Real-world experience with filgotinib for rheumatoid arthritis in Germany : A retrospective chart review.

BACKGROUND: Real-world data for filgotinib, a Janus kinase (JAK)1 inhibitor, are limited in patients with rheumatoid arthritis (RA). OBJECTIVES: To explore real-world filgotinib use in patients with RA in Germany. MATERIALS AND METHODS: This retrospective chart review included patients aged ≥ 18 years with confirmed moderate to severe RA who initiated filgotinib before December 1, 2021, with ≥ 6 months of medical records available prior to filgotinib initiation or after initial diagnosis. Patient characteristics, prior treatments, reasons for initiating/discontinuing filgotinib, disease activity, dose adjustments and concomitant treatments were recorded. RESULTS: In total, 301 patients from 20 German rheumatology outpatient units were included. One-third were aged ≥ 65 years and almost half had ≥ 1 cardiovascular (CV) risk factor. Most patients initiated filgotinib as monotherapy (83.7%; 12.7% of whom with glucocorticoids) and at the 200 mg dose (84.7%); higher proportions of those initiating the 100 versus 200 mg dose were aged ≥ 65 years and had renal impairment or ≥ 1 CV risk factor. Oral administration (78.4%), fast onset of action (66.8%) and administration as monotherapy (65.4%) were the most common reasons for initiating filgotinib. At 12 months, 41 (18.4%) patients had discontinued filgotinib, most commonly due to lack of effectiveness. After 6­months of follow-up, 36.8% of patients had achieved Clinical Disease Activity Index (CDAI) remission and 45.6% had achieved CDAI low disease activity. CONCLUSIONS: In clinical practice in Germany, reasons for initiating filgotinib in patients with RA were related to dosing flexibility and general JAK inhibitor attributes. Filgotinib was used predominantly as monotherapy and was effective and generally well tolerated; however, longer-term data in larger, prospective cohorts are needed.

The impact of C-reactive protein levels on the effectiveness of upadacitinib in patients with rheumatoid arthritis: a 12-month prospective, non-interventional German study.

OBJECTIVES: We investigated whether the effectiveness of upadacitinib in rheumatoid arthritis (RA) treatment is affected by baseline CRP levels in a real-world setting. METHODS: UPwArds was a prospective, non-interventional study. Patients had moderate-to-severe RA and an inadequate response or intolerance to ≥1 disease-modifying anti-rheumatic drug (DMARD). The primary endpoint was clinical remission (Clinical Disease Activity Index [CDAI] ≤2.8) at 6 months. Secondary endpoints at 12 months included clinical remission and low disease activity assessed by CDAI and Simple Disease Activity Index criteria, DAS28-CRP <2.6/≤3.2, and patient-reported outcomes. The impact of baseline CRP levels (normal vs. above the upper limit of normal [ULN]) on primary and secondary endpoints was evaluated. The effect of concomitant MTX and prior inadequate response to biologic or targeted synthetic DMARDs (b/tsDMARD-IR) on the effectiveness of upadacitinib was also assessed. Safety was evaluated through 12 months. RESULTS: 518 patients were included in the effectiveness analyses. At 6 months, 24.4% of patients achieved the primary endpoint (CDAI ≤2.8). At 12 months, similar proportions of patients with normal CRP and CRP above the ULN at baseline achieved CDAI ≤2.8 (27.3% and 29.1%) and other key secondary endpoints. The effectiveness of upadacitinib was comparable with and without concomitant MTX and in b/tsDMARD-naive and b/tsDMARD-IR patients. The safety results were consistent with the known safety profile of upadacitinib; no new safety signals were identified. CONCLUSIONS: Upadacitinib therapy was effective for RA in a real-world setting. Baseline CRP levels had no significant impact on the effectiveness of upadacitinib.

Physical Function of RA patients Tapering Treatment-A Post Hoc Analysis of the Randomized Controlled RETRO Trial.

