Different risk profiles of biologic agents for new-onset psoriasis in patients with rheumatoid arthritis.

OBJECTIVE: To investigate rates and risk factors for incident and recurrent psoriasis in rheumatoid arthritis (RA) patients treated with different biologic (b) and conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs). METHODS: RA patients enrolled in the German biologics register RABBIT without (n = 14,525) or with a history of psoriasis (n = 375) were analyzed separately. All first events of psoriasis reported until October 2017 were assigned to the treatments prescribed in the previous 3 months. Crude incidence rates (IR) of psoriasis were calculated per 1000 patient-years. To investigate risk factors for psoriasis, cox regressions with and without inverse probability weights were applied to adjust for confounding by indication. RESULTS: 117 incident and 37 recurrent psoriatic events were reported. Patients exposed to TNFi had a significantly higher incidence rate (IR = 3.04/1,000 PY) than those exposed to csDMARDs only (IR = 0.65), whereas IRs for abatacept, rituximab and tocilizumab did not differ significantly from csDMARDs. Adjusted Cox regression confirmed a higher risk for TNFi. Female sex (HR: 1.7) and smoking (HR: 2.1) were significantly associated with incident psoriasis while methotrexate decreased the risk (HR: 0.5). For recurrent psoriasis, IRs for TNFi, abatacept and rituximab were significantly higher than for csDMARDs. CONCLUSIONS: Our data confirm a previously observed increased risk of incident psoriasis in patients exposed to TNFi compared to csDMARDs. However, the overall risk is low and the event is usually non-serious. Comedication of TNFi with methotrexate seems to lower the risk of incident psoriasis. In patients with a history of psoriasis, recurrence as adverse event is rare.

[Outpatient specialist medical treatment (ASV)-a new treatment level in rheumatology]. / Ambulante spezialfachärztliche Versorgung (ASV) ­ eine neue Versorgungsebene in der Rheumatologie.

Since April 2018, the new third level care model of outpatient specialist care (ASV) according to §116b of the Social Code Book V (SGBV) has been available for patients with chronic inflammatory rheumatic diseases in Germany. Not only is a multiprofessional cooperation between the disciplines involved in treating rheumatic diseases promoted but also the cooperation between specialized rheumatologists and other specialists in private practice and in hospitals is encouraged. As budget capping limiting services and number of cases do not apply in ASV, a significant improvement of patient care in rheumatology is expected due to an increase in provider capacity. At the end of May 2019, 72 rheumatologists in the first 9 newly approved ASV teams had qualified for this new care concept. Bureaucratic obstacles have so far delayed the implementation of ASV. Difficulties arose in building a team with different specialties, in the process of registration of the teams and the assessment of the registration by certain regional boards responsible for access control. The national associations of rheumatologists, the Professional Association of German Rheumatologists (BDRh), the VRA (Verband der Rheumatologischen Akutkliniken e. V.) and the German Society of Rheumatology (DGRh) campaign for an easier admission of providers to the ASV and for adequate financing of all specialties involved in the ASV. The aim is to realize the chance of the ASV for better rheumatological care nationwide with shorter waiting times for a medical appointment and a better cooperation between specialists.

[Inpatient rheumatology treatment in Germany]. / Stationäre rheumatologische Versorgung in Deutschland.

Acute inpatient treatment plays an important role in the care of patients with rheumatic diseases in Germany. Inpatient facilities are usually departments in general hospitals or highly specialized clinics. The introduction of the diagnosis-related groups (DRG) system has led to a change in form which is most obviously characterized by more homogeneous structures and shorter hospital stays. Many rheumatic patients are, however, treated in general hospitals due to a lack of specialized clinics. The presence of a department of rheumatology in medical schools is deficient which therefore leads to only a small number of specialists in rheumatology. The rheumatologists in inpatient facilities are also involved in the care of outpatients, whereby the number of licensed internal medical rheumatologists is declining. Further possibilities in outpatient treatment in hospitals were created with new governmental regulations (§116b). Changes are expected with the implementation of the new outpatient specialist medical care (ASV).

