Horneff G Asklepios Clinic

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MD Gerd Horneff
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Improvement of functional ability in children with juvenile idiopathic arthritis by treatment with etanercept

M. Halbig, G.

INTRODUCTION

Juvenile Idiopathic Arthritis (JIA) is the most common chronic autoimmune disease in childhood. It results not only to painful and swollen joints but also to a limitation of functional ability and of everyday life in children [START_REF] Petty | Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997[END_REF][START_REF] Woo | Juvenile chronic arthritis[END_REF].

Etanercept, which inhibits TNF-alpha, is licensed for treatment of active, refractory polyarticular chronic arthritis in childhood. The introduction of biologics like etanercept had a major impact on the outcome of patients with polyarticular JIA. The safety and the efficiency of etanercept had been proved in open and controlled studies as well as in long term studies [START_REF] Lovell | Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group[END_REF][START_REF] Lovell | Long-term safety and efficacy of etanercept in children with polyarticular-course juvenile rheumatoid arthritis[END_REF][START_REF] Lovell | Safety and efficacy of up to eight years of continuous etanercept therapy in patients with juvenile rheumatoid arthritis[END_REF][START_REF] Horneff | The German etanercept registry for treatment of juvenile idiopathic arthritis[END_REF][START_REF] Kietz | Clinical response to etanercept in polyarticular course juvenile rheumatoid arthritis[END_REF][START_REF] Kietz | Therapeutic use of etanercept in polyarticular course juvenile idiopathic arthritis over a two year period[END_REF][START_REF] Horneff | Safety and efficacy of combination of Etanercept and Methotrexate compared to treatment with Etanercept only in patients with juvenile idiopathic arthritis (JIA). Preliminary data from the German JIA Registry[END_REF][START_REF] Lahdenne | Infliximab or etanercept in the treatment of children with refractory juvenile idiopathic arthritis: an open label study[END_REF][START_REF] Quartier | Efficacy of Etanercept for the treatment of juvenile idiopathic arthritis according to the onset type[END_REF][START_REF] Robinson | Quality-of-Life Measurements in Juvenile Rheumatoid Arthritis Patients Treated with Etanercept[END_REF][START_REF] Prince | Long-term followup on effectiveness and safety of etanercept in JIA: the Dutch national register[END_REF].

Several measures for functional ability in children with JIA were introduced in the past years.

Among those the Child Health Assessment Questionnaire (CHAQ) is the most common tool used to measure functional ability in children with JIA. The CHAQ is well established for the use in children with JIA [START_REF] Ruperto | Cross-cultural adaptation and psychometric evaluation of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ) in 32 countries. Review of the general methodology[END_REF] and is used as one of six core response variables in clinical drug trials [START_REF] Giannini | Preliminary definition of improvement in juvenile arthritis[END_REF][START_REF] Ruperto | Responsiveness of outcome measures in juvenile chronic arthritis[END_REF][START_REF] Ruperto | A randomized trial of parenteral methotrexate comparing an intermediate dose with a higher dose in children with juvenile idiopathic arthritis who failed to respond to standard doses of methotrexate[END_REF][START_REF] Van Rossum | A randomized, double-blind clinical trial of two doses of meloxicam compared with naproxen in children with juvenile idiopathic arthritis: Short-and long-term efficacy and safety results[END_REF](19)[START_REF] Ruperto | A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular course juvenile rheumatoid arthritis[END_REF]. It has been validated and evaluated in the German language [START_REF] Foeldvari | The German version of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ)[END_REF]. Furthermore, it has been shown to be a useful tool for evaluating outcome in longitudinal studies [START_REF] Duffy | Measurement of health status, functional status, and quality of life in children with juvenile idiopathic arthritis: clinical science for the pediatrician[END_REF][START_REF] Oliveira | Proxy-reported health-related quality of life of patients with juvenile idiopathic arthritis: the Pediatric Rheumatology International Trials Organization multinational quality of life cohort study[END_REF][START_REF] Bekkering | A comparison of the measurement properties of the Juvenile Arthritis Functional Assessment Scale with the childhood health assessment questionnaire in daily practice[END_REF].

The outcome of JIA is variable depending on the subgroup of JIA. In some subgroups many children experience spontaneous remission of their joint disease while in other subgroups persistent destructive arthritis frequently occurs. Clinical experience suggests that more children than expected have ongoing disease in adulthood. Though the physical outcome of patients with JIA is relatively good compared to adult patients with rheumatoid arthritis, many patients still have active disease in adulthood and health status and quality of life are reduced in patients with all types of JIA [START_REF] Foster | Outcome in adults with juvenile idiopathic arthritis: a quality of life study[END_REF]. Approximately half of the patients with JIA have changes in their body function and structure after disease duration of more than 15 years. Fortunately less than 10% are severely disabled or handicapped [START_REF] Minden | Long-term outcome in patients with juvenile idiopathic arthritis[END_REF].

The purpose of the present study was to evaluate the alteration of functional ability in children with JIA before and during treatment with etanercept. Eight areas of everyday life with impact on the functional ability were measured with the CHAQ: "dressing and grooming", "arising", "eating", "walking", "hygiene", "reach","grip" and "activities".

PATIENTS AND METHODS

Study design and Patients. Criteria for inclusion in our analysis were diagnosis of JIA subclasified into the 6 JIA subgroups according to the International League of Associations for Rheumatology (ILAR) criteria and registration in the German etanercept registry from 2001 until 2006 [START_REF] Woo | Juvenile chronic arthritis[END_REF]. In order to be eligible for treatment with etanercept, failure to respond or intolerance to methotrexate was required [START_REF] Horneff | Arbeitgemeinschaft Kinder-und Jugendrheumatologie. Recommendations by the Pediatric and Adolescent Rheumatology Study Committee on therapy with Etanercept (p75 TNF-alpha receptor immunoglobulin fusion protein). Pharmacotherapy Committee[END_REF]. Patient data were collected at start of therapy with etanercept and every six months during therapy. Data of 437 children were analyzed for disease severity and impact of the disease on functional abilities. Owing to the study-character not all criteria were available from every point in time from every patient. Data of 114 children with a complete data set and a continuous treatment for at least 24 months were used for analysis of the impact of treatment on functional abilities.

Functional ability.

The patient of at least 13 years of age or parents of patients younger than 13 years was asked to complete the CHAQ. The CHAQ includes 30 questions concerning 8 areas of daily living "dressing and grooming", "arising", "eating", "walking", "hygiene", "reach", "grip" and "activities". The response modalities range on a 4-point ordinary scale with 0 for "no difficulty", 1 for "some difficulties", 2 for "much difficulties" and 3 for "unable to do". An additional response modality, "not applicable for age", could be used if a child was too young for a certain activity. Besides the 30 items the CHAQ contains 14 questions related to the use of aids/devices plus 8 questions that are related to the child's need of help from another person. Each of the 8 areas is scored as the highest item in that area. If aids/devices or assistance from another person for one of the 8 CHAQ areas are required for an activity, the score is further corrected to at least 2 points for the corresponding area. The 8 areas of the CHAQ are averaged to calculate the CHAQ disability index (CHAQ DI) which ranges from 0 (no or minimal physical dysfunction) to 3 (very severe physical dysfunction).

Besides the 30 items the CHAQ includes a patient's or parent's global assessment of the overall patient's well-being in the previous week on a 0-10 cm visual analogue scale (VAS) (0=very well; 10=very poor) and a patient's or parent's global assessment of the child's pain in the previous week on a 0-10 cm VAS (0=no pain; 10=very severe pain).

JIA disease activity.

Efficacy was assessed with the PedACR30, 50 and 70 criteria including the German CHAQ. These core set parameters consisted of 1) physician global assessment of disease activity, on a 10-cm visual analogue scale (VAS); 2) parent/patient global assessment of overall well-being, on a 10-cm VAS; 3) the CHAQ; 4) the number of joints with active arthritis, defined by the presence of swelling or, if no swelling was present, limitation of motion accompanied by pain, tenderness, or both 5) the number of joints with limited range of motion; and 6) the erythrocyte sedimentation rate. The PedACR30 was reached if there was an improvement of ≥30% in at least 3 of 6 core variables, with no more than 1 of the remaining variables worsened by ≥30% [START_REF] Giannini | Preliminary definition of improvement in juvenile arthritis[END_REF].

Patients were also evaluated for improvement of ≥50% or ≥70% improvement in at least 3 of 6 core variables, with no more than 1 of the remaining variables worsened by ≥30% (PedACR50 and PedACR70). Other assessments not included in the PedACR score were the duration of morning stiffness, and serum C-reactive protein levels.

Statistical Analysis. Data were collected using Microsoft Excel and statistical analysis was processed with SPSS for windows 14.0. Continuous variables were evaluated with descriptive statistic analysis using means and SD.

Categorical variables were evaluated using frequencies and percentages.

Statistical tests included 1-way analysis of variance, Chi-Square test, Kruskal-Wallis test, ANOVA and GLM repeated measures. P values less than 0.05 were considered to be significant.

The dimension of functional limitation was categorized by a system proposed by [START_REF] Ruperto | Long-term health outcomes and quality of life in American and Italian inception cohorts of patients with juvenile rheumatoid arthritis. I. Outcome status[END_REF]. A CHAQ DI 0 implicates no disability, 0.1-0.5 implicates a mild disability, 0.6-1.5 implicates a moderate disability and >1.5 implicates a severe disability [START_REF] Ruperto | Long-term health outcomes and quality of life in American and Italian inception cohorts of patients with juvenile rheumatoid arthritis. I. Outcome status[END_REF]. The mean (±SD) disease duration before therapy with etanercept was 5.1±4.0 years. At start of therapy with etanercept the mean (±SD) age of the patients was 12.1 (±4.5) years. As expected, patients of the single JIA subgroups differed in part markedly from patients of other subgroups. Patients with seropositive (14.3±3.1 years) and seronegative polyarthritis (12.3±4.2 years), those with enthesitis related arthritis (15±2.9 years) and those with psoriasis arthritis (13.5±3.8 years) were older than patients with systemic arthritis (9.2±5.1 years) or persistent or extended oligoarthritis (10.0±4.7 years).

