[Future of rheumatologists: what are the perspectives? : Survey of resident physicians in rheumatology in middle Germany]. / Rheumatologin/Rheumatologe in spe: Wie geht es weiter? : Befragung der rheumatologischen Assistenzärzte und -ärztinnen in Mitteldeutschland.

BACKGROUND AND OBJECTIVE: The work environment for rheumatologists has significantly changed over the last years. The healthcare of patients with rheumatic diseases is at risk due to the age structure of specialized rheumatologists in middle Germany and the limited availability of training positions for rheumatologists. In this context, it is important to have detailed information on the resident physicians in rheumatology concerning their own visions regarding their future professional career. MATERIAL AND METHODS: A questionnaire was sent to resident physicians in 25 rheumatology training hospitals in the middle of Germany (Saxony, Saxony-Anhalt and Thuringia). The questionnaire was completed and returned by 27 participants (17 women and 10 men). RESULTS: Most of the participants (60%) aimed to qualify as a specialist in internal medicine followed by a specialization in rheumatology (altogether training for a minimum of 8 years). After finishing training 44% would prefer to work in an outpatient setting while 30% planned to work in a combined outpatient and clinical setting. Of the participants 48% would prefer to work as part-time rheumatologists and 74% (women 94% and men 40%) were interested in employment in an outpatient medical healthcare center. The compatibility of family and work as well as the work-life balance was considered to be highly relevant for the future professional life. CONCLUSION: Less than half of the participants intended to work exclusively in an outpatient setting after completing the training in rheumatology. In addition, the participants preferred a part-time employment with compatibility of professional and private life. Consequently, alternative models of employment should be created in rheumatology to be attractive for future physicians. On the other hand, the study revealed that the independent rheumatological practice has a lower priority for the young rheumatologists taking part in this survey.

[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.

High prevalence of anti-CD74 antibodies specific for the HLA class II-associated invariant chain peptide (CLIP) in patients with axial spondyloarthritis.

OBJECTIVES: The pathogenesis of axial spondyloarthritis (axSpA) is still unclear. There is a strong association with HLA-B27 and other genes. Recently, anti-CD74 antibodies with specificity to a class II-associated invariant chain peptide (anti-CLIP-ABs) were found in axSpA patients. We examined the prevalence, sensitivity and specificity of anti-CLIP-ABs in axSpA in comparison with controls. METHODS: Sera of axSpA and non-SpA patients were analysed for IgG-antibodies against CD74 by ELISA with specificity for CLIP developed in cooperation with AESKU Diagnostics (Germany). A cut-off of ≥4 SDs of arbitrary units (AU) from mean serum levels was used to differentiate the results. The laboratory workers were completely blinded for clinical data. RESULTS: We analysed 145 sera from 94 axSpA and 51 non-SpA patients. AxSpA patients were more often male and younger. HLA-B27 status was available in 72 patients. Anti-CLIP-ABs were detected in 85.1% in axSpA but in only 7.8% in non-SpA patients (p≤0.0001). AxSpA patients showed higher levels of anti-CLIP-ABs versus non-SpA: mean 14.5 versus 0.8 AU (p≤0.0001). The sensitivity of anti-CLIP-ABs for diagnosing axSpA was 85.1%, specificity 92.2%, likelihood ratio (LR) LR+ was 10.8 and LR- was 0.08. Anti-CLIP-ABs and HLA-B27 were positive in 87.5% patients with axSpA, but only 14.9% were anti-CLIP-negative, while 23.6% were HLA-B27-negative. CONCLUSIONS: Anti-CLIP antibodies were strongly associated with axSpA. The LR for confirming axSpA by using anti-CLIP was even higher than by using HLA-B27. More studies using this promising new method in patients with non-radiographic axial SpA or peripheral SpA are needed to establish its usefulness in clinical practice.

Which spinal lesions are associated with new bone formation in patients with ankylosing spondylitis treated with anti-TNF agents? A long-term observational study using MRI and conventional radiography.

