Unmet needs in ankylosing spondylitis patients receiving tumour necrosis factor inhibitor therapy; results from a large multinational real-world study.

BACKGROUND: Symptoms and comorbidities of ankylosing spondylitis (AS) considerably reduce health-related quality of life (HRQoL) and ability to work. This real-world study assessed rates of tumour necrosis factor inhibitor (TNFi) use and switching, treatment failure, and associations between failing TNFi and HRQoL, work productivity and activity impairment (WPAI). METHODS: AS patients and their treating physicians completed questionnaires capturing patient demographics, clinical status, TNFi treatment history, reasons for switching TNFi, HRQoL and WPAI. Current TNFi was determined as "failing" if, after ≥3 months, physician-rated disease severity had worsened, remained severe, was "unstable/deteriorating", physicians were dissatisfied with disease control and/or did not consider treatment a "success". RESULTS: The analysis included 2866 AS patients from 18 countries. Of 2795 patients with complete treatment data, 916 (32.8%) patients had never received TNFi therapy, 1623 (58.1%) patients were receiving their 1st TNFi and 200 (7.2%) patients had ever received ≥2 TNFi (treatment switch). Primary or secondary lack of efficacy were the commonest reasons for switching, and the mean delay in switching after primary lack of efficacy was 11.1 months. 232 (15.4%) patients on TNFi were currently "failing" who, compared to those with treatment success, reported poorer HRQoL: 5-dimension EuroQoL (EQ-5D-3 L): 0.63 vs. 0.78; Medical Outcomes Study Short-Form Health Survey version 2 (SF-36v2) mental component summary (MCS): 41.8 vs. 46.3; physical component summary (PCS): 40.2 vs. 45.1; impaired work productivity: 46.4% vs. 25.0%; and activity: 44.5% vs. 29.6%; all P < 0.001. CONCLUSIONS: Among AS patients, switching TNFi is uncommon and delayed by nearly 1 year despite primary lack of efficacy. Patients currently failing TNFi experience worse physical function, HRQoL and work productivity.

[Janus kinase inhibitors : State of the art in clinical use and future perspectives]. / Januskinase-Inhibitoren : State of the Art im klinischen Einsatz und Zukunftsperspektiven.

BACKGROUND: Cytokines and associated intracellular signal cascades play a major role in the pathogenesis of autoimmune diseases. Janus kinases (JAK) are part of these intracellular signal transduction processes. A relatively new drug group of targeted synthetic disease-modifying antirheumatic drugs (tsDMARD) are JAK inhibitors (JAKi) and are a promising treatment approach for autoimmune diseases. EFFICACY: Hitherto, three JAKis, Tofacitinib, Baricitinib and Upadacitinib, have been approved for treatment of Rheumatoid Arthritis (RA) in the USA, Switzerland and the EU. Filgotinib, another JAKi, also showed promising results in the treatment of RA. Furthermore, tofacitinib received approval for the treatment of ulcerative colitis and psoriatic arthritis. In addition to the JAKis already mentioned, several other JAKis, e.g. filgotinib and peficitinib, are being and were investigated in various studies on indications, such as atopic dermatitis, ankylosing spondylitis and systemic lupus erythematosus. SAFETY: Being immunosuppressants, JAKis show an elevated incidence of severe infections, comparable to biologics. The increased reactivation of varicella zoster virus is especially noteworthy. Under JAKi treatment cytopenia is also more frequent. Lymphopenia under JAKi treatment is of particular clinical relevance because of its association with an increase in the number of severe infections. Furthermore, an elevated risk of thromboembolic events, particularly pulmonary embolism has been noted. The risks concerning metabolic alterations and the occurrence of malignant neoplasms are comparable to those under treatment with biologics.

[S2e guideline: treatment of rheumatoid arthritis with disease-modifying drugs]. / S2e-Leitlinie: Therapie der rheumatoiden Arthritis mit krankheitsmodifizierenden Medikamenten.