Several studies have shown that tapering or stopping disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients in sustained remission is feasible. However, tapering/stopping bears the risk of decline in physical function as some patients may relapse and face increased disease activity. Here, we analyzed the impact of tapering or stopping DMARD treatment on the physical function of RA patients. The study was a post hoc analysis of physical functional worsening for 282 patients with RA in sustained remission tapering and stopping DMARD treatment in the prospective randomized RETRO study. HAQ and DAS-28 scores were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and HAQ and DAS-28 scores were evaluated every 3 months. The effect of treatment reduction strategy on functional worsening was assessed in a recurrent-event Cox regression model with a study-group (control, taper, and taper/stop) as the predictor. Two-hundred and eighty-two patients were analyzed. In 58 patients, functional worsening was observed. The incidences suggest a higher probability of functional worsening in patients tapering and/or stopping DMARDs, which is likely due to higher relapse rates in these individuals. At the end of the study, however, functional worsening was similar among the groups. Point estimates and survival curves show that the decline in functionality according to HAQ after tapering or discontinuation of DMARDs in RA patients with stable remission is associated with recurrence, but not with an overall functional decline.

[DMARD (disease-modifying antirheumatic drug) treatment in patients with former or current cancer]. / DMARD("disease-modifying antirheumatic drug")-Therapie bei früherer und aktiver Tumorerkrankung.

In contrast to the original fear that treatment with disease-modifying antirheumatic drugs (DMARDs) and especially with biologic DMARDs (bDMARDs), was associated with an increased risk of the induction of malignancies, this has meanwhile fortunately not been confirmed over the long-term administration. Evaluations from register-based investigations as well as from other long-term cohort studies confirm that neither conventional DMARDs, such as methotrexate, nor tumor necrosis factor (TNF) inhibitors or biologics with a different mode of action show such a risk for induction of cancer or hematological malignancies (for skin tumors see the other article). Regarding the question whether recurrences of former malignancies can be induced by DMARDs, the database is considerably smaller; however, published investigations dealing with this topic so far signal that also in this respect no increased risk can be found. When comparing the individual substances with each other no substantial differences can be found. Although used in the treatment of hematological cancers, rituximab does not offer any advantages in comparison to other biologics. For the group of Janus kinase (JAK) inhibitors, which have been in use only for a few years, data outside the randomized controlled studies (which are limited in time and are conducted with a selected patient population) are limited so that a clear statement regarding the malignancy risk is not yet possible for these substances. In a solitary study comparing tofacitinib with TNF inhibitors in high-risk patients, the malignancy risk of the JAK inhibitor was increased compared to that under TNF inhibitor treatment; however, these results have not yet been confirmed by a second investigation.

Perioperative management of patients with inflammatory rheumatic diseases : Updated recommendations of the German Society for Rheumatology.

BACKGROUND: Prior to surgical interventions physicians and patients with inflammatory rheumatic diseases remain concerned about interrupting or continuing anti-inflammatory medication. For this reason, the German Society for Rheumatology has updated its recommendations from 2014. METHODS: After a systematic literature search including publications up to 31 August 2021, the recommendations on the use of of glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologics (bDMARDs) were revised and recommendations on newer drugs and targeted synthetic (ts)DMARDs were added. RESULTS: The glucocorticoid dose should be reduced to as low as possible 2-3 months before elective surgery (in any case <10 mg/day) but should be kept stable 1-2 weeks before and on the day of surgery. In many cases csDMARDs can be continued, exceptions being a reduction of high methotrexate doses to ≤15 mg/week and wash-out of leflunomide if there is a high risk of infection. Azathioprine, mycophenolate and ciclosporin should be paused 1-2 days prior to surgery. Under bDMARDs surgery can be scheduled for the end of each treatment interval. For major interventions Janus kinase (JAK) inhibitors should be paused for 3-4 days. Apremilast can be continued. If interruption is necessary, treatment should be restarted as soon as possible for all substances, depending on wound healing. CONCLUSION: Whether bDMARDs increase the perioperative risk of infection and the benefits and risks of discontinuation remain unclear based on the currently available evidence. To minimize the risk of a disease relapse under longer treatment pauses, in the updated recommendations the perioperative interruption of bDMARDs was reduced from at least two half-lives to one treatment interval.

