initial symptom, at least in the patients, who had been referred to our center. We’re still lacking a specific lab test for relapsing polychondritis. We have different diagnostic criteria by McAdam, Damiani and Michet. I’ve already written about the disease on this blog, less than I should have considering the fact that I treat patients with this disease. There have been four abstracts at the 2016 ACR Annual Meeting. I’ll also talk about the abstracts/studies, which doesn’t concern biologics.

Guillaume Moulis and his more than 20 co-authors presented [#1329]: “Efficacy and Safety of Biologics in Relapsing Polychondritis: A National Multicenter Study in France”. Conclusion: “Overall, biologics are an interesting option for RP treatment. “ You might call this statement laconic, but there’s lots of work included. The authors saw 41 patients and had to try several drugs until one worked. The rate of partial and complete remission is about 60-70%, with anakinra and abatacept being lowest at 50-53%. The authors looked at all TNF alpha inhibitor, anakinra, abatacept, tocilizumab, and rituximab.

Marcela Ferrada and colleagues presented [#1330]: “Clinical Presentations of Relapsing Polychondritis: More Than a Swollen Ear”. The authors acquired data via an internet-based questionnaire to catalogue the variety of possible clinical presentations of relapsing polychondritis. They could evaluate 180 questionnaires. In results the authors point out: “Common initial symptoms included dizziness, eye inflammation, constochondritis, and shortness of breath, nose pain, and voice changes. Some patients also reported fatigue, flu-like symptoms, fever and difficulty swallowing as initial symptoms. Complications of RP included disability (25%), tracheomalacia (16%) and intubation related to RP (12%).”  The study has limitations as you can’t validate the diagnosis and there’s a recall bias. But still, I think the study is very valuable.

Chee Ken Cheah and collegues presented [#1331]: “Disease Patterns and Long Term Outcome Amongst Patients with Relapsing Polychondritis – Single Centre Experience”. Conclusions: “Our study revealed higher number of initial organ presentation, and younger age of disease onset correlated with potential diagnosis delay. Male gender with airway involvements correlated with higher number of organ damages and poorer outcome. Multicenter registries may lead to a better understanding of this disease.”

Toshiki Nakajima and colleagues looked at 33 patients with relapsing polychondritis in this study [#1332]: “Severe Complications and Immunosuppressive Treatments in 33 Patients with Relapsing Polychondritis”. In results the authors inform us about HLA haplotypes, which are associated with relapsing polychondritis: “Positivity of HLA-DQB1 05:02 was 17.6% (3/17),　higher than 2.6% in healthy Japanese.” [The authors recently reported an association of disease onset and 3 HLA haplotypes (DQB1*05:02, B*67:01 and DRB1*16:02 in linkage disequilibrium) in C. Terao et al.: Rheumatology (Oxford) doi: 10.1093/rheumatology/kew233]. “Methotrexate (MTX), azathioprine (AZP), intravenous cyclophosphamide (IVCY), infliximab (IFX) and tocilizumab (TCZ) were used along with glucocorticoid ….” Conclusion: “The linkage with certain haplotypes of HLA and the positivity of autoantibodies (~30%) consolidate that RP is an autoimmune disease. IVCY showed a good response in patients with TB lesions in the present study. The prognosis of patients with CNS lesions was poor. Further collection of cases is required to elucidate pathophysiology and improve treatments.”

So we have different approaches according to disease severeness, organ involvement, and activity. Immunosuppressants as well as biologics are used. As the disease is rare there won’t be any randomized controlled trials and any drug will be off label. Anyway, a partial remission of 50-70% is feasible with biologics. Hopefully one can speed up approval proceedings with insurance companies because of the off label use.

