Psoriatic,arthritis:combinational,therapy,of,biologics,and,methotrexate,-,What,do,we,know?

Stephanie Dauth ,Michaela Köhm ,Frank Behrens

1 Fraunhofer Institute for Molecular Biology and Applied Ecology (IME),Branch for Translational Medicine and Pharmacology,Frankfurt am Main,Germany

2 Fraunhofer Cluster of Excellence Immune-mediated Diseases CIMD,Frankfurt am Main,Germany

3 Rheumatology Department,University Hospital,Frankfurt am Main,Germany

Abstract

Key words:biological therapy；
combinational therapy；
methotrexate；
psoriatic arthritis；
ustekinumab

Psoriatic arthritis (PsA) is a systemic inflammatory disease characterized by musculoskeletal involvement mostly associated with skin psoriasis.Usually,skin disease is diagnosed years before musculoskeletal involvement appears.The heterogeneous clinical features of PsA include peripheral arthritis(oligo or polyarthritis),inflammatory spine disease,enthesitis,dactylitis as well as skin and nail psoriasis.1Furthermore,associated extra-musculoskeletal features such as uveitis and gut inflammation could be present.The heterogeneous spectrum of clinical features in PsA is reflected in its complex pathogenesis:both genomic and environmental triggers are named to interfere with the innate and acquired immune system.1-3

PsA is associated with significant morbidity and disability,and thus constitutes a major socioeconomic burden.It is not only more common but also more severe than previously thought.1,2By the time patients present to a PsA clinic,67%have at least one joint with erosion.4Over 10 years of followup,55% of the patients have at least five clinically damaged joints.5Even in early disease,of 129 patients seen within 5 months of symptom onset in an early arthritis clinic,47%developed erosions within the first 2 years.6The diagnosis of PsA is often delayed or missed,partly because patients may present with inflammatory spinal pain,tendinitis,enthesitis,or dactylitis rather than a “true arthritis”.If PsA is not identified early and managed appropriately,progressive joint damage with deformities and disability may result.Early sufficient treatment results in better outcome.7-9

For therapeutic strategies,early diagnosis and sufficient treatment lead to the best outcome with prevention of structural damage (osteoproliferative and erosions) and loss of function.First-line treatments of PsA that are chosen according to international guidelines,are,after failure of non-steroidal anti-inflammatory drugs (NSAIDs),conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) such as methotrexate (MTX).10Therapy with csDMARDs is limited due to their relatively low effect size,as well as their tolerability and safety profile:approximately 55% of patients must be escalated to the second-line treatment according to treatment recommendations.11Several randomized clinical trials (RCTs)have proven the efficacy of tumour necrosis factor-inhibitors(TNFi),such as adalimumab (ADA),infliximab (INF) or golimumab (GOL),after failure of csDMARD-therapies for PsA.1,12However,a percentage of PsA patients do not respond to TNFi-therapy,emphasizing the need for additional treatment modalities with distinct mechanisms of action.

In clinical routine care as well as in clinical studies,it is important to reliably evaluate disease activity.PsA is a heterogeneous disease with the possible involvement of several domains,which makes diagnosis and reliable evaluations challenging.There are several disease activity assessments,which are available and commonly used:examination of 68 joints for tenderness and 66 joints for swelling,pain,enthesitis,and dactylitis.In addition,several skin specific assessments and composite scores for skin manifestation are available and commonly used:Psoriasis Area and Severity Index,involvement of nails,and involved body-surface area.Single assessments such as pain intensity or swollen and tender joints can then be implemented into a composite score to evaluate disease activity.Examples include the disease activity score 28 (DAS28)that includes swollen and tender joints (subset of 28 joints),C-reactive protein or erythrocyte sedimentation rate and patients" assessment of disease activity or the Leeds enthesitis index score as an assessment for severity of enthesitis.1In clinical trials,outcome measures and composite scores known for rheumatoid arthritis (RA) are used for PsA as well,such as the DAS28 or American College of Rheumatology (ACR)20,50 and 70 response rates.The latter indicates reduction in the number of tender and swollen joints of at least 20%,50% or 70%,with improvement in at least three of five additional parameters:patient and physician global assessments,pain,disability,and an acute phase-reactant (e.g.,C-reactive protein).1,11