OBJECTIVE: To study the relationship of spinal inflammation and fatty degeneration (FD) as detected by MRI and new bone formation seen on conventional radiographs (CRs) in ankylosing spondylitis (AS). METHODS: CRs at baseline, 2 years and 5 years and spinal MRIs at baseline and 2 years of 73 AS patients treated with infliximab in European AS Infliximab Cohort were available. Relative risks (RR) were calculated with a general linear model after adjustment for within-patient variation. RESULTS: In a total of 1466 vertebral edges (VEs) without baseline syndesmophytes, 61 syndesmophytes developed at 5 years, the majority of which (57.4%) had no corresponding detectable MRI lesions at baseline. VEs with both inflammation and FD at baseline had the highest risk (RR 3.3, p=0.009) for syndesmophyte formation at 5 years, followed by VEs that developed new FD or did not resolve FD at 2 years (RR=2.3, p=0.034), while inflammation at baseline with no FD at 2 years had the lowest risk for syndesmophyte formation at 5 years (RR=0.8). Of the VEs with inflammation at baseline, >70% resolved completely, 28.8% turned into FD after 2 years, but only 1 syndesmophyte developed within 5 years. CONCLUSIONS: Parallel occurrence of inflammation and FD at baseline and development of FD without prior inflammation after 2 years were significantly associated with syndesmophyte formation after 5 years of anti-tumour necrosis factor (TNF) therapy. However, the sequence 'inflammation-FD-new bone formation' was rarely observed, an argument against the TNF-brake hypothesis. Whether an early suppression of inflammation leads to a decrease of the risk for new bone formation remains to be demonstrated.

[SAPHO syndrome]. / SAPHO-Syndrom.

The SAPHO syndrome, an acronym for synovitis, acne, pustulosis, hyperostosis and osteitis, is a rare disease which affects bones, joints and the skin. The main osteoarticular features are hyperostosis and osteitis. Osteoarticular symptoms predominantly occur on the anterior chest wall but the spine and the peripheral skeleton can also be involved. The most important skin affections are palmoplantar pustulosis and severe acne. The etiology of this syndrome remains unclear but infectious, immunological and genetic factors are involved. The diagnostic features of SAPHO syndrome are clinical and radiological. The most important diagnostic procedure is Tc-99 m bone scintigraphy but conventional x-rays as well as computed tomography (CT) and magnetic resonance imaging (MRI) can also contribute to the final diagnosis. Bone histology and positron emission tomography CT (PET-CT) may help to differentiate SAPHO syndrome from malignancies and infectious osteomyelitis. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the cornerstone of treatment. The results obtained using antibiotics and disease-modifying antirheumatic drugs (DMARDs), such as sulfasalazine and methotrexate are inconsistent. Bisphosphonates and anti-tumor necrosis factor (anti-TNF) drugs have shown promising results in small studies but further research is still necessary.

[What is ascertained in the therapy of axial spondyloarthritis?]. / Was ist gesichert in der Therapie der axialen Spondyloarthritis?

The new term axial spondyloarthritis (axSpA) includes classic ankylosing spondylitis and non-radiographic (nr-) axSpA. The definition was introduced in 2009 as part of the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA, where-apart from chronic back pain starting before the age of 45 years and the presence of HLA-B27-magnetic resonance imaging demonstrated bone marrow edema of the sacroiliac joints (osteomyelitis) or structural changes on x-rays may play an important role. These criteria can also be used for diagnosis. A major advantage of the new criteria is the identification of patients in early disease stages. In addition to physical therapy, drug treatment with steroidal anti-inflammatory agents (NSAIDs), corticosteroid injections, and biologics [blocker of tumor necrosis factor (TNF)] have all been shown to be effective, while conventional disease modifying drugs (DMARDs) such as sulfasalazine and methotrexate seem to work mainly for peripheral arthritis but not for enthesitis. Biologics are indicated when NSAIDs in optimal dosage have failed. Both these drugs have the potential to improve pain, stiffness, and function but they may also have an influence on new bone formation (syndesmophytes). NSAIDs need to be given continuously and biologics for longer periods of time. Patients with elevated C-reactive protein levels benefit most when treated consequently.