[Diagnostics of Interstitial Lung Diseases - Practical Instructions with a Focus on Rheumatologic Systemic Diseases]. / Diagnostik interstitieller Lungenerkrankungen ­ Handlungsempfehlung mit Fokus auf rheumatologische Systemerkrankungen.

Interstitial lung diseases (ILD) are etiologically heterogeneous with unknown and known causes like rheumatologic systemic diseases differing in their therapeutic and prognostic consequences. In consensus between pulmonologists, rheumatologists, radiologists, and pathologists, we developed practical instructions for ILD diagnosis in rheumatologic systemic diseases, in particular because ILD can present in early stages of rheumatic systemic diseases. ILD diagnosis is based on clinical assessment results including a detailed medical history, physical examination, focused laboratory tests, radiology with a high-resolution computed tomography, lung function, and histopathology also to differentiate it from cardiac and infection associated lung diseases. The ILD diagnosis is made in a multidisciplinary discussion leading to therapeutic and prognostic consequences. The occurrence of acute exacerbations is especially critical. They are often the causes for ILD progression and are associated with considerable mortality.

Sarilumab reduces disease activity in rheumatoid arthritis patients with inadequate response to janus kinase inhibitors or tocilizumab in regular care in Germany.

OBJECTIVES: The aim was to evaluate the safety and effectiveness of sarilumab in RA patients after inadequate response (IR) to janus kinase inhibitors (JAKi) and tocilizumab. METHODS: The prospective, observational, 24-month single-arm PROSARA study (SARILL08661) is currently running in Germany at 96 sites. RA patients were prospectively selected at the physician's discretion according to label. This interim analysis included 536 patients over a treatment course of ≤6 months. Patients were stratified in four groups according to pretreatment before the start of sarilumab therapy: last prior treatment JAKi (JAKi-IR); last prior treatment tocilizumab (tocilizumab-IR); any other biological DMARD (bDMARD) in treatment history (bDMARD TH); and patients who had not received any bDMARDs or targeted synthetic (ts) DMARDs (b/tsDMARD naive) before. RESULTS: For this preplanned interim analysis, 536 patients were included in the baseline population, of whom 502 patients had at least one corresponding post-baseline effectiveness assessment documented (main analysis population). In all analysed cohorts, safety was consistent with the anticipated profile of sarilumab, without new safety signals. Six months of sarilumab treatment attenuated disease activity in JAKi-IR, tocilizumab-IR, bDMARD TH and b/tsDMARD-naive patients to a very similar extent. Physical function did not change substantially over the course of treatment. Rates of premature study discontinuation were comparable between cohorts. CONCLUSION: Sarilumab treatment was effective in patients with IR to JAKi and tocilizumab, with an expectable safety profile and drug retention over 6 months. Confirmation of these promising results should encourage further studies on this treatment sequence, which is of high practical relevance. STUDY REGISTRATION: Paul-Ehrlich-Institut-Federal Institute for Vaccine and Biomedics, SARILL08661.

[Innovative strategies for treatment of rheumatoid arthritis]. / Neues zu Therapiestrategien bei der rheumatoiden Arthritis.

Besides excellent guidelines and newly developed highly effective drugs, evidence-based strategic use of these new drugs has especially contributed to enormous advances in rheumatoid arthritis treatment, apparent especially since 2000. Currently, the treat-to-target (T2T) strategy has proven to be the most successful in several studies and systematic reviews. The target is to achieve remission, which should be reached and sustained for an optimal outcome (i.e. stable over a long time period). If the initial disease-modifying antirheumatic drug (DMARD) treatment fails, the best strategy for continuing treatment is controversial, with swap or switch being open to debate (change within a class of drugs or change in the mechanism of action). Recent studies seem to indicate that switching to another mechanism of action is the most successful approach. A hotly discussed topic is the question whether DMARD treatment can or should be tapered when sustained remission has been achieved? Many patients wish for a reduction of drugs in cases of stable remission; however, the stable disease control might become destabilized by tapering. The main priority is the reduction or tapering of glucocorticoid treatment. When the decision for reduction of DMARD treatment is made together with the patient, a complete cessation bears a high risk of a flare, therefore, a careful step by step reduction of DMARD treatment should be preferred. In the case of a running combination, the question whether the conventional DMARD (mostly methotrexate), the biological (b)DMARD or targeted synthetic (ts)DMARD should be reduced first, must be decided on an individual basis. Most patients prefer to first reduce methotrexate and transfer to a monotherapy.