The authors used the following inclusion criteria for this non-systematic review:clinical studies that discussed the concomitant use of methotrexate (or DMARDs) with biological treatments.English language and full-text articles published between 2005 and 2019 were included.Participants were males and females above the age of 18 years with a clinical diagnosis of psoriatic arthritis.The authors searched the PubMed database to identify relevant publications.The literature search strategy was conducted with the following key words or combinations thereof:psoriatic arthritis,concomitant methotrexate,biologics/biological therapy/biological treatment,etanercept,tofacitinib,adalimumab,infliximab,apremilast,golimumab,TNF inhibitors,ixekizumab,secukinumab,and ustekinumab(UST).The authors also screened the reference list of included studies to identify other potentially useful studies.The data extraction process focused on the information about each study type,the indication and the applied therapy.

MTX therapy plays a key role in the treatment of RA and PsA,even in the age of biologic therapies:In the national and international therapy recommendations,MTX as csDMARD is part of the first-line therapy of both diseases if there are no contraindications against its clinical use.13,14Reasons for the early use of MTX are the proof of clinical efficacy in RA,its potential to decelerate radiographic progression in RA and that there is no data that the use of biologics instead of MTX brings significant advantages at the time of RA diagnosis.15Even if MTX therapy is no longer sufficient in the course of the disease and other DMARDs (such as leflunomide or biologics) are used,therapy with MTX is usually continued as a combination partner in the treatment of RA,but often also in the treatment of PsA.16In RA treatment,MTX therapy is usually continued as concomitant medication to biologic therapy,as this combinational therapy has shown to be efficacious with e.g.,INF,etanercept (ETA),ADA and GOL.12In addition,MTX has a synergistic and inhibitory effect on the formation of anti-drug antibodies.17Treatment options for PsA have historically mirrored those of RA；
therefore,MTX is often used as the first drug of choice in PsA as well.However,despite MTX being one of the most commonly used drugs in PsA after NSAIDs,few data are available from RCTs to indicate its efficacy.12

The combination of biologics (e.g.,TNFi) and MTX shows a significantly stronger clinical effect than biologic monotherapy in the treatment of RA.However,the influence of MTX on the biologic therapy of PsA remains questionable,due to the lack of data from RCTs.Registration studies are only able to show that the addition of biologic therapy to MTX (i.e.,inadequate response to MTX alone) or to NSAIDs (i.e.,inadequate response to NSAIDs；
no concomitant MTX) in patients with active PsA achieves a comparable clinical improvement.Currently available data,mostly as analyses from subgroups of regulatory studies,from registry data or data from noninterventional studies are controversially discussed (Table1).For most biological therapies,it remains unclear whether MTX naive patients benefit more from the combination of MTX and biologic treatment than from biologic monotherapy and whether MTX patients receiving biologic therapy clinically worsen when MTX is discontinued.At least for ETA part of this question was answered with a recent randomized,controlled clinical trial that showed similar clinical results in PsA patients receiving combination therapy (ETA/MTX) and ETA monotherapy (details below).18

Overall,the efficacy of concomitant MTX use with biologics does not seem to differ from that of biologic monotherapy in PsA,but the combination therapy tends to show a lower side effect rate in PsA patients.12,19

Fragerli et al.20demonstrated no superiority in the efficacy of the TNFi/MTX combination therapy compared to biologic monotherapy,measured by DAS28 and ACR/EULAR response.56.1%,40.9% and 24.2% of PsA patients with TNFi monotherapy achieved ACR20,50 and 70 after 6 months.In the combination therapy group (TNFi/MTX),the rates were 59.6%,36.2%,and 26.2%.EULAR remission was 44.1%(TNFi monotherapy) and 46.6% (TNFi/MTX) after 6 months.20

Table1:Selected studies with data regarding concomitant MTX to biologic treatment or targeted basic therapeutics

A prospective Swedish study with 261 PsA patients found no differences in the number of painful and swollen joints or in the evaluation of pain during the study comparing TNFi monotherapy and TNFi/MTX combination therapy.21Other studies with TNFi also showed no additional improvement in clinical response (ACR response) with concomitant MTX.22-24