BACKGROUND: Medication-based strategies to treat rheumatoid arthritis are crucial in terms of outcome. They aim at preventing joint destruction, loss of function and disability by early and consistent inhibition of inflammatory processes. OBJECTIVE: Achieving consensus about evidence-based recommendations for the treatment of rheumatoid arthritis with disease-modifying anti-rheumatic drugs in Germany. METHODS: Following a systematic literature research, a structured process among expert rheumatologists was used to reach consensus. RESULTS: The results of the consensus process can be summed up in 6 overarching principles and 10 recommendations. There are several new issues compared to the version of 2012, such as differentiated adjustments to the therapeutic regime according to time point and extent of treatment response, the therapeutic goal of achieving remission as assessed by means of the simplified disease activity index (SDAI) as well as the potential use of targeted synthetic DMARDs (JAK inhibitors) and suggestions for a deescalating in case of achieving a sustained remission. Methotrexate still plays the central role at the beginning of the treatment and as a combination partner in the further treatment course. When treatment response to methotrexate is inadequate, either switching to or combining with another conventional synthetic DMARD is an option in the absence of unfavourable prognostic factors. Otherwise biologic or targeted synthetic DMARDs are recommended according to the algorithm. Rules for deescalating treatment with glucocorticoids and-where applicable-DMARDs give support for the management of patients who have reached a sustained remission. DISCUSSION: The new guidelines set up recommendations for RA treatment in accordance with the treat-to-target principle. Modern disease-modifying drugs, now including also JAK inhibitors, are available in an algorithm.

[Drug therapy of fibromyalgia syndrome : Updated guidelines 2017 and overview of systematic review articles]. / Medikamentöse Therapie des Fibromyalgiesyndroms : Aktualisierte Leitlinie 2017 und Übersicht von systematischen Übersichtsarbeiten.

BACKGROUND: The regular update of the guidelines on fibromyalgia syndrome, AWMF number 145/004, was scheduled for April 2017. METHODS: The guidelines were developed by 13 scientific societies and 2 patient self-help organizations coordinated by the German Pain Society. Working groups (n =8) with a total of 42 members were formed balanced with respect to gender, medical expertise, position in the medical or scientific hierarchy and potential conflicts of interest. A literature search for systematic reviews of randomized controlled drug trials from December 2010 to May 2016 was performed in the Cochrane library, MEDLINE, PsycINFO and Scopus databases. Levels of evidence were assigned according to the classification system of the Oxford Centre for Evidence-Based Medicine version 2009. The strength of recommendations was achieved by multiple step formalized procedures to reach a consensus. Efficacy, risks, patient preferences and applicability of available therapies were weighed up against each other. The guidelines were reviewed and approved by the board of directors of the societies engaged in the development of the guidelines. RESULTS AND CONCLUSION: Amitriptyline and duloxetine are recommended in the case of comorbid depressive disorders or generalized anxiety disorder and pregabalin in the case of generalized anxiety disorder. Off-label use of duloxetine and pregabalin can be considered if there are no comorbid mental disorders or no generalized anxiety disorder. Strong opioids are not recommended.

[Evidence-based recommendations for diagnostics and treatment of gouty arthritis in the specialist sector : S2e guidelines of the German Society of Rheumatology in cooperation with the AWMF]. / Evidenzbasierte Empfehlung zur Diagnostik und Therapie der Gichtarthritis im fachärztlichen Sektor : S2e-Leitlinie der Deutschen Gesellschaft für Rheumatologie (DGRh) in Kooperation mit der AWMF.

Due to the increasing prevalence of gout, particularly in old age, the disease is becoming of increasing importance in Germany. Gout is one of the most common forms of recurrent inflammatory arthritis and is induced by the deposition of monosodium urate crystals in synovial fluid and other tissues. The principal goals of therapy in chronic gout are the symptomatic treatment of the acute joint inflammation and the causal treatment of the underlying metabolic cause, the hyperuricemia. Only a consistent and permanent reduction of the serum uric acid level ultimately results in an efficient avoidance of further gout attacks and therefore the prevention of structural damage. Due to an often inadequate treatment of gout, the target of healing the disease is often not achieved. A correct and timely diagnosis and adequate assessment of comorbidities associated with gout are, however, of substantial importance for patient and physician to achieve remission of the disease. In order to create a solid basis for a timely and effective treatment of affected patients, in 2016 the German Society of Rheumatology (DGRh) initiated the development of S2e guidelines on gouty arthritis for specialists. This article summarizes these S2e guidelines on the management of gouty arthritis in the specialist sector.

Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1).