RESULTS

Until

High disease activity was reflected by high numbers of active joints, elevated ESR and C-reactive protein and a prolonged duration of morning-stiffness (table 1). Patients with polyarthritis had the highest numbers of active joints (13±10), patients with persistent oligoarthritis had the lowest numbers (3±2). Highest inflammatory parameters were observed in patients with systemic JIA (ESR 56±32 mm/h, C-reactive protein 73.2±66.0 mg/l). Morning stiffness was longest in patients with seropositive polyarthritis and in patients with extended oligoarthritis (51±63 min and 49±67 min), while patients with persistent oligoarthritis had the shortest duration of morning stiffness (3±5min). Among patients with JIA those with systemic arthritis and with seronegative polyarthritis most frequently needed aids/devices (mean number 3±4). Physician's global assessment of the overall disease activity was worst in patients with systemic arthritis (7.7±2.1 cm on a 10 cm VAS) as well as patients's/parent's global assessment of the overall patient's well-being (6.3 ±2.7 cm on a 10 cm VAS).

The mean (±SD) CHAQ DI of all patients was 0.9±0.7. This implicates a moderate disability according to the categorization of Ruperto et al. [START_REF] Ruperto | Responsiveness of outcome measures in juvenile chronic arthritis[END_REF]. Higher scores in the CHAQ DI were present in patients with systemic arthritis, seropositive or seronegative polyarthritis and extended oligoarthritis (p<0,0001 in the Kruskal Wallis test), patients with elevated ESR, C-reactive protein, patients with a large number of active joints, patients experiencing prolonged duration of morningsstiffness, those with higher scores in physician's global assessment of the overall disease activity and parent's global assessment of the overall patient's well-being and with the need of many aids/devices. Univariant analysis showed a significant correlation of the parameters of JIA-severity (number of active joints, duration of morning stiffness, parent's global assessment of the overall patient's well-being, need of aids/devices, physician's global assessment of the overall disease activity, CRP) with the CHAQ DI (p<0.005, table 1).

At start of treatment with Etanercept, the scores of the eight functional CHAQ areas varied (table 2). According to the classification by Ruperto et al. children had a moderate disability in most functional areas before etanercept therapy. The rheumatic disease had the greatest impact on "activities" (1.4 ±1.0), "reach" (1.1 ±0.9), "dressing and grooming" (1.0 ±1.0) and "grip" (1.0 ±1.0). "Eating" (0.7 ±0.9) and "walking" (0.7 ±0.9) were less affected. Patients with systemic arthritis and patients with enthesitis related arthritis had more severe disability while doing "activities" (1.6 ±1.1 and 1.6 ±1.0). "Eating" was easiest ("mild disabilities") for children with persistent oligoarthritis, enthesitis related arthritis, psoriasis and arthritis and extended oligoarthritis (0.1 ±0.4, 0.3 ±0.6, 0.4 ±0.8, 0.5 ±0.8). Children with persistent oligoarthritis had "mild disability" in all functional areas except for "activities" (0.9 ±0.9). Significant differences (p<0,005 in the Kruskal Wallis test) between the JIA-Subtypes were found for the CHAQ-areas "dressing and grooming", "eating", "hygiene", "reach" and "grip".

Therapeutic efficacy of the treatment with etanercept.

For analysis of the influence of treatment with etanercept on functional ability those patients were included who had been treated for at least 24 months and in whom a complete set of data was available. By this way, 114 patients could be identified. There was a significant improvement of the CHAQ DI before therapy to the CHAQ DI during therapy in the JIA population in the GLM repeated measures (p<0.0001). The mean±SD of the CHAQ DI before therapy was 0.92±0.77 (median 0.75).After six months of treatment the CHAQ DI decreased to a mean±SD of 0.39±0.53 (median 0.13) and after 18 months to a minimum of 0.32±0.5 (median 0, figure 1). At start of therapy the mean CHAQ DI corresponded to "moderate disability", after six months and thereafter to "mild disability" [START_REF] Ruperto | Long-term health outcomes and quality of life in American and Italian inception cohorts of patients with juvenile rheumatoid arthritis. I. Outcome status[END_REF].

Comparing the subtypes there were markedly higher CHAQ DI in patients with seropositive or seronegative polyarthritis than in other JIA subgroups as outlined in table 3. Seronegative polyarthritis patients were the largest patient group (n=33) in this analysis and remained with the highest CHAQ DI during etanercept therapy followed by patients with seropositive polyarticular JIA. Disability disappeared in the majority of patients leading to a decrease of the mean CHAQ DI.

At month 0, 6, 12, 18 and 24 the mean CHAQ DI in seronegative polyarticular JIA patients was 0.96, 0.68, 0.62, 0.53 and 0.57, in seropositive polyarticular JIA it was 1.0, 0.37, 0.36, 0.41 and 0.46. The CHAQ DI for patients with persistent oligoarthritis were the lowest at all points of time (0.25, 0.03, 0.05, 0.05 and 0.03 at 0, 6, 12, 18 and 24 months).

High disease activity was accompanied by large numbers of active joints, elevated ESR and Creactive protein, high scores in physician's global assessment of the overall disease activity, high scores in parent's global assessment of the overall patient's well-being and a prolonged duration of morning-stiffness and was reflected by a high CHAQ DI at start of therapy (table 1). Significant improvement in active joints, parent's global assessment of the overall patient's well-being, physician's global assessment of the overall disease activity, duration of morning stiffness, ESR and C-reactive protein was seen after 6, 12, 18 and 24 months (p<0.0001 for all parameters and all points of time) (table 4). Functional ability improved though parameters of disease activity were high before therapy. While high scores in active joints, CRP, ESR, parent's global assessment of the overall patient's well-being, physician's global assessment of the overall disease activity and morning stiffness were attended by high DI before therapy, patients reached lower levels of CHAQ DI during therapy.

At start of therapy with etanercept, those children treated with a combined therapy of methotrexate and etanercept had a higher CHAQ DI (0.9±0.79). However, they showed a marked improvement of Linking powered by eXtyles scores during therapy and reached after 24 months a minimum level of 0.33±0.52. Patients treated with etanercept monotherapy at start of therapy had a CHAQ DI of 0.72±0.61 which decreased to 0.34±0.53 after 24 months of treatment.

All functional areas of the CHAQ improved significantly during therapy with etanercept (p<0.0001) (figure 2). Before therapy children had most problems with "activities", "dressing and grooming", "reach" and "grip" (mean score of those areas 1.44, 1.12, 1.05, 0.94). These scores corresponded to "moderate disability". At 24 months of therapy the patients still had most problems with "activities", "reach", "dressing and grooming" and "grip" (mean score of those areas 0.61, 0.51, 0.44, 0.38). These levels of disabilities finally corresponded to "mild disability" in all functional areas except for "activities" with a "moderate disability".

Measuring therapeutic efficiency by the maximal improvement of the PedACR-Score reached during 24 month of therapy, 96.5%, 93.8% and 90.3% of the patients reached a PedACR-30, -50 and -70 score. Subtype analysis showed that 90.9%, 81.8% and 72.7% of the patients with systemic arthritis reached a Ped-ACR-30, -50 and -70 score which was somewhat lower than in children with non-systemic JIA, who reached a PedACR-30, -50 and -70 score with 97.1%, 95.1% and 92.2% of their patient-group (Figure 3).

In our patient population 8.8% of the patients discontinued the therapy due to inefficiency, 5.1% discontinued due to intolerance. About 7% discontinued treatment due to remission.

DISCUSSION

This study provides data about children who started treatment with etanercept in Germany between 2001 and 2006. Data of 437 children were analyzed for disease severity and impact of the disease on functional abilities. Data of 114 children with a complete data set and a continuous treatment for at least 24 months were used for analysis of the impact of treatment on functional abilities. Patients have still not been treated so far and could therefore not be included. Only a minority of 8.8% of patients of the registy cohort discontinued due to inefficacy, only 5.1% discontinued due to intolerance. About 7.0% discontinued treatment due to remission. The results confirm previous studies on the German etanercept registy (6; 9). The major gains of etanercept therapy were as follows:

-Children with long standing JIA had poor functional ability and high disease activity before start of treatment with etanercept.

-Among those, patients with either seronegative or seropositive polyarthritis, extended oligoarthritis and with systemic JIA suffered from higher disease activity concerning the number of active joints, inflammatory parameters (ESR, C-reactive protein), duration of morning-stiffness, parent's global assessment of the overall patient's well-being, physician's global assessment of the overall disease activity and number of aids/devices needed.

-JIA patients with higher disease activity parameters also had higher CHAQ DI.

-There was a high response rate to etanercept in children who previously were unresponsive or intolerant to several antirheumatic drugs.

-There was a rapid improvement during the first six months of therapy concerning CHAQ DI and disease activities which remained at lower levels during 24 months of treatment.

-Combination therapy of etanercept and MTX led to higher improvement-rates and led to better abilities in fulfilling every day's duties. Functional ability was lowest in patients with either seronegative or seropositive polyarthritis.

Patients with polyarthritis remained to have higher CHAQ DI scores during therapy than patients with other JIA-subtypes. This effect suspected that a lower physical ability remains during therapy in patients with higher numbers of affected joints.

Patients with systemic JIA who responded to etanercept and continued treatment for 24 months had an equal improvement of their disease activity as patients with other JIA-Subtypes. This finding is similar to a finding of Prince et al. This Dutch long term follow up study included 146 JIA-patients who were treated with etanercept for a median of 2.5 years [START_REF] Prince | Long-term followup on effectiveness and safety of etanercept in JIA: the Dutch national register[END_REF].