ADALIMUMAB

Two studies with ADA with/without concomitant MTX therapy showed that combination therapy (ADA/MTX) in PsA patients led to a comparable clinical efficacy and radiographic progression reduction compared to ADA alone.24,2555%,36%,and 17% of PsA patients with ADA/MTX therapy achieved ACR20,50,and 70 at week 12 compared to 61%,36%,and 23% with ADA monotherapy.24Gladman et al.25reported that the ACR values were numerically greater for patients with MTX combination therapy compared to ADA monotherapy,but a significant difference was not achieved.50%,38%,and 29% of patients with ADA monotherapy achieved ACR 20,50,and 70 at week 48 compared to 63%,49%,and 31% with combination therapy.

The clinical response to ADA monotherapy compared to ADA/MTX combination therapy in a study by Behrens et al.26was almost the same.In this analysis,PsA patients with and without axial involvement were evaluated,since MTX is certainly ineffective for axial manifestation.Therefore,a potential positive effect should be evident especially in patients without spinal involvement.After 24 months,patients with axial PsA showed a DAS28 change of -1.9 (ADA monotherapy) and-2.2 (ADA/MTX) and patients without axial manifestation of-2.2 (both treatment groups).Accompanying MTX therefore has no effect on joint results in PsA patients who begin ADA therapy,regardless of axial involvement.26

ETANERCEPT

Mease et al.18recently completed a multicenter,double-blind,randomized,controlled trial to compare the efficacy and safety of ETA/MTX combination therapy with ETA or MTX monotherapy in MTX-naive PsA patients.The study enrolled 851 PsA patients.Primary endpoint was the clinical efficacy at week 24 measured by the ACR20 response.50.7% of patients with MTX monotherapy achieved ACR20 response at week 24,60.9% of patients in the ETA group,and 65% in the ETA/MTX group.ACR20 response at week 24 was signi ficantly greater for ETA monotherapy and ETA/MTX combination therapy compared to MTX monotherapy,but combination therapy(ETA/MTX) and ETA monotherapy had similar results.18

Combe et al.27observed a comparable number of PsA patients in the ETA monotherapy and ETA/MTX combination therapy group achieving the PsA response criteria (PsARC；
80% and 83%) and ACR20 (70%,both).Furthermore,a recent study by Behrens et al.reported that a comparable proportion of PsA patients with ETA monotherapy and ETA/csDMARDs combination therapy showed treatment response.28Treatment response was measured against three treatment goals:(1)Achieving low disease activity based on the DAS28 value,(2) involved body surface area ≤ 3% and (3) short form-12 score ＞ 45.After 52 weeks,24.3% (monotherapy) and 24.5%(combination therapy) achieved all three treatment goals.The combination of ETA and csDMARD did not improve clinical response compared to ETA monotherapy.28

INFLIXIMAB AND GOLIMUMAB

Subgroup analyses of RCTs with INF showed no significant difference in the ACR20 response when MTX was taken simultaneously compared to monotherapy.22,23In a study with PsA patients receiving GOL with/without continued MTX use,MTX did not affect the ACR20 response at week 14.Interestingly,no patient who took MTX at baseline developed antibodies against GOL,while 4.6% of patients without additional MTX did.29

IXEKIZUMAB

Data from the Spirit-P1 study,which included PsA patients receiving ixekizumab/MTX combinational therapy or ixekizumab monotherapy,showed higher ACR20 response rates at week 24 in the ixekizumab group compared to placebo,regardless of MTX concomitant therapy.30A larger proportion of patients in the ixekizumab group reported adverse events compared to the placebo group,and again,this was regardless of MTX concomitant therapy.30

USTEKINUMAB AND SECUKINUMAB

A subgroup analysis of the PSUMMIT 1 study,which included PsA patients receiving UST/MTX combinational therapy or UST monotherapy,reported numerically lower ACR20 response rates at week 24 for patients with combinational therapy(UST/MTX) compared to monotherapy,but significance tests were not performed.31The numerically lower response rates were only observed in the 90 mg UST groups,but not in the 45 mg UST groups.ACR20 response in the 90 mg UST group was ～41% at week 24 for the UST/MTX combinational therapy and ～52% for the UST monotherapy.With 45 mg UST both groups (UST/MTX and UST) showed a ～40% ACR20 response rate at week 24 (data were only shown graphically in the supplementary material).31The number of patients with adverse events was independent of MTX use.31