[Perioperative management of treatment of patients with inflammatory rheumatic diseases : Updated recommendations of the German Society of Rheumatology]. / Perioperativer Umgang mit der Therapie von Patienten mit entzündlich rheumatischen Erkrankungen : Aktualisierte Empfehlungen der Deutschen Gesellschaft für Rheumatologie.

BACKGROUND: Prior to surgical interventions physicians and patients with inflammatory rheumatic diseases remain concerned about interrupting or continuing anti-inflammatory medication. For this reason, the German Society for Rheumatology has updated its recommendations from 2014. METHODS: After a systematic literature search including publications up to 31 August 2021, the recommendations on the use of of glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologics (bDMARDs) were revised and recommendations on newer drugs and targeted synthetic (ts)DMARDs were added. RESULTS: The glucocorticoid dose should be reduced to as low as possible 2-3 months before elective surgery (in any case <10 mg/day) but should be kept stable 1-2 weeks before and on the day of surgery. In many cases csDMARDs can be continued, exceptions being a reduction of high methotrexate doses to ≤15 mg/week and wash-out of leflunomide if there is a high risk of infection. Azathioprine, mycophenolate and ciclosporin should be paused 1-2 days prior to surgery. Under bDMARDs surgery can be scheduled for the end of each treatment interval. For major interventions Janus kinase (JAK) inhibitors should be paused for 3-4 days. Apremilast can be continued. If interruption is necessary, treatment should be restarted as soon as possible for all substances, depending on wound healing. CONCLUSION: Whether bDMARDs increase the perioperative risk of infection and the benefits and risks of discontinuation remain unclear based on the currently available evidence. To minimize the risk of a disease relapse under longer treatment pauses, in the updated recommendations the perioperative interruption of bDMARDs was reduced from at least two half-lives to one treatment interval.

German Society of Rheumatology recommendations for management of glucocorticoid-induced osteoporosis.

BACKGROUND: Glucocorticoids are of substantial therapeutic importance in the treatment of inflammatory diseases, but are also associated with bone mineral density loss, osteoporosis, and fractures, especially with long-term use. OBJECTIVE: To develop recommendations for the management of glucocorticoid-induced osteoporosis (GIOP) in adult patients on long-term glucocorticoid (GC) treatment. METHODS: A systematic literature search (SLR) was conducted to synthesize the evidence for GIOP prevention and treatment options. Recommendations were developed based on SLR/level of evidence and by previously defined questions and in a structured group consensus process. RESULTS: Recommendations include supplementation with calcium and vitamin D under long-term GC therapy in adults. If specific osteologic treatment is indicated, we recommend bisphosphonates or denosumab as first-line treatment. If fracture risk is high, we recommend teriparatide as primary specific osteologic treatment. Denosumab should be used in cases of severe renal insufficiency, and specific osteologic treatment should not be given in pregnancy. For patients who have not reached the treatment goal, a switch to another class of specific osteologic drugs should be performed. We recommend re-evaluation after a treatment duration of 3-5 years or after termination of long-term GC treatment. CONCLUSION: This work aims to provide evidence-based and consensus-based recommendations for the best possible management of GIOP in Germany and to support treatment decisions.

[Importance of mycophenolate mofetil for treatment of interstitial lung disease in systemic sclerosis]. / Stellenwert von Mycophenolat-Mofetil zur Behandlung der interstitiellen Lungenerkrankung bei systemischer Sklerose.