A combination therapy with etanercept and MTX was well accepted by the patients. Physical ability improved in both groups. However the extend of improvement of the CHAQ DI was higher in patients with combination therapy of methotrexate and etanercept than in those with etanercept monotherapy. In another analysis of data of the German registry on a patient cohort of 604 patients similar results have been described for the PedACR-Score [START_REF] Horneff | Safety and efficacy of combination of Etanercept and Methotrexate compared to treatment with Etanercept only in patients with juvenile idiopathic arthritis (JIA). Preliminary data from the German JIA Registry[END_REF]. Here, the likelihood of achieving a PedACR 70 increased with combination therapy. Earlier studies including fewer patients confirm our results (6; 11; 30). The 8 functional areas of the CHAQ differed before and during therapy. Functional ability improved in all areas and the discrepancy between the areas decreases during therapy. Before and during therapy "activities", "dressing" and "reach" were hardest for children with JIA, "eating" and "walking" were less affected. Duties of everyday life concerning actions that are indispensable in everyday life like "cutting meat", "lift up a cup or glass to mouth", "open a new cereal box", "walk outdoors on flat ground" and "climb up five steps" were easier to practice and to accomplish than duties that can be avoided or need fine motor skills. Examples are "cut fingernails" or "ride bike or tricycle". Avoided skills or skills which claim fine motor skills cause higher counts in the respective areas since the question with the highest count is used for calculation the CHAQ. Another aspect was stated by Pouchot et al. They found that for the "run and play" item, it is possible that parents of older children may consider the "run" activity, whereas parents of younger children may concentrate on the "play" activity [START_REF] Pouchot | Validity of the childhood health assessment questionnaire is independent of age in juvenile idiopathic arthritis[END_REF]. If this is correct one can argue that "running" may be a more difficult activity than "playing". Oliveira et al. found in their study about health related quality of life (HRQOL) that children with JIA have a greater impairment in physical well-being than in psychosocial health and that physical disability and pain are important determinants of HRQOL [START_REF] Oliveira | Proxy-reported health-related quality of life of patients with juvenile idiopathic arthritis: the Pediatric Rheumatology International Trials Organization multinational quality of life cohort study[END_REF]. These findings indicate that improvement of physical ability and reduction of pain are the major goals of JIA therapy.

In summary, we found dramatical improvement of functional ability in children with severe and so far treatment resistant JIA. The major findings of our study were a rapid improvement of functional ability and disease activity parameters already evident after six months of therapy which was prolonged and further improved during at least 24 months. Duties of everyday life were easier to accomplish and HRQOL improved. 1.1 ± 1.0 1.1 ± 0.9 0.4 ± 0.7 0.9 ± 0.8 0.7 ± 0.9 0.7 ± 1.0 <0.0001 1.0 ± 1.0 Arising 1.1 ± 1.0 1.0 ± 0.9 0.8 ± 0.8 0.4 ± 0.7 0.8 ± 0.9 0.9 ± 0.8 0.4 ± 0.7 <0.01 0.9 ± 0.9 Eating 0.8 ± 1.1 0.8 ± 0.9 0.8 ± 0.9 0.1 ± 0.4 0.5 ± 0.8 0.3 ± 0.6 0.4 ± 0.8 <0.0001 0.7 ± 0.9 Walking 0.9 ± 0.9 0.8 ± 0.9 0.6 ± 0.8 0.4 ± 0.8 0.8 ± 0,9 0.8 ± 0.8 0.5 ± 0.8 0.2 0.7 ± 0.9 Hygiene 1.3 ± 1.1 1.0 ± 1.0 0.9 ± 0.8 0.1 ± 0.4 07 ± 0.9 0.7 ± 0.9 0.4 ± 0.7 <0.0001 0.9 ± 1.0 Reach 1.4 ± 1.1 1.1 ± 1.0 1.2 ± 0.9 0.3 ± 0.6 1.0 ± 0.8 0.9 ± 0.9 0.8 ± 0.7 <0.001 1.1 ± 0.9 Grip 1.2 ± 1.1 1.3 ± 1.1 1.2 ± 0.9 0.1 ± 0.5 0.8 ± 0.9 0.5 ± 0.8 1.0 ± 1.0 <0.0001 1.0 ± 1.0 Activities 1.6 ± 1.1 1.3 ± 1.0 1.4 ± 1.0 0.9 ± 0.9 1.2 ± 0.9 1.6 ± 1.0 0.9 ± 0.9 <0.009 1.4 ± 1.0 CHAQ DI ¤ 1.1 ± 0.8 1.0 ± 0.8 1.0 ± 0.7 0.3 ± 0.4 0.8 ± 0.6 0.8 ± 0.6 0.6 ± 0.5 <0.0001 0.9 ± 0.7 * Kruskal Wallis test, comparing the JIA-subtypes § The range for CHAQ DI is 0-3 (0= best, 3=worst), mean ± SD is expressed ¤ CHAQ DI is the mean score of the 8 functional areas

  The mean (±SD) age for disease onset in children with JIA was 6.6±4.6 years. Earliest disease onset was found in children with systemic JIA (3.9±3.4 years). Children with enthesitis related arthritis and with seropositive polyarthritis were oldest at disease onset (11±3.1 years and 10.3 ±3.5 years).

  Our results indicate that functional ability improves strongly during[START_REF] Bekkering | A comparison of the measurement properties of the Juvenile Arthritis Functional Assessment Scale with the childhood health assessment questionnaire in daily practice[END_REF] months of therapy with etanercept. Clinical improvement was indicated by a decrease of the CHAQ DI and by an improvement according to the PedACR-30, -50 and -70 score. An improvement of the CHAQ DI was already evident after 6 months of treatment and persisted until 24 months with a further decrease of the mean CHAQ DI. A marked decrease of all clinical parameters was noted after six months. The results of this long term study confirm previous findings by Lovell et al. (3-5) on a limited number of patients as well as several other case series that were published thereafter (6-13). Lovell et al. first started a randomized placebo-controlled study. Later on patients of this study went in a long-term open-label extension study. 69 patients started the initial study with a mean CHAQ DI 1.5 (±0.1), one year later the mean CHAQ DI was 0.8 (±0.1) and four years later the CHAQ DI was 0.6 (±0.1). After eight years of therapy a PedACR 70 was achieved all patients who continued on treatment.

Figure 1 :

 1 Figure 1 : Improvement of CHAQ DI in the first 24 months of therapy with etanercept (n=114).▲: median, ▼: mean, grey: 25 th -75 th percentile.

Figure 2 .

 2 Figure 2. Functional ability in 8 functional areas of the CHAQ during therapy.

Figure 3 :

 3 Figure 3: Therapeutic efficiency measured by the Ped-ACR-Score after 24 month of therapy comparing systemic and non-systemic JIA

  values are mean ± SD´ $ on a 10cm visual analogue scale (0= very well, 10=very poor) § CHAQ= Childhood Health Assessment Questionnaire, range: 0-3 (0=best, 3=worst) ° Change of characteristics of disease activity during therapy, GLM repeated measures

  June 1 st , 2006 data on 437 patients (70% female) feasible for analysis have been collected.

	Patients were treated in several pediatric rheumatology centers all over Germany and Austria for 1
	to 72 months (mean (±SD) 16 (±14.6) months, median 12 months). The main demographic, clinical
	and laboratory features of the total group of JIA patients are shown in table 1. According to the
	ILAR criteria 76 (17.3%) of the patients had systemic JIA, 138 (31.6%) had seronegative
	polyarthritis, 53 (12.1%) had seropositive polyarthritis, 15 (3.4%) had persistent oligoarthritis, 73
	(16.7%) had extended oligoarthritis, 51 (11.7%) had enthesitis related arthritis and 31 (7%) had

psoriasis arthritis. During therapy with etanercept concomitant treatment with methotrexate was used in 362 (82.5%) patients.

Table 1 . Demographic, Clinical and laboratory characteristics of the study participants before therapy with etanercept*

 1

	Characteristic	Systemic	Seronegative	Seropositive	Persistent	Extended	Enthesitis	Psoriasis-	All JIA	P °
		arthritis	Polyarthritis	Polyarthritis	Oligo-	Oligo-	related	arthritis	patients*
		n=76	n=138	n=53	arthritis	arthritis	Arthritis	n=31	n=437
						n=73	n=51
					n=15
	Age at therapy start, years	9.2 ± 5.1	12.3 ± 4.2	14.3 ± 3.1	9.7 ± 3.9 11.0 ± 4.2 15.0 ± 2.9 13.5 ± 3.8 12.1 ± 4.5	0.06
	Age at JIA onset, years	3.9 ± 3.4	6.1 ± 4.1	10.3 ± 3.5	5.9 ± 5.0	3.7 ± 3.9	11.0 ± 3.1	8.0 ± 4.5	6.6 ± 4.6	0.3
	Disease duration, years ~	4.8 ± 4.3	5.7 ± 4.0	3.4 ± 3.0	3.3 ± 3.5	7.0 ± 4.0	3.2 ±2.4	5.0 ± 4.5	5.1 ± 4.0	0.04
	Female gender, no. (%)	45 (59.2)	106 (76.8)	45 (84.9)	9 (60)	56 (76.7)	25 (49.0)	20 (64.5)	306 (70)	0.6
	Concomitant therapy with MTX, no. (%)	62 (84.9)	109 (79.0)	52 (92.9)	14 (93.3)	58 (78.4)	44 (83.0)	23 (76.7) 362 (82.5)	0.3
	No. of active joints	10 ± 11	13 ± 10	13 ± 9	3 ± 2	8 ± 6	5 ± 5	6 ± 4	10 ± 9	< 0.0001
	Physician's global assessment of the	7.7 ± 2.1	6.5 ± 2.3	6.3 ± 2.7	4.7 ± 3.0	6.6 ± 2.2	6.1 ± 2.3	4.9 ± 2.6	6.5 ± 2.4	0.002
	overall disease activity $
	Erythrocyte sedimentation rate, mm/h	56 ± 32	29 ± 24	36 ± 26	19 ± 20	37 ± 26	34 ± 28	28 ± 24	36 ± 28	0.02
	C-reactive protein mg/l	73.2 ± 66.0 23.7 ± 30.4	30.4 ± 28.0 12.3 ± 18.8 32.5 ± 41.8 21.5 ± 21.8 31.6 ± 74.3 34.7 ± 46.8	0.003
	Morning stiffness (minutes)	37 ± 56	41 ± 56	51 ± 63	3 ± 5	49 ± 67	42 ± 70	47 ± 68	42 ± 61	< 0.0001