OBJECTIVES: To evaluate the efficacy and safety of different doses and regimens of filgotinib, an oral Janus kinase 1 inhibitor, as add-on treatment to methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and inadequate response to MTX. METHODS: In this 24-week phase IIb study, patients with moderate-to-severe active RA receiving a stable dose of MTX were randomised (1:1:1:1:1:1:1) to receive placebo or 50, 100 or 200 mg filgotinib, administered once daily or twice daily. Primary end point was the percentage of patients achieving a week 12 American College of Rheumatology (ACR)20 response. RESULTS: Overall, 594 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib 100 mg once daily or 200 mg daily (both regimens) achieved an ACR20 response versus placebo. For other key end points at week 12 (ACR50, ACR-N, Disease Activity Score based on 28 joints and C reactive protein value, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index), differences in favour of 100  or 200 mg filgotinib daily were seen versus placebo; responses were maintained or improved through to week 24. Rapid onset of action and dose-dependent responses were observed for most efficacy end points and were associated with an increased haemoglobin concentration. No significant differences between once-daily and twice-daily regimens were seen. Treatment-emergent adverse event rates were similar in placebo and filgotinib groups. Serious infections occurred in one and five patients in the placebo and filgotinib groups, respectively. No tuberculosis or opportunistic infections were reported. CONCLUSIONS: Filgotinib as add-on to MTX improved the signs and symptoms of active RA over 24 weeks and was associated with a rapid onset of action. Filgotinib was generally well tolerated. TRIAL REGISTRATION NUMBER: NCT01888874.

[Structural and morphological changes in the eyes of arterial hypertensive patients with and without anti-CCP-positive rheumatoid arthritis]. / Strukturelle und morphologische Veränderungen am Auge bei Patienten mit arterieller Hypertonie mit und ohne Anti-CCP-positiver rheumatoider Arthritis.

INTRODUCTION: To investigate the additive systemic inflammatory process of rheumatoid arthritis (RA) in arterial hypertension patients, structural and morphological changes of the retina and optic nerve head were assessed by modern topographic technologies. Similarities of underlying vascular mechanisms between RA and arterial hypertension are interesting and have not been researched in depth. The aim of this study is to evaluate changes of RA and arterial hypertension with the optic coherence topography (OCT) and Heidelberg retina tomography (HRT III), to validate RA changes in comparison to arterial hypertension only patients and, finally, if these methods are useful to detect the chronic inflammatory influence of the RA on the eye. METHODS: In this prospective study design, data of 18 patients with RA and arterial hypertension (55.3 ± 4.31 years old), positive for antibodies against cyclic citrullinated peptides, 21 patients with arterial hypertension (54.2 ± 4.18 years old) and 19 healthy subjects (53.1 ± 3.25 years old) were included. Intensive ophthalmologic and internistic screening tests were carried out in all subjects. All participants were investigated for the retinal nerve fiber layer (RNFL) and macula thickness with the OCT (Carl Zeiss AG Germany) and for stereometric parameters of the optic nerve head with the Heidelberg Retina Tomograph III (Heidelberg Engineering Germany). The pachymetry was conducted by the Orbscan II system (Bausch & Lomb). Statistical data were assessed by SPSS, v20.0. RESULTS: No significant differences were found in visual function, diastolic and systolic blood pressure. RNFL, and macular thickness (Stratus-OCT) were almost consistent between the groups and even the main stereometric parameters measured with HRT III showed no significant differences. CONCLUSION: Contrary to our study hypothesis no structural and morphological changes could be detected in patients with arterial hypertension without RA compared to healthy subjects. Furthermore, no RA-specific effects could be shown in comparison with the hypertension group. Thus, the used examination techniques are not suitable to prove the systemic inflammatory influence of RA on the eye.

[Autoimmune reactions to immune checkpoint inhibitors]. / Autoimmunologische Reaktionen bei Immun-Checkpoint-Inhibitoren.

Immune checkpoint inhibitors (ICI) have dramatically changed the face of cancer treatment and are gaining in importance. The ICIs have now been approved for the treatment of advanced cancers, including melanoma, non-small-cell and small cell lung cancers, renal cell carcinoma, Hodgkin's lymphoma, head and neck cancers and urothelial carcinoma and further indications are to be expected. The organs most affected by an autoimmune reaction are the intestines, the musculoskeletal system, skin, endocrine organs, the liver and the lungs. As the indications for immune checkpoint blockade expand and ICIs are used in combination, it becomes increasingly more important for rheumatologists to recognize immune-related adverse events (irAEs), their connection to cancer immunotherapy and how to treat these events appropriately. The role of rheumatologists will take on growing importance as immunotherapies become more common as standard treatment of cancer and when used earlier in the course of the disease. Previously controlled autoimmune diseases can deteriorate when using ICIs, so this is a consideration when evaluating patients. Increased awareness of inflammatory arthritis, as well as other rheumatic manifestations as an adverse association with cancer immunotherapies, is imperative for making the diagnosis. Treatment algorithms are based on the severity of symptoms but in the case of rheumatic disease, treatment often needs to be tailored to the individual. The general strategy for evaluation and management of irAEs includes a thorough evaluation for infections. Mild irAE may be self-limiting, while more severe reactions are generally steroid responsive, albeit with potentially high dosage requirements.