A subgroup analysis of the FUTURE 2 study,which included PsA patients receiving secukinumab/MTX combinational therapy or secukinumab monotherapy,suggested that improvements in ACR response rates at week 24 occurred independent of concomitant MTX use.32

APREMILAST

In a subgroup analysis of a phase II placebo-controlled study with PsA patients receiving either apremilast/MTX combinational therapy or apremilast monotherapy,no signi ficant differences in the ACR20 response rate were observed between combinational therapy and monotherapy.33

DRUG SURVIVAL

TNFi therapy might be improved due to a greater drug survival (i.e.how long patients maintain a therapy) with concomitant MTX use in in flammatory arthritis,including PsA.In RA,immunogenicity may play a role in reduced drug concentrations and efficacy:the formation of antidrug antibodies in response to monoclonal antibodies may result in low serum drug concentrations,loss of therapeutic response,and poor drug survival.12Therefore,concomitant MTX might reduce the frequency of anti-drug antibody formation in the treatment of inflammatory arthritis.

Concomitant MTX therapy in PsA was associated in two studies (261 and 172 PsA patients) with an increased drug survival of TNFi therapy and was associated with significantly fewer therapy discontinuations due to adverse events during the study.21,34In addition,data from the Danish DANBIO registry with 764 PsA patients receiving TNFi/MTX combinational therapy or TNFi monotherapy showed that concomitant MTX at baseline was associated with a longer drug survival.35This result could not be reproduced in the 2016 data analysis of a non-interventional study from Germany in which data from 1455 PsA patients (ADA with/without MTX) and another study with 82 PsA patients (ETA with/without MTX) were examined.26,36Also,data from the CORRONA registry with 519 PsA patients with TNFi/MTX combinational therapy or TNFi monotherapy showed no difference in drug survival.37In the British Society for Rheumatology Biologics Register,patients (596 PsA patients) treated with INF/MTX and ADA/MTX showed a better drug survival compared to monotherapy,whereas patients treated with ETA/MTX showed no difference in drug survival compared to monotherapy.38In the PROVE observational study,the use of MTX did not significantly affect drug survival over 5 years in ETA-treated PsA patients.39In the IMPACT 2 trial,which evaluated the efficacy of INF in PsA,only 3.6% of patients receiving MTX were positive for anti-INF antibodies,while 26.1% of patients not receiving MTX tested positive for anti-INF antibodies.40Concomitant MTX has also been associated with lower incidence of anti-drug antibodies to GOL in PsA patients.29

Figure1:MUST study:overview of study design.

Anti-drug antibodies against INF and ADA in combination with low trough level of the drug correlate with lower response rates,while concomitant MTX use reduced the formation of anti-drug antibodies.27However,antibodies against the fusion receptor protein ETA are rarely detected.41Overall,this suggests that potentially positive effects of MTX concomitant therapy are most likely to be expected with monoclonal antibodies.A meta-analysis evaluating the immunogenicity in inflammatory arthritis including PsA reported that the use of immunosuppressants,primarily MTX,reduced the proportion of patients receiving INF and ADA with detectable anti-drug antibodies by about 41%.42

MUST STUDY

The data available so far indicate that MTX does not signif icantly improve the clinical efficacy of biologic therapy in PsA patients.It remains unclear whether and to what extent MTX alters drug survival by influencing the formation of neutralizing antibodies,whether MTX naive patients benefit more from the combination of MTX and biologic therapy than from biologic monotherapy,and whether MTX patients receiving biologic therapy deteriorate when MTX is discontinued.

The MUST study (“Impact of concomitant methotrexate on efficacy,safety and adherence of ustekinumab-treatment in patients with active psoriatic arthritis”) is an Investigator Initiated,German multicenter,randomized clinical trial in patients with active PsA to investigate the impact of placebo-controlled MTX therapy combined with initiated biologic therapy with UST (interleukin 12/23 inhibitor) on efficacy,safety and adherence (Figure1).In addition,the MUST study evaluates whether the disease activity of patients who are already taking MTX and who are initiating UST therapy will worsen when MTX is discontinued (EudraCT No.2015-005777-20).