[Diagnostic spectrum, treatment indication and symptom duration in initial referrals to the rheumatologist]. / Diagnosespektrum, Behandlungsindikation und Symptomdauer von Erstzuweisungen zum Rheumatologen.

There is evidence that early initiation of therapy in inflammatory rheumatic diseases, in particular rheumatoid arthritis (RA), has a positive effect on disease course.To investigate referral procedures, 198 German rheumatologists reported over a 3-month period and for each patient seen for the first time on: patient characteristics, specialization of the referring physician, symptom duration, time interval between making the appointment and the first visit, diagnoses and relevant drug history. Multivariate logistic regression analyses were performed to investigate the odds ratios for a first consultation within 3 months after symptom onset.The 17,908 newly referred adult patients were 54 years old on average and 72% were women. Inflammatory rheumatic disease was diagnosed in 53%. Mean disease duration was 30 ± 57 months (median 7.3 months). There was no apparent association between patient age, education, disease severity or specialisation of the referring physician; however, there was a clear association with waiting times to first consultation.A higher number of early arthritis clinics could significantly shorten the time to first rheumatological consultation. Therefore, more efforts need to be made to fast-track referrals from primary care physicians to rheumatologists as well as to optimise rheumatologists' appointment regulations for new patients. However, these efforts can only succeed with a significant increase in the number of rheumatologists, while ensuring a firm economic basis.

Mass spectrometric and peptide chip epitope analysis on the RA33 autoantigen with sera from rheumatoid arthritis patients.

As the potential of epitope chips for routine application in diagnostics relies on the careful selection of peptides, reliable epitope mapping results are of utmost interest to the medical community. Mass spectrometric epitope mapping in combination with peptide chip analysis showed that autoantibodies from patients who suffered from rheumatoid arthritis (RA) were directed against distinct surface structures on the full-length human autoantigen RA33 as well as against partial sequences. Using the combined mass spectrometric epitope extraction and peptide chip analysis approach, four sequence motifs on RA33 emerged as immuno-positive, showing that epitopes were not randomly distributed on the entire RA33 amino acid sequence. A sequential epitope motif ((245)GYGGG(249)) was determined on the C-terminal part of RA33 which matched with the Western blot patient screening results using the full-length protein and, thus, was regarded as a disease-associated epitope. Other epitope motifs were found on N-terminal partial sequences ((59)RSRGFGF(65), (111)KKLFVG(116)) and again on the C-terminal part ((266)NQQPSNYG(273)) of RA33. As recognition of these latter three motifs was also recorded by peptide chip analysis using control samples which were negative in the Western blot screening, these latter motifs were regarded as "cryptic epitopes". Knowledge of disease-associated epitopes is crucial for improving the design of a customized epitope peptide chip for RA and mass spectrometric epitope mapping pivotally assisted with selecting the most informative peptide(s) to be used for future diagnostic purposes.

Rheumatoid pneumoconiosis (Caplan's syndrome).

In 1953, Caplan described a characteristic radiographic pattern in coal miners with rheumatoid arthritis (RA) that was distinct from the typical progressive massive fibrosis pattern of coalworkers' pneumoconiosis. It consists of multiple well-defined rounded nodules on chest X-ray, from about 0.5 to about several centimetres in diameter, distributed throughout the lungs but predominantly at the lung periphery. Lesions appear often in crops, may coalesce and form a larger confluent nodule. Nodules often cavitate or calcify. They typically occur in the setting of pre-existing mild pneumoconiosis, but pneumoconiosis is not a prerequisite. The onset of the nodules is typically sudden, and their course varies thereafter, ranging from regression to progression. Histologically, the nodules have a characteristic appearance and are distinguishable from silicotic nodules or progressive massive fibrosis. Individual susceptibility is considered to play a role in the development of the disease. However, the pathogenetic link between exposure to silica, pneumoconiosis and RA has not been clarified conclusively. This review summarizes history, definition and current knowledge on epidemiology, pathology, pathophysiology, clinical presentation and treatment of Caplan's syndrome.