[Practical problems by implementation of vaccination recommendations]. / Praktische Probleme bei der Umsetzung von Impfempfehlungen.

Patients with inflammatory rheumatic diseases are known to have an increased risk of infections due to the rheumatic disease itself and due to therapy with immunosuppressive agents. The most important procedure to prevent infections is vaccinations, which are usually well-tolerated. The German National Commission for Immunization ( STIKO) has published recommendations for patients with an immunodeficiency. The German Society of Rheumatology (DGRh) has generally implemented these recommendations for patients with chronic inflammatory rheumatic diseases. The immunization status of patients with rheumatic diseases is of increasing importance in routine patient care because some of the recently approved drugs may influence the strength of the immune response to vaccination. However, there is almost no information about the current immunization status and the willingness of patients with rheumatic diseases to undergo vaccination procedures in Germany. There are also no epidemiologic data on the implementation of recommendations for immunization at the level of general practitioners. Here we present the results of a prospective study on the efficacy of standardized recommendations for immunization given to different patient groups with rheumatic diseases treated in a hospital specialized in rheumatology.

Treatment of active ankylosing spondylitis with abatacept: an open-label, 24-week pilot study.

OBJECTIVE: To prospectively explore the short-term efficacy and safety of abatacept in patients with ankylosing spondylitis (AS). METHODS: In this prospective open-label pilot study, abatacept (10 mg/kg) was administered intravenously on days 1, 15, 29 and every 28 days thereafter up to week 24 in 15 tumour necrosis factor α (TNFα)-inhibitor naive patients (group 1) and 15 patients with inadequate response to TNFα inhibitors (group 2) with active AS. The primary end point was the proportion of patients with 40% improvement according to the Assessment of SpondyloArthritis international Society criteria (ASAS40) in both groups at week 24. RESULTS: At week 24, ASAS40 was reached by 13% of group 1 and 0% of group 2; 20% improvement (ASAS20) was reached by 27% and 20%, respectively. There was no significant change of Bath Ankylosing Spondylitis Disease Activity Index score, patient global assessment or C reactive protein. Overall, abatacept was well tolerated. CONCLUSIONS: In this pilot open-label AS study a major response was not observed.

The European ankylosing spondylitis infliximab cohort (EASIC): a European multicentre study of long term outcomes in patients with ankylosing spondylitis treated with infliximab.

OBJECTIVES: To study the long-term efficacy and safety of treatment with infliximab in patients with ankylosing spondylitis (AS) in a real life setting. METHODS: AS patients from 6 European countries who had finished the 2-year trial ASSERT were invited to participate in the open- label investigator-driven study EASIC. At baseline, 2 groups were formed: patients of group 1 had not been treated with infliximab after ASSERT, while those of group 2 had continuously received it. Patients of group 1 were further subdivided in group 1a: patients with a relapse and 1b: in remission. All patients of group 1a and 2 continuously received infliximab for 96 weeks, mean dose 5 mg/kg, intervals 6-8 weeks. Patients of group 1b were also treated in case of relapse. RESULTS: A total of 103/149 patients (69%) were included in EASIC, 1.3 ± 0.9 years after the end of ASSERT: 9 in group 1a, 5 in group 1b and 89 in group 2. Most patients were male (83%), mean age 44 years. Most patients of group 2 completed the trial (86%) vs. only 5 of group 1 (33%) - mostly due to allergic reactions after readministration of infliximab. In total, there were 22 drop-outs due to 6 adverse events, 4 lack of efficacy, 3 planned pregnancy. All standard assessments indicated beneficial values over time, at week 96 significantly better than at baseline of ASSERT. CONCLUSIONS: The majority of patients were continuously and successfully treated with infliximab for 5 years, whereas discontinuation and reintroduction of therapy was less satisfactory due to the frequent occurrence of hypersensitivity reactions. Anti-TNF therapy with infliximab proved to be effective and safe on a long-term basis.