UST is a fully human monoclonal antibody targeting the p40 subunit shared by IL-12 and IL-23.The cytokines interleukin(IL)-12 and IL-23 are involved in the pathogenesis of psoriasis and PsA.UST prevents the binding of IL-12 and IL-23 to their receptors and blocks the Th1 and Th17 inflammatory pathways.UST was investigated for the treatment of various chronic immune-mediated diseases such as psoriasis and PsA.Most data on the safety of UST are derived from experience in the treatment of patients with psoriasis,but clinical studies have demonstrated the efficacy and safety of UST in the treatment of both diseases.43

TNFi must be administered every 1,2 or 4 weeks,whereas UST is administered only every 12 weeks after the two ini-tial doses.This could improve therapy adherence.This is of great importance as the efficacy of drugs in clinical practice depends on whether patients adhere to their medication.A cohort analysis of 1219 patients who received TNFi showed that treatment adherence was 51% with INF,27% with ETA and 23% with ADA.44

The primary objective of the MUST study is to demonstrate that UST monotherapy is not inferior to MTX/UST combination therapy in the mean DAS28 at week 24.In total,196 patients are planned to be enrolled in this study.Currently,163 patients have been included in the MUST study in 28 centers(as of October 28,2019).

Patients with ongoing MTX therapy as well as MTX-naive patients will be included in the clinical trial.Further inclusion criteria are the diagnosis of active PsA (diagnosis according to CASPAR criteria),the presence of ≥ 4 tender joints,≥ 4 swollen joints (from 68/66 joints) and a DAS28 ≥ 3.2.In addition,UST pre-treatment is not allowed.During the study,the following data will be collected to measure efficacy:DAS28,tender joints,swollen joints,ACR20/50/70 response,Psoriasis Area and Severity Index,body surface area,BASDAI,compliance(questionnaire CQR5),quality of life (questionnaires HAQ,EQ5D,DLQI),Leeds enthesitis index,dactylitis,mtNAPSI and ultrasound (PsASon22,selected centers only).Safety data are also collected.Within a biomaterial collection,factors of immunogenicity can later be determined.

According to the MTX pre-therapy,patients are distributed to the treatment arms as follows (Figure1):

Group A:active PsA with MTX at stable dose (15 mg 1×weekly) at study start

Arm 1:UST (45 mg or 90 mg according to product information) + placebo

Arm 2:UST (45 mg or 90 mg according to product information) + MTX (15 mg once a week)

Group B:active PsA without MTX at study start

Arm 1:UST (45 mg or 90 mg according to product information) + placebo

Arm 2:UST (45 mg or 90 mg according to product information) + MTX (15 mg once a week)

The patients are assessed after the baseline examination at week 4,16,24,28,40,52,and 90 days after week 52 (followup telephone visit).The total duration of treatment with UST is 52 weeks (Figure1).

CONCLUSION

The influence of concomitant MTX on the clinical efficacy of biologic therapy in PsA has not yet been sufficiently investigated in a placebo-controlled setting.So far,only one randomized,controlled study regarding the concomitant use of MTX with ETA has been performed and results were recently published.The otherwise available study data,which mainly originate from subgroup analyses,registry data and data from non-interventional studies,cannot be clearly evaluated with regard to the clinical evaluation of combination therapy.Nevertheless,the current data indicate that in PsA,in terms of clinical efficacy,combination therapy with MTX appears to have less clinical significance than in other indications compared to monotherapy.Open questions remain,e.g.,(I)what is the impact of MTX on neutralizing antibody formation and adherence,(II) do MTX naive patients benefit more from the combination of MTX and biologic therapy than from biologic monotherapy,and (III) do MTX patients receiving add-on biologic therapy deteriorate when MTX is discontinued.The MUST study offers the ideal opportunity to answer these questions in a controlled study.

Author contributions

Manuscript writing:SD；
critical revision of the manuscript for intellectual content:MK and FB.All authors approved the final version of the manuscript.

Conflicts of interest

SD,MK,and FB received research support from Janssen-Cilag GmbH,Neuss,Germany.

Financial support

No financial support was received for writing this article.

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