Links:

https://en.wikipedia.org/wiki/Relapsing_polychondritis

http://rheumatologe.blogspot.de/2011/12/biologics-in-relapsing-polychondritis.html

Moulis G, Pugnet G, Costedoat-Chalumeau N, Mathian A, Leroux G, Boutemy J, Bouillet L, Berthier S, Gaultier JB, Jeandel PY, Konaté A, Mékinian A, Solau-Gervais E, Terrier B, Wendling D, Garnier C, Cathebras P, Arnaud L, Cacoub P, Amoura Z, Piette JC, Arlet P, Palmaro A, Lapeyre-Mestre M, Sailler L. Efficacy and Safety of Biologics in Relapsing Polychondritis: A National Multicenter Study in France [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). http://acrabstracts.org/abstract/efficacy-and-safety-of-biologics-in-relapsing-polychondritis-a-national-multicenter-study-in-france/. Accessed December 15, 2016.

Ferrada M, Choudhury SD, Newman K, Sinaii N, Guma M, Christie T, Katz JD. Clinical Presentations of Relapsing Polychondritis: More Than a Swollen Ear [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). http://acrabstracts.org/abstract/clinical-presentations-of-relapsing-polychondritis-more-than-a-swollen-ear/. Accessed December 15, 2016.

Cheah CK, Sangle (Joint First Author) S, D'Cruz D. Disease Patterns and Long Term Outcome Amongst Patients with Relapsing Polychondritis – Single Centre Experience [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). http://acrabstracts.org/abstract/disease-patterns-and-long-term-outcome-amongst-patients-with-relapsing-polychondritis-single-centre-experience/. Accessed December 15, 2016.

Nakajima T, Yoshifuji H, Terao C, Murakami K, Kuramoto N, Nakashima R, Imura Y, Tanaka M, Ohmura K, Mimori T. Severe Complications and Immunosuppressive Treatments in 33 Patients with Relapsing Polychondritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). http://acrabstracts.org/abstract/severe-complications-and-immunosuppressive-treatments-in-33-patients-with-relapsing-polychondritis/. Accessed December 15, 2016.

COVA322 and Bispecificity at the ACR Annual Meeting 2014 in Boston

Cova322 is a bispecific TNF/IL-17A inhibitor. Is this a new hype? Or are we going to see a change of view on combining biologics? To my knowledge there is no biologic agent, where a combination with another biologic agent is advocated. Some people combine biologics with denosumab, so the principle isn’t that new, but let’s say it isn’t accepted on a large scale. There had been studies combining anakinra and etanercept or abatacept and a TNF-alpha-inbibitor, so that remicade for instance dicidedly warns to be combined with other biologic agents. On the other hand we have ustekinumab, which is a monoclonal antibody against interleukins 12 and 23.

W. Lemke and colleagues presented the following paper [#1511]: “COVA322: A Clinical Stage Bispecific TNF/IL-17A Inhibitor for the Treatment of Inflammatory Diseases.” “COVA322 was analyzed for its cross-reactivity in a GLP study with human and Cynomolgus tissues.”  In “results” we’re told: “COVA322 showed no unexpected tissue cross-reactivity and no indication for the potential to cause a cytokine release syndrome.” Conclusions: “COVA322 is a unique bispecific TNF/IL-17A inhibitor, which was well tolerated in non-clinical safety studies. The non-clinical data package supports the planned dose range for the currently ongoing first in man, single dose escalation, tolerability, safety, PK and efficacy Phase Ib/IIa study in psoriasis.” It isn‘t a conclusion that COVA322 is a unique bispecific TNF/IL-17A inhibitor, that’s marketing! The only conclusions I see are cell studies, mouse arthritis model studies  and tests in Cynomolgus monkeys hadn’t raised safety concerns.

There is another study by D. Grabulovski and colleagues [#1491]: “Discovery and Characterization of COVA322, a Clinical Stage Bispecific TNF/IL-17A Inhibitor for the Treatment of Inflammatory Diseases.” I recomment to read the whole text as methods and results are really interesting to read.  Conclusion: “COVA322 is a unique bispecific TNF/IL-17A inhibitor with excellent biophysical properties. It is currently being tested in a first in man, single dose escalation, tolerability, safety, PK and efficacy Phase Ib/IIa study in psoriasis.” Too much marketing!