Different response to rituximab in tumor necrosis factor blocker-naive patients with active ankylosing spondylitis and in patients in whom tumor necrosis factor blockers have failed: a twenty-four-week clinical trial.

OBJECTIVE: Histologic studies have shown B cell clusters in the subchondral bone marrow of the spine of patients with ankylosing spondylitis (AS). An immunotherapy targeting B cells in AS is therefore of interest. We undertook this study to examine the efficacy and safety of rituximab in patients with AS refractory to nonsteroidal antiinflammatory drugs in whom previous treatment with tumor necrosis factor alpha (TNFalpha) blockers either had not been tried or had failed. METHODS: In this phase II clinical trial, 1,000 mg rituximab was administered intravenously at baseline and at week 2 in 20 patients with active AS. Ten of these patients had never received TNF blockers, and treatment with TNF blockers had failed in the other 10 patients. The primary end point was a 20% improvement in disease activity at week 24 according to the criteria of the Assessment of SpondyloArthritis international Society (an ASAS20 response). RESULTS: Seventy-five percent of the patients were male, 90% were HLA-B27 positive, their mean age was 39.7 years, and their mean disease duration was 16.8 years. Patients had active disease, defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score >or=4. While there was no clear response at week 24 in the group in whom TNF blockers had failed (30% had achieved an ASAS20 response, 10% had achieved an ASAS40 response, none had achieved partial remission according to the ASAS criteria, and none had achieved 50% improvement on the BASDAI [a BASDAI50 response] beyond an expected placebo response), we observed a good improvement in the TNF blocker-naive group at week 24 (50% had achieved an ASAS20 response, 40% had achieved an ASAS40 response, 30% had achieved partial remission according to the ASAS criteria, and 50% had achieved a BASDAI50 response). CONCLUSION: Although rituximab does not seem to be effective in patients with AS that does not respond to TNF blockers, it had significant efficacy in TNF blocker-naive patients. Therefore, further controlled trials with B cell-directed therapies should be performed in TNF blocker-naive AS patients in the future.

[Perioperative use of biologicals in rheumatoid arthritis]. / Perioperativer Umgang mit Biologika bei rheumatoider Arthritis.

The high prevalence of patients with rheumatoid arthritis (RA) treated with biologics and the high proportion of RA patients requiring elective orthopaedic surgery indicates that the question of whether to continue or to interrupt biologic therapy in the context of a surgical procedure is a clinically relevant problem. Few data are available and the quality of the studies performed is somewhat limited. Thus, a straightforward recommendation on how this problem should be handled cannot be given on this basis. Therefore, individualized management based on risk stratification for postoperative complications seems currently to be the best solution.

Perioperative use of methotrexate.

Methotrexate (MTX) is the disease modifying antirheumatic 'anchor' drug for the treatment of patients with rheumatoid arthritis (RA). Despite its widespread use and the frequent need of elective orthopaedic and other types of surgical procedures in patients with RA, some confusion exists concerning the use of MTX in the perioperative period. Currently available data do not suggest a need to discontinue MTX because of surgery. There is some evidence that treatment with MTX is safe prior to and after elective surgical procedures. Importantly, disease activity is better controlled when MTX is not interrupted from weekly administration.

Long-term efficiency of infliximab in patients with ankylosing spondylitis: real life data confirm the potential for dose reduction.