Patient-reported outcomes improve with etanercept plus methotrexate in active early rheumatoid arthritis and the improvement is strongly associated with remission: the COMET trial.

OBJECTIVES: To compare the effects of etanercept (ETN) 50 mg once weekly plus methotrexate (MTX) versus MTX alone on patient-reported outcomes (PROs) and the relationship between remission and PRO improvement. METHODS: In this double-blind, randomised clinical trial (COMET), PROs included: the Health Assessment Questionnaire (HAQ), EuroQoL health status, fatigue and pain visual analogue scales, Hospital Anxiety and Depression Scale, and Medical Outcomes Short-Form-36. Mean changes from baseline were analysed by analysis of covariance using the last observation carried forward method. Results from week 52 are presented. RESULTS: Most PROs demonstrated significantly greater improvements with ETN+MTX than MTX alone, including physical functioning, pain, fatigue and overall health status. A significantly greater improvement in HAQ score was observed in the ETN+MTX than the MTX group (-1.02 vs -0.72; p<0.001) and a greater proportion reached the minimal clinically important difference of 0.22 (88% vs 78%; p<0.006). The relationship between PRO score and clinical status indicated that improvement was greatest among patients achieving remission. CONCLUSIONS: Early treatment with ETN+MTX leads to significantly greater improvements in multiple dimensions of PROs than MTX alone. The close relationship between disease activity and PRO improvement suggests that early treatment, with remission as a goal, should maximise the chance of restoring normal functioning and HRQoL.

["TRECID", TNFalpha related chronic inflammatory diseases - a new multiple diseases bridging concept]. / "TRECID": TNFalpha-assoziierte chronisch entzündliche Erkrankungen - Eine neue Krankheits-übergreifende Sichtweise.

The pro-inflammatory cytokine TNF alpha (TNF) has a key position in the pathogenesis of various infectious and inflammatory diseases. Clarification of its pivotal role in the pathogenesis of rheumatoid arthritis, spondyloarthritis, uveitis, psoriasis and inflammatory bowel disease has resulted in the successful development of TNF- blocking therapies, which have disease-modifying properties that exceed the effects of conventional therapeutic options. For this reason data on the concurrence of several chronic inflammatory diseases have led to the hypothesis of common pathogenetic processes of cytokine dysregulation. The acronym TRECID describes this concept of "TNF RElated Chronic Inflammatory Diseases". Physicians of different specialties have integrated new therapeutic options with TNF-blocking therapies into their strategies for the management of the affected patients. Thus the concept of TRECID can be regarded as a role model for a dynamic, interdisciplinary cooperation based on shared pathophysiological aspects.

[Bone densitometry in inflammatory rheumatic diseases : Characteristics of the measurement site and disease-specific factors]. / Knochendichtemessungen bei entzündlich-rheumatischen Erkrankungen : Besonderheiten der Messorte und krankheitsspezifische Einflussfaktoren.

Bone densitometry should be performed earlier in patients with inflammatory arthritis, since factors such as inflammation and drug therapy, in particular treatment with glucocorticoids, have an important impact on the development of osteoporosis. DXA (Dual energy X-ray Absorptiometry) is considered the gold standard for bone densitometry. According to the German guidelines for osteoporosis, bone densitometry plays a crucial role in the choice of therapy.In patients with rheumatoid arthritis, measurement of peripheral bone (forearm) density in addition to lumbar spine and hip is recommended, since local bone loss is pathognomonic for this disease. DXA measurements of the hand enable the diagnosis of juxtaarticular osteoporosis at an earlier stage; however, this has not yet been established in routine practise.Bone measurement in patients with ankylosing spondylitis can be performed in the lumbar spine and the hip at disease onset. In systemic lupus erythematosus, bone loss is more frequent in patients with high inflammatory activity. Patients with psoriasis arthritis frequently have osteoporosis in the case of a destructive development of the joints.

[Possibilities and limitations of genomic analyses in rheumatoid arthritis]. / Möglichkeiten und Grenzen genomischer Analysen bei rheumatoider Arthritis.