Table 1 . Demographic, Clinical and laboratory characteristics of the study participants before therapy with etanercept*

 1

	Aids/devices needed, no.	3 ± 4	3 ± 4	2 ± 3	1 ± 2	2 ± 3	1 ± 3	1 ± 2	2 ± 3	< 0.0001
	Patient's assessment of overall well being $ 6.3 ± 2.7	5.5 ± 2.7	5.5 ± 2.6	4.5 ± 3.3	5.4 ± 2.8	5.8 ± 2.6	5.5 ± 2.1	5.6 ± 2.7	< 0.0001
	CHAQ DI §	1.1 ± 0.8	1.0 ± 0.8	1.0 ± 0.7	0.3 ± 0.4	0.8 ± 0.6	0.7 ± 0.6	0.6 ± 0.5	0.9 ± 0.7
	*JIA= juvenile idiopathic arthritis, values are mean ± SD, unless otherwise indicated
	$ on a 10cm visual analogue scale (0= very well, 10=very poor)
	§ CHAQ= Childhood Health Assessment Questionnaire, range: 0-3 (0=best, 3=worst)

° Correlation of all JIA-patients with the CHAQ, univariant analysis of variance ~ before therapy with etanercept

Table 2 . The 8 functional areas of the CHAQ at start of therapy with etanercept

 2

Table 3 : Mean CHAQ DI (± SD) for JIA subtypes during therapy with etanercept (n=114)

 3

	Month after treatment was started	0	6	12	18	24
	Systemic arthritis (n=12)	1.0 ± 0.84	0.21 ± 0.33	0.23 ± 0.43	0.27 ± 0.51	0.19 ± 0.39
	Seronegative polyarthritis (n=33)	0.96 ± 0.83	0.68 ± 0.72	0.62 ± 0.65	0.53 ± 0.67	0.57 ± 0.67
	Seropositive polyarthritis (n=19)	1.0 ± 0.84	0.37 ± 0.46	0.36 ± 0.47	0.41 ± 0.52	0.46 ± 0.6
	Persistent oligoarthritis (n=5)	0.25 ± 0.25	0.03 ± 0.06	0.05 ± 0.11	0.05 ± 0.11	0.03 ± 0.06
	Extended oligoarthritis (n=23)	0.86 ± 0.72	0.26 ± 0.39	0.21 ± 0.33	0.18 ± 0.32	0.21 ± 0.35
	Enthesitis related arthritis (n=17)	0.82 ± 0.71	0.22 ± 0.34	0.09 ± 0.13	0.1 ± 0.21	0.13 ± 0.27
	Psoriasis and arthritis (n=5)	0.58 ± 0.68	0.25 ± 0.35	0.15 ± 0.34	0.03 ± 0.06	0.08 ± 0.12

Table 4 : Characteristics of disease activity during therapy with Etanercept*

 4

	Time in month	0	6	12	18	24	P°
	Characteristic
	No. of active joints	10±9	3±7	2±5	3±7	3±6	<0.0001
	Physician's global assessment of the overall	6.2±2.6	1.6±2	1.5±1.9	1.4±1.9	1.5±2	<0.0001
	disease activity $
	Erythrocyte sedimentation rate, mm/h	33±26	14±15	14±14	13±14	14±12	<0.0001
	C-reactive protein mg/l	40.9±55.2	6.6±19.5	7.9±14.8	10.2±19.9	8.8±15.7	<0.0001
	Morning stiffness (minutes)	42±66	3±11	4±10	3±13	5±19	<0.0001
	Patient's assessment of overall well being $	5.2±2.8	1.4±1.8	1.4±1.5	1.3±1.6	1.4±1.7	<0.0001
	CHAQ DI §	0.92±0.77	0.39±0.53	0.37±0.51	0.32±0.5	0.34±0.52	<0.0001


Anuj Mr
email: anujdr@gmail.com

MS(Orth Jaiswal

+441233616163 2 Mr

Raman Thakur

Tr Orth

William Harvey

Hospital Ashford

Jaikumar Mr

MS(Orth Relwani

DNB(Orth),FRCS(Tr Orth

Wallace Mr

FRCS Ogufere

Spontaneous displacement of olecranon fracture through geode salvaged by elbow replacement

Keywords:

We present a case of pathological fracture of olecranon through a giant geode. Fracture was initially undisplaced and was treated conservatively. It later progressed to a transolecranon dislocation as a result of a pseudarthrosis at the fracture site. The patient presented 4 years later when she developed symptoms of ulnar nerve palsy. She was treated by a total elbow arthroplasty with ulnar nerve transposition. The current report highlights this unusual case and reviews the relevant literature

Case report

A 71-year old lady suffering form rheumatoid arthritis presented with a painful right elbow of 5 months duration and paraesthesia in the ring and little fingers for 2 months. There was no history of recent trauma. She was a known case of rheumatoid In view of the pain, instability and tardy ulnar nerve palsy with underlying rheumatoid arthritis, a cemented GSB-III total elbow replacement was performed (Fig. 4) The small proximal olecranon fragment was excised. The ulnar nerve was found to be severely stretched. It was released and transposed anteriorly.

Postoperatively, the paraesthesiae resolved at 2 weeks. At 3 months, she achieved a range of painless movement from 10-130 degrees with physical therapy and was doing extremely well at her 2-year follow-up.

Discussion

Geode is a subchondral cystic lesion often seen in rheumatoid arthritis patients. [START_REF] Hirose | Giant geode as differential diagnosis of a large lobular radiolucency in the distal femur of a patient with rheumatoid arthritis[END_REF][START_REF] Rennell | Subchondral pseudocysts in rheumatoid arthritis[END_REF] Jacobs suggested this to be more appropriate term than 'cyst' to describe these lesions as it does not have an epithelial lining and generally are not fluid filled. [START_REF] Jacobs | Large geode in elbow with spontaneous fracture[END_REF] Geode are common in rheumatoid patients but spontaneous fracture through them is rare. Most commonly affected sites are femoral neck, and tibial plateau [START_REF] Rennell | Subchondral pseudocysts in rheumatoid arthritis[END_REF][START_REF] Resnick | Subchondral cysts (geodes) in arthritic disorders: pathologic and radiographic appearance of the hip joint[END_REF] but they are also reported in olecranon. [START_REF] Magyar | Giant bone cysts in rheumatoid arthritis[END_REF][START_REF] Rappoport | Spontaneous fractures of the olecranon process in rheumatoid arthritis[END_REF][START_REF] Wordsworth | Fracture through a geode in the proximal ulna[END_REF] As giant geode can progress to fracture of the olecranon. It has been suggested to perform curettage and bone grafting of the lesion to prevent pathological fractures. [START_REF] Nakagawa | Giant geode at the olecranon in the rheumatoid elbow--two case reports[END_REF][START_REF] Torikai | The occurrence of a geode in the olecranon of a patient with rheumatoid arthritis[END_REF] This patient was initially managed conservatively by rheumatologist and was subsequently lost to follow up. She progressed on to develop transolecranon fracture dislocation of the elbow with ulnar nerve palsy 4 year later.It was an incomplete fracture initially which then went on to become a complete transverse undisplaced fracture. It was treated conservatively in a plaster cast taking into account the low energy trauma, the apparently stable undisplaced transverse configuration and the fact that the patient was a 67 year old rheumatoid lady with limited demands. However, on careful review, subsequent radiographs over the next 8 months did show the fracture beginning to drift and the radial head moving anteriorly. This should have prompted the treating surgeon to perform internal fixation with bone. Unfortunately, as her symptoms improved, she was lost to follow-up. She was seen 4 years later with symptoms of tardy ulnar nerve paresis that developed as the displacement and valgus deformity increased causing traction on the nerve. By then, she had a pseudarthrosis at the fracture site, which had displaced completely along with the intact superior radio-ulnar articulation. The radius and ulna had migrated anterolaterally and proximally by about 3.5 centimetres. The rheumatoid process eroded the radial head and olecranon. The soft tissues anterior to the elbow were contracted and she was in severe pain.

Options at this stage were limited because of poor bone quality and damage to the joint due to chronic dislocation and rheumatoid process. The patient was 71 years old with limited demands, but good triceps function. Hence, we decided to perform a total elbow replacement and used the technique described by Gallay S. et al to preserve the fibrous attachment of the triceps to the proximal ulna by working through the intervals on the medial and lateral aspects of the triceps. [START_REF] Gallay | Operative treatment of nonunions about the elbow[END_REF] The proximal olecranon fragment however was too small and needed excision. The GSB-TII replacement was used which has a 'plug-in' non-constrained sloppy hinge. Its intrinsic stability means that one does not need to rely entirely on the collateral ligaments [START_REF] Gschwend | Long-term results of the GSB III elbow arthroplasty. [Miscellaneous Article][END_REF][START_REF] Schneeberger | Total elbow replacement with the GSB HI prosthesis[END_REF] . She also had an ulnar nerve transposition to relieve her neuropraxia.

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Elbow replacement is good option to salvage distal humeral fractures with poor bone quality [START_REF] Kalogrianitis | Unlinked elbow arthroplasty as primary treatment for fractures of the distal humerus[END_REF][START_REF] Prasad | Outcome of total elbow replacement for distal humeral fractures in the elderly: a comparison of primary surgery and surgery after failed internal fixation or conservative treatment[END_REF] . This case shows that elbow replacement can be successfully used to salvage proximal ulnar fractures with degenerative changes in the elbow joint.