Let’s sum it up. Cova322 is a bispecific TNF/IL-17A inhibitor. It is a promising new agent, which could result in a new drug. It might be working in (at least) psoriasis and psoriatic arthritis. And maybe it will help us to find a safe way to combining biologic agents. Godspeed COVA322!

Link to ACR Abstracts: 

http://www.acrannualmeeting.org/abstracts/ 

Anakinra at the ACR 2012 in Washington

There have been 8 studies at the ACR 2012 in Washington mentioning anakinra (IL-1Ra-Receptor antagonist).

Pascal Zufferey and colleagues presented a study on rotator cuff calcifications (Abstract No. 135): “A Pilot Study of the Efficacy of IL1 Blockade by Anakinra in Acute Calcific Periarthritis of the Rotator Cuff”. Conclusion: This pilot open study suggests that IL-1Ra inhibition may be an interesting therapeutic approach in acute calcific periarthritis, especially in patients who have not responded adequately to NSAIDs.” The debate will be opened if anakinra is better than steroid injection, which has a clear cost advantage.

Mary Bach and colleagues looked at gouty arthritis (Abstract No. 146): “The Treatment of Acute Gouty Arthritis in Complex Hospitalized Patients with Anakinra”. Conclusion: “Anakinra is an effective and safe alternative treatment for acute gouty arthritis in medically complex patients who fail or cannot undergo more conventional therapy.” Up to now I didn’t have a patient, who “cannot undergo a more conventional therapy”. We should focus on how to decide which patients fit into such a categogy.

Other studies looked at TRAPs, FMF, and other fever syndroms as well as juvenile idiopathic arthritis (Abstracts No. 179, 190 [Schnitzler’s Syndrome], 275 [Juvenile Dermatomyositis], 747, 762, 1142, 2021).

Anakinra is mentioned in a poster on relapsing polychondritis (No. 1923). Two patients were treated with anakinra, but the treatment has been inefficient.

Anakinra and pseudo gout (calcium pyrophosphate crystal arthritis) - what has changed since the EULAR 2012? In abstract No. 146 two case reports on pseudo gout and anakinra are mentioned.

Link to the EULAR evaluation: http://rheumatologe.blogspot.de/2012/07/anakinra-and-pseudogout-calcium.html  

Ankylosing Spondylitis Refractory to TNF-inhibition in the light of EULAR 2012

There has been a recent publication of U. Kiltz et al.: “Treatment of Ankylosing Spondylitis in Patients Refractory to TNF-inhibition”, which is on the net at: http://www.medscape.com/viewarticle/761743
The authors have seen some trends for efficacy of abatacept, anakinra, apremilast, bisphosphonates, rituximab, secukinumab, sulfasalazine, thalidomide, and tocilizumab, but for problems with design and methodology of the evaluated studies “there is at present insufficient evidence to support a recommendation for any of these compounds.” So it came to my mind to look at what has been presented at the EULAR 2012 concerning these drugs and ankylosing spondylitis.

Abatacept – about 40 studies and posters, none on abatacept and ankylosing spondylitis.

Anakinra – around 40 studies, on in one abstract, anakinra is mentioned: “..the efficacy of anakinra, … has not been convincingly shown in AS”. ([SP0060] SPONDYLO-ARTHRITIS/ANKYLOSING SPONDYLITIS DRUG THERAPY / J. Braun. Rheumazentrum Ruhrgebiet, Herne, Germany)

Apremilast – no study in ankylosing spondylitis

Bisphosphonates – there’s a study by H. Forsblad-d'Elia on alendronate in osteoporotic patients with ankylosing spondylitis (NIS). They saw an increase in bone mineral density. In another study M. Soroush an colleagues looked at bone mineral density in ankylosing spondylitis patients with and without alendronate (NIS). They also saw an increase in bone mineral density in patients treated with alendronate. But actually these two studies were concerned rather with osteoporosis in patients with ankylosing spondylitis than treating ankylosing spondylitis with a bisphosphonate.