Interstitial lung disease in systemic sclerosis (SSc-ILD) is a frequent organ complication with considerable mortality. Therapeutically, immunosuppressants are primarily used, particularly cyclophosphamide (CYC) and mycophenolate mofetil (MMF). Recently acquired data also showed an efficacy of the biologics rituximab and tocilizumab. The therapeutic options have most recently been expanded by the approval of the antifibrotic drug nintedanib. It is particularly beneficial in progressive fibrosing courses of ILD despite immunosuppression. The data from controlled trials on the efficacy and safety of CYC and MMF compiled in this review argue for a preferential use of MMF; however, the approval of MMF for this indication is still lacking. This is urgently needed for improved and simplified care of patients with SSc-ILD.

[German Society of Rheumatology Recommendations for the management of glucocorticoid-induced Osteoporosis. German version]. / Empfehlungen der Deutschen Gesellschaft für Rheumatologie zum Management der Glukokortikoid-induzierten Osteoporose.

BACKGROUND: Glucocorticoids are of substantial therapeutic importance in the treatment of inflammatory diseases, but are also associated with bone mineral density loss, osteoporosis, and fractures, especially with long-term use. OBJECTIVE: To develop recommendations for the management of glucocorticoid-induced osteoporosis (GIOP) in adult patients on long-term glucocorticoid (GC) treatment. METHODS: A systematic literature search (SLR) was conducted to synthesize the evidence for GIOP prevention and treatment options. Recommendations were developed based on SLR/level of evidence and by previously defined questions and in a structured group consensus process. RESULTS: Recommendations include supplementation with calcium and vitamin D under long-term GC therapy in adults. If specific osteologic treatment is indicated, we recommend bisphosphonates or denosumab as first-line treatment. If fracture risk is high, we recommend teriparatide as primary specific osteologic treatment. Denosumab should be used in cases of severe renal insufficiency, and specific osteologic treatment should not be given in pregnancy. For patients who have not reached the treatment goal, a switch to another class of specific osteologic drugs should be performed. We recommend re-evaluation after a treatment duration of 3-5 years or after termination of long-term GC treatment. CONCLUSION: This work aims to provide evidence-based and consensus-based recommendations for the best possible management of GIOP in Germany and to support treatment decisions.

[Does methotrexate influence the efficacy of vaccination against SARS-CoV-2?] / Beeinflusst Methotrexat die Wirksamkeit der Impfung gegen SARS-CoV-2?

The question whether an ongoing treatment with methotrexate (MTX) actually impairs the protective immune response after SARS-CoV­2 vaccination cannot be answered with certainty on the basis of the available data. However, in view of the fact that a short discontinuation (once or twice) of the weekly MTX treatment in patients with a stable disease situation is probably associated with a comparatively low risk of inducing a flare of the underlying inflammatory rheumatic disease, such a short discontinuation of treatment can be considered according to the individual decision involving the patient and the treating rheumatologist. Nevertheless, discontinuation of MTX treatment does not appear to be absolutely necessary-especially since discontinuation would have to occur twice within a short period of time for most COVID-19 vaccines. Under no circumstances should longer periods of discontinuation of treatment be considered as this could result in a flare of the underlying disease. A more detailed assessment of the data situation and the resulting consequences (also with respect to DMARD) will follow soon in the updated recommendations for action of the German Society for Rheumatology (DGRh) on the management of patients with inflammatory rheumatic diseases in the context of the SARS-CoV­2 pandemic, especially COVID-19.

[Current state of vaccination against SARS-CoV-2]. / Aktueller Stand der Impfung gegen SARS-CoV-2.

On 21 December 2020 the European Medicines Agency (EMA) approved the mRNA vaccine BNT162b2 (Comirnaty®, BioNTech, Mainz, Germany; Pfizer, New York City, NY, USA) as the first vaccine against SARS-CoV­2 in the European Union and the second vaccine (Moderna®, Moderna, Cambridge, MA, USA) followed on 6 January 2021. Many more approvals will follow within a short period of time. With the availability of the vaccination many questions have arisen for patients as well as for physicians, which are addressed as up to date as possible in this hot topic article.