We agree with previous reports that giant geode at this site should be treated surgically with bone grafting because of its susceptibly to progress on to fracture and dislocation. In this patient elbow was salvaged by elbow replacement.

Conclusion

Geode in olecranon in patients with rheumatoid arthritis should me managed surgically at early stage.

Figure Legends

  arthritis. Examination revealed a swollen and deformed and unstable right elbow with evidence of dislocation of the radial head. The elbow had a range of movement from 40 degrees to 70 degrees. She also had early clawing of the ring and little fingers and reduced sensation in the little finger. However, the clinical picture was atypical on account of the underlying rheumatoid deformities of both hands. A radiograph of the affected elbow revealed a transolecranon fracture-dislocation of the elbow through a pseudarthosis in the ulnar fracture(Fig la and ib). She had been seen 4 years earlier by a rheumatologist for discomfort in the right elbow and the radiograph done then showed a hairline fracture through a pre-existing simple cyst in the proximal ulnar metaphysis (Fig 2). This had been treated conservatively in an above elbow cast for 12 weeks. Subsequent radiographs showed minimal although progressive displacement of the fracture over the next 7 months (Fig 3). As she remained asymptomatic, she was lost to follow-up for 4 years.

  Figure LegendsFig la


Prof. Dr. med Daniela Steinberger
email: daniela.steinberger@uni-giessen.de

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Keywords: TRAPS, hereditary periodic fever syndrome, autoinflammatory syndromes, monoallelic mutation, TNFRSF1A

Hereditary periodic fever syndromes (HPFSs) are a subset of human autoinflammatory diseases characterized by periodic episodes of fever and signs of inflammation with or without involvement of inner organs. In this paper, we report phenotypic features of an index patient and affected family members that present a previously not described mutation type in the TNFRSF1A-gene. The phenotype of a HPFS of affected family members was shown to be associated with two monoallelic mutations in TNFRSF1A. Primarily, the index patient was clinically diagnosed as being affected by familial Mediterranean fever (FMF). However, with molecular genetic analyses it could be shown that the patient was in fact affected by tumor necrosis factor receptor-associated periodic syndrome (TRAPS), which requires a different therapy compared to FMF. Thus, molecular genetic analyses of currently known disease loci enable the most precise diagnosis presently available and are consequently the basis for the most effective therapeutic intervention.

INTRODUCTION

Recurrent fever episodes can develop from different hereditary and non-hereditary origins. The aetiology is often difficult to assess. Relevant non-hereditary factors are, in particular, neoplasias, infections, chronic systemic disorders, e.g. Morbus Crohn, or rheumatic diseases [START_REF] Timmann | Genetisch bedingte Fiebersyndrome[END_REF][START_REF] Gattorno | Diagnosis and management of autoinflammatory diseases in childhood[END_REF]. In case of persistent periodical fever attacks over a long time period, hereditary periodic fevers, also called autoinflammatory syndromes, should be considered in differential diagnosis.

Human autoinflammatory diseases are characterized by periodic episodes of fever and signs of inflammation with or without involvement of organs leading to symptoms such as arthritis, pericarditis, pleuritis, peritonitis, abdominal pain, or myalgia. The disease group includes syndromes such as familial Mediterranean fever (FMF), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS).

Among the hereditary periodic fever syndromes, FMF and HIDS are autosomal recessively inherited, while TRAPS has a dominant mode of transmission. FMF is caused by mutations in the MEFV (for MEditerranean FeVer)-gene [START_REF] Pras | Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16[END_REF], HIDS by mutations in the mevalonate kinase (MVK)-gene [START_REF] Houten | Organization of the mevalonate kinase (MVK) gene and identification of novel mutations causing mevalonic aciduria and hyperimmunoglobulinaemia D and periodic fever syndrome[END_REF], and TRAPS develops due to mutations in the Tumor Necrosis Factor Receptor Superfamily Member 1A (TNFRSF1A)-gene. The latter is encoding for the 55 kDa TNF receptor TNFRSF1A, an archetypal proinflammatory receptor and member of a large group of proteins with homology in their extracellular domain [START_REF] Galon | TNFRSF1A mutations and autoinflammatory syndromes[END_REF][START_REF] Hull | The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder[END_REF][START_REF] Mcdermott | Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes[END_REF].

While each syndrome has a specific genetic background and some phenotypic characteristics, all HPFS share a quite similar clinical expression that makes diagnosis based alone on clinical features more difficult [START_REF] Yao | Autoinflammatory diseases: an update of clinical and genetic aspects[END_REF]. Hence, often affections remain unrecognized and undiagnosed for years. During the last decade molecular studies revealed important progresses for the understanding of HPFSs [START_REF] Mcdermott | Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes[END_REF][START_REF] Yao | Autoinflammatory diseases: an update of clinical and genetic aspects[END_REF][START_REF]Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever[END_REF][START_REF] Aksentijevich | Mutation and haplotype studies of familial mediterranean fever Linking powered by eXtyles reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population[END_REF][START_REF] Cuisset | International Hyper-IgD Study Group (2001) Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD and periodic fever syndrome[END_REF]. Recent advances in molecular techniques have led to the identification of mutations that occur in several genes and are the underlying causes for these syndromes.

Here we report on phenotypic features of an index patient and other affected family members that presented a previously not described mutation type in the TNFRSF1A-gene. The phenotype of the affected family members was shown to be associated with two mutations in TNFRSF1A, and as we demonstrated, they were present in a monoallelic state in all affected family members. Primarily, the index patient was clinically diagnosed as being affected by familial Mediterranean fever [START_REF] Hawle | Familial mediterranean fever in a German family[END_REF]. With molecular genetic analyses it could be shown that the patient was in fact affected by TRAPS. This molecular diagnosis had relevant consequences since it resulted in reconsidering the further therapy.

Case report

A 36 year old patient (index III:2, fig. 1) with German ancestry came for clarification of recurrent febrile attacks. He reported recurrent episodes of abdominal pain and fever since the age of 7 years. After a severe fever attack at the age of 10 accompanied by colicky abdominal pain and ongoing fever episodes for 2-4 days, familial Mediterranean fever (FMF) was diagnosed due to characteristic signs and symptoms. Typical laboratory biochemical findings indicated an inflammatory episode. Laparoscopy showed histologically a fibrinous purulent peritonitis.

In the course of his life, symptoms within intervals of affection diminished. Acute febrile episodes occurred three to four times a year accompanied by chill, general sensation of being ill, abdominal pain, headache and pain in limb muscle groups.

Independent of this pathology, he suffered from recurrent pain of the flanks without fever, dysuria and gross hematuria. For medication, Indometacin (maximum of 150mg/d) was administered on demand. Currently, disease episodes occur approximately once every two years for 7-21 days with an increase in temperature up to 40 °C. Noteworthy, the patient´s father at adolescence as well as his aunt and several cousins were affected by similar fever symptoms (fig. 1). For further clarification, molecular genetic analyses of the MEFV-, MVK-and TNFRSF1A-gens were performed.

METHODS

Clinical description

At the time of physical examination, the patient (185cm, 83kg) was in good general condition. The abdomen was soft without resistances and palpation gave no hint for a renal affection. A neurological examination showed regular findings.

Laboratory results showed an increased erythrocyte sedimentation rate (44/64mm) and a normal hemogram. Further diagnostic examinations, such as sonography of the abdomen, echocardiography and a rectum biopsy revealed regular findings, and were not suggestive of amyloidosis.

Molecular genetic analyses

DNA was extracted from peripheral blood of the patients and controls according to standard procedures using the QIAamp DNA Blood Mini Kit (Qiagen, Hildesheim, Germany). Sequence analyses were undertaken according to standard protocols.

For index patient III:2 the genes MEFV, MVK and TNFRSF1A were analyzed completely. Subsequent to the findings in exon 4 of TNFRSF1A and exon 2 of MVK for the index patient, the clinically suspicious family members II:3 and III:1 and the healthy mother II:4 were also analyzed for these alterations.

RESULTS

For the index patient, two nucleotide substitutions in exon 4 of TNFRSF1A were detected via sequencing of the coding region: first, the amino acid substitution guanine to cytosine at position 263 of the nucleotide sequence (c.263G>C), and second, the substitution of cytosine to adenine at position 264 (c.264C>A). Both alterations were detected as heterozygous, which means a nucleotide of the normal wildtype sequence was apparent on one allele, and the substitutions on the other (fig. 2). Molecular genetic analysis of the complete MEFV-gene (associated with FMF) and the MVK-gene (associated with the clinical phenotype HIDS) revealed no indication for disease causing mutations. However, in the MVK-gene a G>A transition (c.155G>A) resulting in the amino acid substitution serine to Linking powered by eXtyles asparagine (p.Ser52Asn) was shown to be present in heterozygous state for the index patient and other affected family members studied. This alteration is described to represent a common polymorphism [START_REF] Cuisset | International Hyper-IgD Study Group (2001) Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD and periodic fever syndrome[END_REF].

After molecular analyses of the index patient only, the question could not be answered whether one gene copy was affected by both mutations (monoallelic), or each gene copy by one mutation (compound heterozygosity). Hence, for clarification, both parents of the index patient (father II:3 and mother II:4; see fig. 1) as well as the paternal cousin (III:1) were molecular genetically analyzed. The analyses of the patient´s parents revealed that the father carries the same two alterations and the mother a wildtype sequence. With the molecular genetic analysis of the patient´s affected cousin III:1 the same genotype as for II:3 (father) and III:2 (index patient) was identified. Thus, it could be concluded that both mutations were inherited in a monoallelic mode. Given the newly obtained information on the allelic distribution of mutations, it is likely that the nucleotide substitutions resulted in the transformation of the triplet TGC to TCA, which consequently results in the amino acid substitution cysteine to serine at position 88 of the protein (p.Cys88Ser; fig. 3). The substitutions affect the cysteine-rich domain 2 (CRD 2) of TNFRSF1A and interfere most likely with the tertiary structure of the receptor by eliminating a disulfide bridge (fig. 4).