OBJECTIVE: To analyse the treatment outcome of patients with ankylosing spondylitis (AS) in the European AS infliximab cohort (EASIC) study after a total period of 8 years with specific focus on dosage and the duration of intervals between infliximab infusions. METHODS: EASIC included patients with AS who had received infliximab for 2 years as part of the ASSERT trial. After that period, rheumatologists were free to change the dose or the intervals of infliximab. Clinical data were status at baseline, end of ASSERT and for a total of 8 years of follow-up. RESULTS: Of the initially 71 patients with AS from EASIC, 55 patients (77.5%) had completed the 8th year of anti-tumour necrosis factor (TNF) treatment. Of those, 48 patients (87.3%) still continued on infliximab. The mean infusion interval increased slightly from 6 to 7.1±1.5 weeks, while 45.8% patients had increased the intervals up to a maximum of 12 weeks. The mean infliximab dose remained stable over time, with a minimum of 3.1 mg/kg and a maximum of 6.4 mg/kg. In patients receiving <5 mg/kg infliximab, the mean infusion interval increased to 7.0±1.2 weeks. In total, the mean cumulative dose per patient and per year decreased from 3566.30 to 2973.60 mg. CONCLUSIONS: We could observe that over a follow-up of 8 years of treatment with infliximab, >85% patients still remained on the same treatment, without any major safety events. Furthermore, both the infusion intervals and also the mean infliximab dose were modestly reduced in ≥70% of the patients without the loss of clinical efficiency.

[Generalized osteoarthritis in a young adult with type II collagenopathy]. / Generalisierte Arthrose im jungen Erwachsenenalter bei Typ-II-Kollagenopathie.

HISTORY AND ADMISSION FINDINGS: In the 20-year-old patient increasing arthralgia since the age of seven years had caused functional impairment. As seronegative osteodestructive rheumatoid arthritis had been suspected, he was treated with methotrexate and steorid for ovemore than one year, without success.r INVESTIGATIONS: The clinical examination revealed a compromised function of the knee and hip joints. Conventional radiographs showed severe degenerative changes in these regions. The radiographs of the lumbar and the thoracic spine were suggestive of osteoporotic fractures. DIAGNOSIS, TREATMENT AND COURSE: The clinical and radiological findings led to the suspicion of a hereditary collagenous disease. Genetic analyses revealed a COL2A1 mutation. The treatment included analgesics, non-steroidal antirheumatic drugs, opiates and regular physiotherapy to build up and maintain muscle strength. CONCLUSION: In young adult patients with osteoarthritis mutations in the COL2A1 gene should considered. This mutation with the substitution pArg75Cys should be in focus because of the phenotypes in clinical manifestations.

[A 46-year-old-patient with granulomatous prostatitis, arthralgia and haemorrhagic rhinitis]. / 46-jähriger Patient mit granulomatöser Prostatitis, Arthralgien und blutiger Rhinitis.

HISTORY AND ADMISSION FINDINGS: A 46-year-old, having developed developed gross haematuria and pain in the genital region, was referred to a urological unit. Because palpation of his prostatic gland was abnormal, a transurethral prostatic resection was performed. The histology showed a necrotizing and granulomatous inflammation of the prostate with small-vessel vasculitis and eosinophilic infiltrates. As the patient had also developed arthralgia and symptoms in the upper respiratory tract, he was admitted to our hospital. The test for c-ANCA with specifity for proteinase 3 was positive. There was no history or symptoms of asthma. DIAGNOSIS: Wegener's granulomatosis. TREATMENT AND COURSE: To achieve remission bolus therapy with cyclophosphamide and prednisolone was initiated and planned to be the first of three pulses But when the patient developed epididymitis and a neuropathy associated with Wegener"s granulomatosis, the dose was increased and cyclophosphamide was given for a longer period. CONCLUSION: The early manifestation of Wegener"s granulomatosis at the prostatic gland is rare in this disease. This case presented with an impressive variation of symptoms, which may occur especially in the early course of vasculitis. The findings of c-ANCA with specifity for proteinase 3 is important for the diagnosis of this disease.