The application of genetic analyses in the molecular diagnosis of patients with rheumatoid arthritis (RA) has experienced an enormous increase in recent years. Despite significant growth in experimental data there is no direct benefit for the individual patient as yet. The search for validated genetic diagnostic markers is currently being continued by genome-wide association studies. Hopefully, by combining multiple genetic markers a genetic profile can be generated which will enable prediction of the risk for RA, the disease course and response to certain therapies.

Comparative effectiveness of tumour necrosis factor alpha inhibitors in combination with either methotrexate or leflunomide.

OBJECTIVE: The objective of this study was to compare the effectiveness of a combination of tumour necrosis factor alpha (TNFalpha) inhibitors with either methotrexate or leflunomide in the treatment of patients with rheumatoid arthritis in a real-world setting. METHODS: Data from 1769 outpatients enrolled in the German biologics register RABBIT who were treated with one of the TNFalpha inhibitors adalimumab, etanercept, or infliximab in combination with either methotrexate (n = 1375) or leflunomide (n = 394) were included in the analysis. Clinical status including disease activity as well as treatment data were documented by the treating rheumatologist at baseline and at 3, 6, 12, 18, 24, 30 and 36 months of follow-up. RESULTS: Patients treated with a combination of biologics with leflunomide had significantly higher baseline disease activity than those treated with methotrexate. The highest disease activity was found for patients treated with the combination infliximab/leflunomide. After 36 months, the discontinuation rates were 46.3%, 51.3% and 61.5% for combinations of etanercept, adalimumab and infliximab with methotrexate and 53.4%, 63.1% and 67.1% for combinations with leflunomide, respectively. European League Against Rheumatism response rates after 24 months ranged from 74% to 81% for combinations with methotrexate and 72% to 81% for combinations with leflunomide. CONCLUSION: The current clinical practice is to use methotrexate as a first choice for the combination with TNFalpha antagonists. In a number of patients methotrexate has to be replaced by another disease-modifying antirheumatic drug. Our data support the view that leflunomide is a useful alternative if methotrexate is contraindicated.

[Current status of ambulatory rheumatologic health care in Germany. Structure of health care and range of services]. / Bestandsaufnahme der ambulanten rheumatologischen Versorgung in Deutschland. Versorgungsstruktur und Leistungsspektrum.

AIM: To gather information on current organizational structures in rheumatologic ambulatory health care in Germany. Based on the results recommendations on future structures will be discussed. METHODS: This study involved data collection and statistical analysis via a structured 10-page questionnaire among the members of the German Association of Rheumatologists. The questions concerned a variety of topics including information on office structures, patient structure, structure of services offered, co-operation with colleagues and hospitals, quality assurance measures, economic factors, and a subjective assessment of the health care structures in rheumatology by the participants. RESULTS: Data obtained from 197 rheumatologists who participate in health care were analyzed. In this paper results concerning the organizational as well as the medical ambulatory health care structure will be presented. Data on economic factors will be presented in part 2 of this study. CONCLUSIONS: The organization of ambulatory treatment regarding processes and treatment differences between office-based physicians and rheumatologic outpatient departments in hospitals was very homogeneous. However, physicians in the eastern regions treated significantly more patients compared with the western parts of Germany. This difference was also observed between the north and south. Differences in patient groups (e.g. underlying diseases) were reported between different sub-groups of rheumatologists (e.g. internal specialists vs. GP vs. orthopedic rheumatologists). Integrated health care, as promoted by German social law, did not play a major role. Overall there was a high level of self-initiated training of physicians and participation in education of patients and other physicians.

[Current status and perspectives of ambulatory rheumatologic health care in Germany : economic structural conditions and motivation of rheumatologists]. / Bestandsaufnahme und Perspektiven der ambulanten rheumatologischen Versorgung in Deutschland : Okonomische Rahmenbedingungen und Motivation der Rheumatologen.