DISCUSSION

The mutations in TNFRSF1A detected in our study have previously not been described, neither as single entities nor as a combination. They were detected as heterozygous appearing signals which could be proven to have occurred in a monoallelic state. Hence, they result in the amino acid substitution cysteine to serine at position 88 of the protein (p.Cys88Ser). Cysteine at position 88 is located in the second extracellular, cysteine-rich subdomain (CRD2) of the TNFRSF1Aprotein. The cysteine-motif of this domain is well-conserved and occurs homologous in different species. Cysteine is essential for the formation of disulfide bonds, and thus in the formation of the protein specific tertiary structure (fig. 3) [START_REF] Mcdermott | Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes[END_REF]. The putative affect of this amino acid substitution reported above is the disintegration of a disulfide bridge in the cysteine-rich domain 2 (CRD2) of TNFRSF1A. Most probably, this results in the disruption of the tertiary structure, Linking powered by eXtyles thus leading to functional disturbance of the protein. This in turn leads consequently to signs and symptoms of a distinct form of a hereditary periodic fever syndrome that can be -based on the molecular findings -classified as TRAPS. TRAPS formerly known as familial Hibernian fever, was first described as a distinct nosologic entity by McDermott MF in 1999 [START_REF] Mcdermott | Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes[END_REF]. It is classified as one of the hereditary periodic fever syndromes, which are a group of autoinflammatory diseases with clinical symptoms that are variable and tend to overlap in a broad spectrum. For TRAPS, relapsing and remitting disease episodes are characteristic, and the onset of disease tends to be later and the duration of the attacks longer than in other HPFSs. This is in particular true for FMF. Episodes of fever typically last 7 to 21 days accompanied by abdominal pain, polyserositis (in most cases peritonitis), lymphadenopathy, myalgias, chest pain, skin manifestations, periorbital edema and rashes as well as conjunctivitis. The disease is very similar to FMF, but can be discordant in the length of fever attacks (7-21 days). Most severe forms of TRAPS show almost permanent clinical signs of inflammation and require daily use of therapy. TRAPS occurs frequently already in childhood and early adolescence, and in general the severity of episodes diminish in the course of life. For therapy, treatment with corticosteroids is recommended to attenuate the length and severity of attacks. Treatment with corticosteroids is usually ineffective in patients that are affected by FMF [START_REF] Galon | TNFRSF1A mutations and autoinflammatory syndromes[END_REF][START_REF] Hull | The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder[END_REF].

Furthermore, patients with TRAPS seem to benefit from TNF inhibitors, e.g. Etanercept, which mimics the effect of normal soluble TNF receptor and thus compensates for its deficit.

Most TRAPS-associated mutations have been identified to be of the missense type and are located predominantly within the first or second cysteine-rich N-terminal extracellular domain (CRD1 and CRD2) of the receptor [START_REF] Hull | The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder[END_REF][START_REF] Kimberley | Falling into TRAPS -receptor misfolding in the TNF receptor 1-associated periodic fever syndrome[END_REF]. Recent studies concentrate on the mechanism of TRAPS signaling pathways and discuss new findings describing aberrant trafficking and function of TNFRSF1A harboring TRAPS mutations, challenging the hypothesis that TRAPS pathology is driven by defective receptor shedding [START_REF] Kimberley | Falling into TRAPS -receptor misfolding in the TNF receptor 1-associated periodic fever syndrome[END_REF]. It is suggested that TNFRSF1A might acquire novel functions in the endoplasmatic reticulum, distinct from its role as a cell surface receptor. The systemic inflammation that is characteristic for TRAPS could result from the consequences of misfolded and intracellularly retained Linking powered by eXtyles TNFRSF1A. However, the large variability of clinical symptoms could be an indication that there is no one unifying mechanism for all TRAPS mutations.

In this study, we detected TRAPS mutations by molecular genetic analyses of a family that had shown periodic fever episodes, which were formerly classified as a potentially rare form of autosomal dominant FMF [START_REF] Hawle | Familial mediterranean fever in a German family[END_REF]. However, the initial diagnosis could be stated at this time alone by clinical observations and respective conclusions. In general, clinical phenotypes of hereditary fever syndromes are not specific for a distinct fever entity and show a remarkable overlap in symptoms.

Thus, molecular genetic analyses of currently known disease loci enable the most precise diagnosis presently available and are consequently the basis for the most effective therapeutic intervention. In the present report, particularly in regards to further therapy, the diagnostic differentiation of TRAPS from the other HPFSs and from the previously diagnosed FMF was very important. Hence, a therapy with colchicine -known as an effective treatment in FMF but not in TRAPS -was not recommended for further disease episodes. Instead, steroids (Prednisolone 1-2mg/kg body weight) and alternatively NSAIDs (Indometacin) are a preferred and effective treatment in this case.

FIGURE LEGENDS

Fig. 1 :

 1 Fig. 1: Pedigree of the index patient's (*) family.

Fig. 2 :

 2 Fig. 2: Electropherogram of sequence analysis of TNFRSF1A for the index patient. The exchanges G263C and C264A are indicated by an arrow.

Fig. 3 :

 3 Fig. 3: Schematic presentation of the TNFRSF1A-gene structure. The nucleotide changes G>C and C>A are shown in red. The monoallelic presence of these mutations results in the amino acid change cysteine to serine at position 88 of the protein sequence.

Fig. 4 :

 4 Fig. 4: Schematic presentation of the functional domains of the TNFRSF1A protein. The extracellular disulfide bonds of TNFRSF1 are numbered according to Mc Dermott et al., 1999 and are shown as lines connecting conserved cysteine residues (5 and 6) [7]. The position of the mutated amino acid is marked with an asterisk. Substitution occurred in the cysteine-rich domain 2 (CRD2) of TNFRSF1A. This is most probably altering the tertiary structure of the receptor by eliminating the disulfide bridge 5.

Fig. 1

 1 Fig. 1

Fig. 2

 2 Fig. 2

Fig. 3

 3 Fig. 3

Fig. 4

 4 Fig. 4

Acknowledgements

Investigation of probands was performed according to the principles of the World Medical Association Declaration of Helsinki (WMA, General Assembly, 2004). We thank Andrea Rathmann-Schmitz for her assistance in preparing the manuscript for publication.


Dr Silvia Sánchez-Ramón

Juan Carlos Ravell

Inmaculada De La Torre

María Montoro

Margarita Rodríguez-Mahou

Luis Carreño-Pérez

Eduardo Fernández-Cruz

Francisco Javier López-Longo

Long-Term Remission of Severe Refractory Dermatopolymyositis with a Weekly-Scheme of Immunoglobulin Followed by Rituximab Therapy

Long-term remission of severe refractory dermatopolymyositis with a weekly-scheme of immunoglobulin followed by rituximab therapy

Indeed, a double-blind placebo-controlled study has shown that IVIG is very effective in improving both muscle strength and skin rash [START_REF] Dalakas | A controlled trial of high-dose intravenous immunoglobulin infusions as treatment for dermatomyositis[END_REF].

Quantitative histological studies in repeated muscle biopsies have also shown a statistically significant increase in the size of muscle fibers and the number of capillaries with normalization of the capillary diameter, resolution of aberrant immunopathological parameters, and modification of immunoregulatory and structural genes in DM patients treated with IVIG [START_REF] Dalakas | The role of high-dose immune globulin intravenous in the treatment of dermatomyositis[END_REF].

The IVIG infusions are an alternative therapy as steroid-sparing agents in those patients who have shown to be either refractory or dependent on steroids. In particular, our patient had developed major side effects associated with steroid treatment without adequate clinical improvement.

She was also intolerant to methotrexate and azathioprine. After high-dose IVIG, there was a rapid improvement in the patient's condition that correlated well with a reduction in the levels of biochemical markers of muscle inflammation. Linking powered by eXtyles

There are encouraging results in individual case reports and small series on the use of rituximab for the treatment of severe and refractory DM/PM, similarly as its effects on other immune-based diseases, whose mechanism of action is not completely understood [START_REF] Levine | Rituximab in the treatment of dermatomyositis: an openlabel pilot study[END_REF][START_REF] Chiappetta | Rituximab in the treatment of refractory dermatomyositis[END_REF]. Although rare, adverse effects are an important concern of the treatment with rituximab, such as the potentially severe infusion-related reactions and the occurrence of opportunistic infections, malignancy and activation of latent viral infections [START_REF] Umemura | Fatal HBV reactivation in a subject with anti-HBs and anti-HBc[END_REF], among others [START_REF] Kimby | Tolerability and safety of rituximab (MabThera)[END_REF].

Even though we initially suggested that treatment with high-dose IVIG or long-term weekly IVIG maintenance scheme may be useful as a steroidsparing agent in patients with DM refractory to conventional therapies or intolerant to immunosuppressive drugs, rituximab seems to be a safe and effective alternative option in those patients who fail to sustain remission.

Rituximab induces a depletion of B cells, and in selected patients can cause hypogammaglobulinemia, with increased risk of infections. We propose the usage of IVIG therapy as a first step in refractory DM/PM patients, which avoids hospitalisations and improves the patient's quality of life, followed by Rituximab therapy as a second step for non-responding patients. Additional multicenter clinical studies should be necessary to further confirm the efficacy of both alternative therapies for PM and DM, in order to establish better recommendations in the future.