[Genitourinary malignancies and rheumatoid arthritis]. / Urologische Malignome und rheumatoide Arthritis.

Genitourinary neoplasms are relatively common and the frequency increases with age. Due to demographic changes more patients with inflammatory rheumatic diseases will have concomitant genitourinary tumors or they will develop them under antirheumatic therapy. In such cases, disease-modifying antirheumatic drugs (DMARD) and immunosuppressive therapy have to be carefully balanced on an individual basis. Based on the limited evidence available large increases in the risks from conventional and/or biological DMARDs for patients with genitourinary malignancies appear to be unlikely for most situations. In addition to these more common situations paraneoplastic symptoms in the musculoskeletal system can occur due to genitourinary malignancies. Moreover, novel drugs with immunostimulating activity for some genitourinary tumors may provoke autoimmune symptoms and thus present new challenges for interdisciplinary cooperation between rheumatologists and uro-oncologists. In this review, the diagnostic procedures, therapies and follow-up of cancers in the field of urology are delineated according to the current German and European guidelines. We describe the core issues that both urologists and rheumatologists should bear in mind. Direct communication, routine exchange and involvement of rheumatologists in interdisciplinary tumor boards should improve future treatment quality of our joint patients.

[Do we still need clinical studies in rheumatology?]. / Brauchen wir noch klinische Studien in der Rheumatologie?

Despite a large number of approved therapies demonstrating efficacy in the treatment of rheumatic diseases, only 60-85 % of patients with the indications for rheumatoid arthritis are adequately treated in Germany. Additionally, approved therapies for other immune-mediated diseases are often entirely lacking, indicating the great medical need for the development of new innovative therapies in this specialized field. The development of new drugs is expensive due to the high costs of conducting clinical trials in all phases of development up to obtaining approval; therefore, pharmaceutical companies are looking for ways to save costs in the particular developmental stages. Although the classical regions for drug development (i.e. western Europe, the USA and Japan) offer both a high level of data quality and a good infrastructure to conduct clinical trials due to high standards of education and quality, clinical trials are expensive in these regions. Beside high costs, the comparatively low recruitment rates in these regions are one of the main reasons for the shifting of drug developmental stages from classical regions to eastern European, Latin American and Asian countries, which provide services for drug development and high recruitment rates for comparatively less money. However, there are many strong arguments for the participation of regions in western Europe, especially German sites in clinical trials. In this article these arguments are discussed and possible solutions and strategies for conducting and compensation of study centers in Germany for clinical trials in the field of rheumatology are provided.

[Biosimilars in rheumatology. Development and results of clinical trials]. / Biosimilars in der Rheumatologie. Entwicklung und Ergebnisse klinischer Studien.

BACKGROUND: This article presents the design of clinical trials for the development of biosimilars in the European Union and the United States, with special focus on inflammatory diseases. METHODS: All information available in PubMed and the Internet relating to the clinical development of biosimilars in inflammatory rheumatic conditions (e.g. rheumatoid arthritis, psoriasis, psoriatic arthritis and ankylosing spondylitis) was collated. The European Medicines Agency (EMA) and US Food and Drug Administration (FDA) websites were screened for guidelines on biosimilars. RESULTS: More than 10 years ago the EMA began to publish guidelines for the development of biosimilars and several biosimilars have now been approved. In the USA the FDA has published guidance for the nonclinical and clinical development of biosimilars but until early 2015 no biosimilar had been approved. CONCLUSION: Clinical trials aim to resolve uncertainties that may remain following nonclinical development regarding the similarity of the proposed biosimilar with the reference product. Pharmacokinetic and pharmacodynamic studies are essential for early clinical development and further phase 3 clinical studies. Factors to be considered in the clinical process include study population, design, endpoints, sample size, duration and analytical methods.

Morning stiffness response with delayed-release prednisone after ineffective course of immediate-release prednisone.