AIM: To gather information about current structures in rheumatologic ambulatory health care in Germany. Based on the results recommendations on future structures will be evaluated. METHODS: Data collection and statistical analysis via a structured 10-page questionnaire answered by members of the German Association of Rheumatologists. Questions in this second part of the study related to two topics: economic factors and a subjective assessment of the health care structures by the participants. RESULTS: Data from 197 ambulatory rheumatologists who participated in health care could be included in the analyses. Extensive and detailed data on economic issues surrounding ambulatory patient treatment and practice management from the perspective of ambulatory rheumatologists are presented (e.g., revenue, income, income differences between regions or practice size). In addition, perceptions of participating rheumatologists on future perspectives of patient treatment, health policy, and their own economical survival are reported. CONCLUSIONS: As in other specialties there is a significant difference not only between the eastern and western regions in Germany but also between the north and the south looking at e.g., revenue, income, with rheumatologists in the east treating significantly more patients. Reasons for those differences are not only related to regional remuneration schemes or the number of patients with a private but statutory health insurance, but are also driven by the number of different services provided (e.g., own laboratory). Physicians perceptions towards their own future in rheumatology are generally positive. Scepticism was reported for the individual economic survival in ambulatory treatment and future changes in health policy.

Treatment continuation in patients receiving biological agents or conventional DMARD therapy.

OBJECTIVE: To compare drug continuation rates in patients with rheumatoid arthritis who start on a biological agent and in a control group of patients with a change in disease modifying antirheumatic drug (DMARD) treatment after previous DMARD failure. METHODS: Patients with rheumatoid arthritis enrolled in the German biologics register between May 2001 and September 2003 were included in the study. Data were available for 511 patients treated with etanercept, 343 with infliximab, 70 with anakinra, and 599 controls. Propensity scores were used to select a subsample of patients from the control group who were likely to be treated with biological agents because of their disease severity, as well as comparable infliximab and etanercept cases. RESULTS: Treatment continuation after 12 months was similar for etanercept (68.6% (95% confidence interval, 62% to 75%)) and infliximab (65.4% (58% to 73%)) but lower for anakinra (59% (41% to 77%)). Treatment continuation was more likely for patients on combinations of biological agents and DMARDs than for those on infliximab or etanercept alone. Patients treated with biological agents were more severely ill than those in the control group and had more previous DMARD failures. After adjustment for baseline differences, the continuation rates were higher in patients treated with biological agents than in comparable control patients treated with leflunomide or leflunomide/methotrexate. CONCLUSIONS: Treatment continuation of biological agents in clinical practice is less likely than in randomised clinical trials but more likely than in comparable controls treated with conventional DMARDs.

Interleukin 10 promoter microsatellite polymorphisms are associated with response to long term treatment with etanercept in patients with rheumatoid arthritis.

OBJECTIVES: To analyse the association of interleukin 10 (IL10) promoter polymorphisms, which have been shown to be related to IL10 secretion capacity, with the response to long term treatment with etanercept in patients with rheumatoid arthritis (RA). METHODS: Fifty patients with active RA were treated for up to 4 years (median 39 months, range 3-52) with stable doses of etanercept as monotherapy. Treatment response was assessed as defined by the EULAR criteria in an intention to treat analysis, with the last observation carried forward. IL10 promoter microsatellite polymorphisms IL10.R and IL10.G were genotyped by fragment length analysis in patients and 189 healthy controls matched for ethnicity, age, and sex. Haplotypes were reconstructed using a method based on bayesian, coalescent theory with the PHASE software. RESULTS: IL10 microsatellite polymorphisms were not associated with susceptibility to RA. When patients with good treatment response (n = 25) were compared with patients with moderate (n = 17) or no response (n = 8), a significantly different distribution of the prevailing alleles R2, R3 and G9, G13, respectively, became evident. Good treatment response was associated with carriage of the R3 allele or R3-G9 haplotype, whereas the allele G13 and the haplotype R2-G13 predominated in patients with moderate or no response. CONCLUSION: Genotyping of the IL10 promoter microsatellites may be useful in predicting the clinical response to etanercept in patients with RA. The high prevalence of the presumptive IL10 low producer allele R3 in patients with a favourable response suggests that IL10 promotes disease activity in RA under the specific condition of tumour necrosis factor antagonism.