  Silvia Sánchez-Ramón, Juan Carlos Ravell, Inmaculada Torre, María Montoro, Margarita Rodríguez-Mahou, Luis Carreño-Pérez, Eduardo Fernández-Cruz, Francisco Javier López-Longo To cite this version: Silvia Sánchez-Ramón, Juan Carlos Ravell, Inmaculada Torre, María Montoro, Margarita Rodríguez-Mahou, et al.. Long-term remission of severe refractory dermatopolymyositis with a weekly-scheme of immunoglobulin followed by rituximab therapy. Rheumatology International, 2009, 30 (6), pp.817-819. 10.1007/s00296-009-1000-x. hal-00568297 Introduction Dermatopolymyositis (DM/PM) is a life-threatening systemic inflammatory disease characterised by substantial muscle weakening, cutaneous lesions, cardiac and lung impairment. Idiopathic inflammatory myopathies comprise a heterogenous group of autoimmune disorders that include polymyositis (PM); dermatomyositis (DM) and other related conditions whose causes and pathogenesis remain unclear. In DM, inflammatory changes occur both in muscle and skin. Although its cause is unknown, autoimmune mechanisms are implicated [1-3]. The first line of treatment for DM/PM consists of corticosteroids alone or in conjunction with other immunosuppressive drugs. Among second-line therapies for patients that present with DM/PM resistant to conventional treatments or with severe drug-induced side effects, intravenous polyvalent immunoglobulin (IVIG) represents an effective and safe alternative. There have been some case reports and open label trials on the beneficial effects of Rituximab (anti-CD20 monoclonal antibodies) in DM/PM [4,5]. We report on a 44 year-old woman affected by DM/PM resistant to conventional therapies who experienced clinical improvement and remission after 2-year treatment with IVIG in a weekly schedule followed by Rituximab therapy. Case report A 44-year-old Caucasian woman diagnosed as having DM/PM for 3 years was referred to our Clinical Immunology Unit due to persistence of DM/PM signs and symptoms in spite of treatment with high-dose systemic corticosteroids. She had been treated with oral prednisone up to 1.5 mg/kg body weight/day, monthly intravenous methyl-prednisolone pulses, methotrexate and azathioprine. The latter two were discontinued because of drug intolerance. Specific myositis autoantibodies were negative. Muscle weakness and fatigue worsened despite therapy with oral prednisone and methyl-prednisolone pulses. She was given IVIG (Flebogamma® 10%, Grifols S.A., Barcelona, Spain) at the dose of 2g per kg of body weight during 5 consecutive days per month for the first 6 months. Serum aldolase and LDH levels were elevated prior to IVIG treatment (8 UI/L and 518 UI/L, respectively) and they both declined to normal values 1 month after the first IVIG cycle (Figure 1 and 2). During the first 6 months of IVIG treatment, the initial prednisone dose of 90 mg/day (1.5 mg/kg/day) was progressively tapered to a maintenance dose of 5 mg/day, while achieving clear clinical improvement in muscle strength with no significant side effects. She was then given a maintenance treatment with an IVIG protocol of weekly infusions of 400 mg/kg/week for other 6 months, with persistent control of clinical and biochemical manifestations. After that, she was progressively placed on a maintenance protocol consisting of an IVIG dose of 200 mg/kg every other week, showing remission of DM related symptoms. Unfortunately, Linking powered by eXtyles every attempt to further reduce the IVIG dosage or to prolong intervals of administration resulted in an early increase in LDH levels and worsening of symptoms. Even though IVIG therapy resulted in sustained clinical improvement throughout the first two years of treatment, after that period the patient started to present a decline in treatment response and remission of symptoms. We decided to switch her to rituximab (anti-CD20 monoclonal antibodies, Mabthera®, Roche) IV infusions at a dose of 375 mg per m 2 of body surface administered weekly for a total of 4 doses. Rituximab treatment was well tolerated. Approximately 1-week after the fourth dose of rituximab treatment, the patient experienced marked and progressive clinical improvement, particularly in her asthenia and muscle strength. This effect lasted for 6 months, after which maintenance schedule of rituximab at a dosage of 1g IV two weeks apart was given, with an excellent clinical response. Due to hypogammaglobulinemia secondary to rituximab treatment associated with recurrent upper respiratory tract infections, our patient was given IVIG therapy at a low maintenance dose of 200 mg per kg of body weight every 4 weeks. As of the time of this writing, the patients' muscle strength and quality of life have improved dramatically up to the point that she is now able to maintain an acceptable physical activity, including weekly swimming practice. Linking powered by eXtyles Discussion In addition to their original administration as antibody replacement therapy, immunoglobulin preparations have also been used to treat several autoimmune and systemic inflammatory diseases due to its antiinflammatory and immunomodulatory effects [6,7]. One of the new modalities in the treatment of patients with DM unresponsive to conventional therapies has been the usage of high-dose IVIG at a classical schedule of 2 grams per kg of body weight administered over 5 days.

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Vincenzo Francesco

Angelo Zullo

Francesca Cristofari

Mariangela Zotti

Giuseppe Stoppino

Maria Rosaria D'agnessa

Michele Castriota

Enzo Ierardi

A juvenile, misdiagnosed case of Whipple's disease

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A juvenile, misdiagnosed case of Whipple's disease

Vincenzo De Francesco 1 , Angelo Zullo 2 , Francesca Cristofari 2 , Mariangela Zotti 1 , Giuseppe Stoppino 1 , Maria Rosaria D'Agnessa 3 , Michele Castriota 3 , Enzo Ierardi 1 .

1: Section of Gastroenterology, Department of Medical Sciences, University of Foggia, Foggia, Italy 2: Gastroenterology and Digestive Endoscopy, Ospedale Nuovo Regina Margherita, Rome, Italy 3: Pathology Unit, "Ospedali Riuniti", Foggia Linking powered by eXtyles Dear Editor, Whipple'disease (WD) is a rare syndrome which generally occurs in patients aged more than 50 years, especially in farmers, carpenters, and gardeners [START_REF] Marth | Whipple's disease[END_REF]. WD may present with different and not specific symptoms, so that diagnosis is frequently a challenge for physicians. An appropriate, long-term antibiotic therapy is effective, and untreated disease is lethal [START_REF] Keinath | Antibiotic treatment and relapse in Whipple's disease. Long-term follow-up of 88 patients[END_REF]. Therefore, a prompt diagnosis is mandatory.

A 37-year-old male baker, with a compensated hypothyroidism, complained of migrant polyarthralgies in 2005, and a diagnosis of seronegative joint disease was performed.

Patient received a therapy with ibuprofen (400 mg b.i.d) for 6 months, and a steroid therapy (prednisone 16 mg/day) was added due to persistence of symptoms. A methotrexate (100 mg/die) therapy was started after 6 months, tapering steroid therapy.

Five months later, patient complained of severe diarrhoea (10-15 bowel movements/day), vomiting, anorexia, low-grade fever, and progressive, severe weight loss (22 kg), and he was admitted to our Unit on May 2007. At entry, sideropenic anaemia (haemoglobin 10 g/dl; ferritin 17 ng/dl), increased ESR to 25 mm/h, and increased leucocytes count with 15,2 x 10 9 /L (neutrophils: 78%). A small bowel follow-through (x-RAY) and a pancolonscopy were unrewarding. A contrast-enhanced computed tomography showed thickness of the mesenterial adipose tissue with several perigastric, para-aortic, and paraoesophageal lymphnodes enlargement. Upper endoscopy revealed several intraepithelial haemorrhages and red spots on enlarged duodenal folds (Figure 1). The histological assessment on the duodenal biopsies showed intestinal villi filled with white material, and clear signs of lymphangiectasia. In the lamina propria, we observed a severe infiltration by foamy macrophages with a coarse granular cytoplasm which stained strongly with the period acid-Schiff reagent (Figure 2), and WD disease diagnosis was performed. Realtime PCR on paraffin-embedded duodenal biopsy specimens confirmed the infection by Linking powered by eXtyles Tropheryma whipplei. A trimethoprim/sulfamethoxazole therapy (160/800 mg b.i.d) was administered for 1 year. In June 2008, the patient was totally asymptomatic and a 10 kg increased body weight was registered.

WD was firstly described in 1907, but only in 1992 Tropheryma whipplei, a rod shaped bacterium, was identified in culture as aetiological agent of the disease [START_REF] Marth | Whipple's disease[END_REF]. Although WD has traditionally been regarded as a gastrointestinal disease, most cases begins insidiously with arthropathy. Indeed, in a large series, a seronegative joint disease was the first symptom in 63% of patients, preceding gastrointestinal symptoms by some years [START_REF] Marth | Whipple's disease[END_REF].

Those subjects which are in contact with soil (farmers, carpenters, gardeners) are at increased risk of WD, and a distinctly higher prevalence in males (M/F = 8:1) has been reported [START_REF] Marth | Whipple's disease[END_REF]. WD in our patient, which was young and without professional risk, started with a seronegative joint disease, requiring methotrexate therapy. Gastrointestinal symptoms occurred 11 months following immunosuppressive therapy (6 months steroid plus 5 months methotrexate therapy), however he was referred to our Gastroenterology Unit only 5 months later with an important weight loss. Since WD is a lifethreatening and potentially lethal disease (1), we would emphasize that the onset gastrointestinal symptoms in a patient with a seronegative joint disease, especially during immunosuppressive treatment (3), should prompt the suspect of WD. Indeed, although methotrexate does not alter Th1/Th2 balance, it reduces cytokine production by T-helper cells [START_REF] Rentenaar | Systemic treatment with either cyclosporin A or methotrexate does not influence the T helper 1/T helper 2 balance in psoriatic patients[END_REF] and it has been reported that low activity of Th1-helper cells could favour clinical manifestations of WD after systemic dissemination (1).

Fig. 1 .

 1 Fig. 1. Endoscopic features of the duodenal mucosa.

Fig. 2 .