[THU0271] INCREASE IN BONE MINERAL DENSITY AND DECREASE IN WNT3A, OPG, CTX-I AND OSTEOCALCIN IN PATIENTS WITH ANKYLOSING SPONDYLITIS TREATED WITH ALENDRONATE
H. Forsblad-d'Elia, M. Nurkkala, K. Zetterberg, E. Klingberg, H. Carlsten, and Center for Bone and Arthritis Research. Department of Rheumatology and Inflammation Research, Institute of Medicine, Gothenburg, Sweden
Conclusions: We show, for the first time, a prompt and sustained decrease of the biomarkers Wnt3a, OPG, CTX-I and osteocalcin in osteoporotic AS patients treated with alendronate during 2 years. The results indicate a down regulatory effect on both osteclastic and osteblastic activity. The treatment also resulted in a significant and large increase in BMD in lumbar spine and total hip.

[AB0855] BONE MINERAL DENSITY IN PATIENTS WITH ANKYLOSING SPONDYLITIS BEFORE AND AFTER ONE YEAR TREATMENT WITH OR WITHOUT BISPHOSPHONATE
M. Soroush1, S. Soroush1, M. Mirtalebi2, B. Nadimi3. 1Rheumatology, Army University of Medical Sciences; 2Rheumatology; 3501 Hospital, Tehran, Islamic Republic Of Iran
Conclusions: Altogether, densitometry survey done over these two groups showed that T-score of diseased in both groups has been improved after treatment in comparison with the period they passed before treating, of course this amount of enhancement was more notable it the first group which received Alendronate.


Rituximab – about 40 studies, but only on abstract addressing the subject. D. Wendling and colleagues looked at data from the AIR registry. They saw moderate efficacy on several subsets of spondyloarthritis. I like to cite this abstract as Francis Berenbaum (@Larhumato) participated.


[AB0848] RITUXIMAB TREATMENT FOR SPONDYLOARTHRITIS. A NATIONWIDE SERIES: DATA FROM THE AIR REGISTRY
D. Wendling1, M. Dougados2, F. Berenbaum3, O. Brocq4, T. Schaeverbeke5, B. Mazieres6, C. Marcelli7, J.-M. Le Parc8, P. Bertin9, M. Robin10, J. Sibilia11, P. Lafforgue12, C. Prati1, B. Combe13, J.-E. Gottenberg11. 1Rheumatology, CHU, Besancon; 2Rheumatology, Cochin Hospital; 3Rheumatology, Saint-Antoine Hospital, Paris; 4Rheumatology, Princess Grace Hospital, Monaco; 5Rheumatology, CHU, Bordeaux; 6Rheumatology, CHU, Toulouse; 7Rheumatology, CHU, Caen; 8Rheumatology, Ambroise Paré Hospital, Boulogne-Billancourt; 9Rheumatology, CHU, Limoges; 10Internal Medicine, Hospital, Laon; 11Rheumatology, CHU, Strasbourg; 12Rheumatology, CHU, Marseille; 13Rheumatology, CHU, Montpellier, France
Conclusions: In this nationwide open experience of rituximab on several subsets of spondyloarthritis, we saw only a moderate efficacy, more evident for patients naive for anti TNF agents.

Secukinumab – 8 abstracts on secukinumab, but not an issue concerning ankylosing spondylitis save for the oberview by J. Braun, which I have already cited above.

Sulfasalazine – J. Sieper stated in his talk: “Furthermore, conventional DMARDs such as methotrexate or sulfasalazine are not effective, …” ([SP0146] NON ANTI-TNF BIOLOGICS IN AXIAL SPONDYLOARTHRITIS J. Sieper. Med Depart I, Rheumatology, Charite, Berlin, Germany). A study by X. Baraliakos and colleagues agrees with this, though the study looked primarily at disease duration and reatment response (X. Baraliakos et al.: [AB0861] RELATIONSHIP BETWEEN DISEASE DURATION AND TREATMENT RESPONSE IN PATIENTS WITH ANKYLOSING SPONDYLITIS (AS)). As there have been 30 abstracts, ankylosing spondylitis isn’t a big issue in current research.