[Specialties in therapy of osteoporosis in inflammatory joint disease]. / Besonderheiten der Osteoporose-Therapie bei entzündlich-rheumatischen Erkrankungen.

The therapeutic specialties of osteoporosis in inflammatory rheumatic diseases has gained mounting interest in the last year. The paper describes special aspects of osteoporosis in rheumatoid arthritis, ankylosing spondylitis and systemic lupus erythematodes. The problems of glucocorticoid therapy are discussed intensively with regard to the recently published recommendations for glucocorticoid-induced osteoporosis. Risk factors of osteoporosis and the therapeutic implications are demonstrated intensively as well as the modifications of the recommendations.

Bone substitutes as carriers for transforming growth factor-beta(1) (TGF-beta(1)).

We studied the suitability of three different hydroxyapatite materials (Endobone, Bio-Oss and Algipore) as carriers for the bone growth promoting factor TGF-beta(1). The hydroxyapatite materials either were incubated for 24 h or directly loaded with hrTGF-beta(1) (Diagnostic Products Corporation, DPC) at a concentration of 10 ng hrTGF-beta(1)/mg. For the release experiment the hydroxyapatite materials covered with hrTGF-beta(1) were either suspended in pure phosphate buffered saline (PBS) or human serum albumin (HSA). The concentration of hrTGF-beta(1) was measured every 6 h the first day and then daily at the 2nd, 7th, 14th and 28th day. With Bio-Oss and Endobone the release of growth factor in HSA showed a two-phase kinetics. TGF-beta(1) reached a maximum concentration within the first 24 h and decreased almost linearly until day 28. With Algipore the concentration of growth factor reached a maximum after 12 h and showed a rapid decline until day 2. From day 2 the TGF-beta(1) concentrations remained low. Significantly, more TGF-beta(1) was released into HSA than into PBS. Our study suggests that the hydroxyapatite materials are suitable as TGF-beta(1) carriers.

Soluble tumour necrosis factor receptor treatment does not affect raised transforming growth factor beta levels in rheumatoid arthritis.

OBJECTIVE: To further elucidate the immunomodulating effects of anti-tumour necrosis factor alpha treatment in rheumatoid arthritis (RA) by studying changes in plasma levels of transforming growth factor beta (TGFbeta) in patients with RA undergoing etanercept treatment. METHODS: Plasma levels of TGFbeta1 and TGFbeta2 were determined in 26 patients with RA during six months of etanercept treatment and compared with disease activity and laboratory parameters, including matrix metalloproteinase-3 (MMP-3) and interleukin 6 (IL6). RESULTS: Before treatment all patients had raised TGFbeta1, IL6, and MMP-3 levels. In the course of treatment IL6 and MMP-3 levels decreased significantly, accompanied by a drop in serological markers (C reactive protein and erythrocyte sedimentation rate) and clinical disease activity (visual analogue scale and Thompson joint score). By contrast, high levels of latent TGFbeta1 were present in all specimens over the entire six months. TGFbeta2 levels did not change during treatment. CONCLUSION: Etanercept treatment induces subtle changes in the cytokine network. Although the proinflammatory cytokine IL6 is down regulated, the persistence of high TGFbeta plasma levels indicates the existence of as yet unknown mechanisms for TGFbeta overexpression in RA. This may predispose to severe infections and can cause an altered tumour defence.

WHO Collaborating Centre consensus meeting on anti-cytokine therapy in rheumatoid arthritis.

Severe adult rheumatoid arthritis is a cause of progressive disability and increased mortality across Europe. A cure for the disease remains elusive, but control of symptoms and maintenance of individual independence is possible. Anti-cytokine therapies offer a new approach to disease management. They are effective after the failure of full doses of methotrexate, and are at least as effective as methotrexate in retarding the progression of radiological changes. Until more is known about the long-term safety and efficacy of these drugs they should be reserved for patients with severe disease who are progressing despite adequate doses of methotrexate or other disease-modifying anti-rheumatic drugs. They should be continued until therapeutic failure or intolerance. A comprehensive health economic evaluation is needed to optimally direct the use of these drugs. This should be undertaken when long-term safety and efficacy studies are completed.