OBJECTIVE: To assess morning stiffness in rheumatoid arthritis (RA) patients switched from immediate-release (IR) to delayed-release (DR) prednisone. METHOD: Circadian Administration of Prednisone in Rheumatoid Arthritis-1 (CAPRA-1) is a 12-week, randomized, multicentre, active-controlled study of morning stiffness that consisted of a double-blind phase and a 9-month open-label extension. Patients receiving IR prednisone with no significant improvement after the double-blind study were switched to DR prednisone. Morning stiffness duration and median absolute and relative changes in pain and global assessment were evaluated (3, 6, and 9 months). RESULTS: In patients switched from IR to DR prednisone (n=110), statistically significant reductions in morning stiffness occurred over 3 months and were sustained for 9 months. Absolute reduction of morning stiffness was ~50 min with >40% relative reduction at each visit. Interleukin (IL)-6 levels were reduced by the same amount. Statistically significant and clinically meaningful mean reductions in morning stiffness were maintained at >67 min at each visit along with significant improvements in pain and patient global assessment. There was no evidence of tachyphylaxis seen over the 9-month study. CONCLUSIONS: Patients receiving disease-modifying anti-rheumatic drugs (DMARDs) and IR prednisone who had not had significant reductions in morning stiffness demonstrated statistically significant and clinically meaningful improvements when switched to DR prednisone.

What Is the Relationship Between Morning Symptoms and Measures of Disease Activity in Patients With Rheumatoid Arthritis?

OBJECTIVE: Little is known about the relationship between morning symptoms of rheumatoid arthritis (RA) and measures of disease activity currently used to assess RA. Information available from the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA-2) study was used to investigate these relationships. METHODS: CAPRA-2 included 350 patients with RA who were symptomatic despite treatment with disease-modifying antirheumatic drugs, randomized 2:1 to additional treatment with a 5-mg daily dose of delayed-release prednisone or placebo. Pearson's correlations were used to evaluate the relationships between change from baseline in symptoms (duration of morning stiffness, severity of morning stiffness, and intensity of pain on waking) and measures of disease activity (the American College of Rheumatology 20% improvement criteria [ACR20], the Disease Activity Score in 28 joints [DAS28], and the Health Assessment Questionnaire disability index). Correlations were defined as weak (<0.3), moderate (0.3-0.7), or strong (>0.7). RESULTS: There was a strong correlation between the severity of morning stiffness and the intensity of morning pain (Pearson's correlation 0.91, P < 0.001). There was a weak correlation between the duration of morning stiffness and measures of disease activity (0.24-0.28), with moderate correlations between the severity of morning stiffness or intensity of pain on waking and DAS28 or ACR20 scores (0.44-0.48). Severity of morning stiffness showed less variability and a greater effect size than did duration of morning stiffness. CONCLUSION: Morning symptoms and measures of disease activity show weak to moderate correlations. Severity of morning stiffness showed less variability and greater effect size than did duration of morning stiffness. These findings suggest that severity is the preferred construct to measure the impact of morning stiffness in patients with RA, information that is not fully captured in the RA core set.

[Depression and rheumatism: options for measuring depression]. / Depressivität und Rheuma: Möglichkeiten der Depressivitätsmessung.

BACKGROUND: The importance of depressive diseases in the treatment of rheumatism patients cannot be denied. It is well-known from publications in the English speaking literature that the proportion of depressive diseases lies between 10% and 45% in patients with rheumatoid arthritis (RA). However, clearly increased numbers can also be seen in a direct comparison with corresponding prevalence rates in the normal population for other diseases included in the category of rheumatism. OBJECTIVE: This manuscript focusses on the possibilities and challenges in measuring states of depressive mood that might serve as an indicator of depressive diseases in the context of treatment of rheumatism. MATERIAL AND METHODS: A search of the current literature was carried out and the results were evaluated. RESULTS: Starting from appropriate background knowledge, the current state of science is discussed while subsequently taking a closer look at a choice of internationally recognized assessment tools which are feasible for use in rheumatology. Finally, this overview is accompanied by hints for hands-on practice and suggestions on how to respond to conspicuous test results indicative of a depressive mood. DISCUSSION AND CONCLUSION: The potential benefits of appropriate screening with measurement instruments are considered to be high for rheumatism patients. The measurement tools presented must be suitably selected for the individual purpose and for each rheumatology institution. In view of test application consideration must be given not only to the total score but also to the individual responses to test items. In cases of conspicuous test results the further approach must be agreed together with the patient and by choosing adequate treatment options for the situation. In cases of acute suicidal tendencies acceptance, care and support are of key importance, while the precautionary presentation in a specialist clinic must be initiated.