Thalidomide – there were three abstracts on thalidomide, none on ankylosing spondylitis.

Tocilizumab – there are 153 abstracts on tocilizumab at the EULAR 2012. J. Sieper and colleagues stated: “Tocilizumab (TCZ) is not effective for the treatment of ankylosing spondylitis (AS) …”. They presented a phase 2 study. J. Braum mentioned tocilizumab in his overview given at the “How to manage 3” session.


[OP0166] TOCILIZUMAB (TCZ) IS NOT EFFECTIVE FOR THE TREATMENT OF ANKYLOSING SPONDYLITIS (AS): RESULTS OF A PHASE 2, INTERNATIONAL, MULTICENTRE, RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL
J. Sieper1, B. Porter-Brown2, L. Thompson2, O. Harari2, M. Dougados3. 1Charité Med U, Berlin, Germany; 2Roche, Welwyn, United Kingdom; 3Paris-Descartes U, Paris, France
Conclusions: The study failed to demonstrate the efficacy of TCZ over placebo for the treatment of symptoms of AS, irrespective of baseline CRP level. CRP levels declined with TCZ, suggesting adequate IL-6R blockade. The change in ASDAS-CRP was driven by the decrease in CRP. The safety profile of TCZ in this study was consistent with that seen in RA pts.


All in all it dim view. Let’s face it, for practical use there are TNF-inhibitors and that’s all currently, which can be recommended based on studies.
Where’s certolizumab? I guess somewhere in another universe. There 34 abstracts mentioning certolizumab and one is on spondyloarthritis. S.A. Rodriguez Montero and colleagues: “Almost all patients were in DMARDs therapy, 96.1%, while 100% were treated with TNF blockers: etanercept 52%, infliximab 31.5%, adalimumab 13.4%, golimumab 2.4% and certolizumab 0.8%.” (S.A. Rodriguez Montero et al.: [AB0906] Prevalence and characteristics of coronary disease and cardiovascular risk factors in a cohort of patients with spondyloarthropathies and biologic therapy).
Which means for the time being we can offer etanercept, infliximab, adalimumab, and golimumab to our patients.

Anakinra and Pseudogout (calcium pyrophosphate crystal arthritis) at the EULAR 2012

As the IL-1Ra-Receptor antagonist anakinra hasn’t been a success story in rheumatoid arthritis, the producer has been looking for alternative targets. Calcium pyrophosphate crystal arthritis is one of these targets. I doubt that calcium pyrophosphate crystal arthritis really is an issue. Most patients do fine on NSAIDs, colchicine, oral and/or local corticosteroids. No wonder the study has only n=16.


S. Ottaviani and colleagues looked at the efficacy of anakinra in calcium pyrophosphate crystal arthritis. It is a multi center retrospective study with five centers involved. Only 16 patients were enrolled in the study. Not all patients had a CPP crystal demonstration in synovial fluid, but only X-ray evidence. Anakinra has been effective, but one patient suffered from pyocyanic pneumonitis.


[FRI0400] EFFICACY OF ANAKINRA IN CALCIUM PYROPHOSPHATE CRYSTAL ARTHRITIS
S. Ottaviani1, L. Brunier1, J. Sibilia2, F. Maurier3, K. Dawidowicz1, E. Palazzo1, G. Hayem1, M. Ardizzone4, D. Wendling5, O. Meyer1, P. Dieudé1. 1Rheumatology, Hôpital Bichat, Paris; 2Rheumatology, CHU Strasbourg-Hautepierre, Strabourg; 3Internal Medicine, CH Metz, Metz; 4Rheumatology, CH Mulhouse, Mulhouse; 5Rheumatology, Hôpital Jean Minjoz, Besançon, France
Conclusions: Anakinra is an effective and relatively well-tolerated treatment of refractory CPP arthritis and should be an alternative in individuals having non-response or contra-indication to conventional therapies.


Maybe there will be the one patients with a decade, where I could imagine prescribing anakinra, but still it would be off-label.