 2 Fig. 2. PAS positive macrophages diffuse infiltration of duodenal mucosa.


MD Erika Angelucci
email: erika.angelucci@yahoo.it

MD Monica Cesarini

MD Piero Vernia

MD. Enrico Corazziari

Successful resolution of pneumonia developed in a patient affected by Crohn's disease, rheumatoid arthritis, myasthenia gravis and recurrent uveitis during concomitant treatment with

Successful resolution of pneumonia developed in a

patient affected by Crohn's disease, rheumatoid arthritis, myasthenia gravis and recurrent uveitis during concomitant treatment with tumour necrosis factor α inhibitors and conventional immunosuppressive drugs

A 68-year-old woman affected by myasthenia gravis, recurrent uveitis, rheumatoid arthritis (RA) and gallstones developed in the first months of 2003 diarrhoea (about 5-6 intestinal movements for day, without blood) and abdominal pain. At that time the patient was treated by systemic corticosteroids (prednisone 10 mg/day) and non steroidal antinflammatory drugs (NSAIDs) for rheumatoid arthritis, topical corticosteroids for recurrent uveitis, ursodeoxycholic acid for gallstones and cholinesterase inhibitors (pyridostigmine) for myasthenia gravis.

An ileocolonoscopy was performed showing ulcers in the terminal ileum. Histological examination of the ileal specimen showed the presence of histopathological findings suggesting the diagnosis of Crohn's disease (CD). A small intestine contrast ultrasonography (SICUS) was also performed showing thickening of bowel wall (3.8 -6 mm) for the last 7 cm of the terminal ileum, supporting the hypothesis of CD. The patient was referred to our GI Unit, daily dose of prednisone was increased to 50 mg/day and maintenance treatment with mesalazine 2.4 g/day was started.

NSAIDs were stopped. The patient failed to taper prednsione at a dose less than 10 mg/day, for the reappearance of abdominal pain in low right quadrant of the abdomen and articular pain. In November 2003, for this condition of steroid-dependancy and for the finding of osteoporosis, treatment with infliximab at a dose of 5 mg/kg at weeks 0, 2, and 6, and azathioprine (2 mg/kg/day) was started. Steroids were withdrawn and for one year patient experienced well being, without abdominal and articular pain. Furthermore myasthenia gravis reached complete remission and neurologists stopped treatment with pyridostigmine. In October 2004 the patient was referred to Emergency Unit due to abdominal pain in the upper and right quadrants of the abdomen and vomiting. Diagnosis of acute pancreatitis was made, azathioprine treatment was stopped, due to a first hypothesis of drug-induced pancreatitis, and an endoscopic retrograde cholangiopancreatography (ERCP) with sphincterectomy and stones extraction was performed. A cholecystectomy wasn't preformed due to opposite opinion of anaesthesists. Six months later, during April 2004, for the reappearance of articular pain first and then abdominal pain prednisone 10 mg was started again. In 2006 due to the further need of NSAIDs and due to the a recurrence of uveitis treated by topical steroids, azathioprine was started again at a dose of 2 mg/kg/day. The drug was well tolerated, without increase in pancreatic enzymes, but the patient failed to stopped steroids over a 2-years period, for the reappearance of articular and abdominal symptoms within 1 month by steroids withdrawal. Another SICUS was performed showing an increased length of the involved terminal ileum (23 cm respect to 7 cm in 2003). Venous blood assessment revealed rise in the erythrocyte sedimentation rate (ESR) (60 mm/h), C-reactive protein (CRP) (18.4 g/dl) and Linking powered by eXtyles fibrinogen (604 U/ml). In June 2008, after a negative screening by Chest X-ray and PPD, induction treatment with adalimumab was started (160 mg at week 0 and 80 mg at week 2) followed by maintenance treatment (40 mg eow). At the beginning of September 2008 the patient stopped steroids. Two months after steroids withdrawal the patient was in well-being and venous blood assessment revealed normal value of ESR (9 mm/h), CRP (0.9 mg/dL) and white blood count (5 100/mmc). The patient continued maintenance treatment with adalimumab 40 mg eow and azathioprine (2 mg/kg/day). Few days before the 11 th injection of adalimumab 40 mg the patient developed fever, chest pain, severe fatigue, dyspnea and non-productive cough. Patients was referred to Emergency Unit. Laboratory findings showed increase in white blood count (15 290/mmc) with prevalence of neutrophils (86%), normal number of lymphocytes (8%, 1 200/mmc) and increase in ESR and CRP (45 mm/h and 4.5 mg/dL, respectively). Chest X-ray showed a consolidation in the lower left lobe (Figure 1). Pathogen agent was not identified but empirical antibiotical therapy with amoxicillin-clavulanic acid was started with success. Adalimumab and azathioprine were immediately stopped. Patient recovered in one week and Chest X-ray performed 15 days later showed resolution of lobar consolidation. However, without immunosuppressive therapy, a relapse of myasthenia with prevalence of ocular symptoms (dyplopia, decrease of visus) appeared, requiring restarting of therapy with steroid (prednisone 10 mg/day) and azathioprine (2 mg/kg/day). At the present time, patient is in well being under this maintenance therapy.

Discussion

Tumour necrosis factor alpha (TNF-α) inhibitors, both the humanized one (infliximab) and the fully human (adalimumab) have been approved for the treatment of both rheumatoid arthritis and CD [START_REF] Scott | Tumor Necrosis Factor Inhibitors for Rheumatoid Arthritis[END_REF][START_REF] Danese | Tumor necrosis factor-alpha monoclonal antibodies for Crohn's disease: tipping the balance[END_REF]. A slight increase in the risk of infections due to prolonged immunosuppression was reported in rheumatological patients as far as in IBD patients, expecially in severe ones requiring concomitant and prolonged steroid use [START_REF] Bonghartz | Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and metaanalysis of rare harmful effects in randomized controlled trials[END_REF][START_REF] Lichtenstein | Serious infections and mortality in association with therapies for crn's disease: TREAT registry[END_REF]. In particular, several cases of pneumonia, including severe cases by Nocardia Cyriacigeorgica (5), Legionella pneumophila and Pneumocysti carinii, were reported in the recent years.

On the other hand the safety of these agents on patients with myasthenia gravis has not been assessed. Only one case report showed the potential benefit coming from therapy with infliximab in one patient with myasthenia gravis, but the appearance of infectious side-effects, as in our patient, lead to withdrawal of this biological agent [START_REF] Kakoulidou | A clinical and immunological study of a myasthenia gravis patient treated with infliximab[END_REF]. To our knowledge this should be the first report of use of adalimumab in a patient with myasthenia gravis.

Figure 1 .

 1 Figure 1. Chest X-ray performed at Emergency Unit showing consolidation in the lower left


Keywords: SAPHO, inflammatory bowel disease, CRMO, Ulcerative colitis

syndrome is a rare group of sterile, inflammatory osteoarticular disorders classically associated with skin lesions. It is occasionally associated with enteropathic disease such as ulcerative colitis. We present a 39 year old patient with chronic ulcerative colitis who developed enteropathic SAPHO and responded well to pamidronate. We discuss the clinicopathological features with particular attention to bone pathology, and perform a literature review of this fascinating syndrome.

Case presentation

A 39 year old female was referred to the rheumatology department with a 6 month history of nontraumatic, relapsing and remitting, right clavicular pain and swelling in 2007. Her past medical

history was significant for a 20 year history of histologically confirmed ulcerative pancolitis which required a subtotal colectomy in 2005. 3 months prior to her colectomy, she had presented to the spinal surgery team with an acute episode of lumbar back pain which had last several weeks.

Technetium scintigraphy was arranged to investigate the possibility of metastatic disease, showing increased uptake to L4 vertebral body. MRI spine excluded a fracture and revealed high intensity T2 lesions in the affected vertebral body. Subsequent biopsy of L4 vertebral body was unremarkable except for irregular, thick trabeculae with osteoblasts and osteoclasts. As the symptoms had spontaneously resolved without recurrence 6 months later, she was subsequently discharged.

On examination, tenderness of the medial aspect of the right clavicle was elicited. Shoulder movement was normal. There were no dermatological findings. Chest X-ray revealed sclerosis of the affected area, which had initially been normal on clavicular X-ray at presentation. Subsequent MRI revealed low-signal T1 lesion and hyperintense STIR signal affecting the entire right clavicle and surrounding soft tissue (Figure 1), with sparing of the sternum, suggestive of a neoplastic or infective process. Her routine blood results revealed mildly elevated serum alkaline phosphatase (ALP) and Creactive protein (CRP) concentrations at 75u/L and 17mg/L respectively. Serum white cell count, neutrophils, urea and electrolytes and remaining liver function parameters were all within normal limits. Corrected calcium was normal at 2.4mmol/L. Blood cultures were negative. CT imaging (Figure 2) to exclude Ewing's sarcoma demonstrated medullary sclerosis, irregular cortical erosion and periosteal reaction of the medial right clavicle, consistent with mild indolent osteomyelitis. Biopsy of the area revealed irregular bony trabeculae with increased osteoblastic and osteoclastic activity and associated fibrosis.

In view of the clinical history of coexistent ulcerative colitis with radiological findings of hyperostosis and osteitis, and with the exclusion of an infective or malignant process, the diagnosis of enteropathic SAPHO syndrome was made. In hindsight, SAPHO may have affected the L4 vertebra prior to colectomy, but was only recognised after presenting in her right clavicle 2 years after. Her symptoms abated with low-dose meloxicam. A trial of oral bisphosphonate failed to relieve symptoms, however, an initial infusion of intravenous bisphosphonate (60mg pamidronate) effectively drove the patient into remission. She now receives 3 monthly pamidronate infusions when required for frequent relapses.

Discussion

First coined by Chamot et al in 1987, [START_REF] Chamot | Le syndrome acnè pustulose hyperostose ostèite (SAPHO) -Resultats d'une enquète nationale[END_REF] the acronym SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) represents all 5 features of their osteoarticular-dermatological syndrome. Over the years, SAPHO has been controversially adapted to encompass a spectrum of disorders sharing clinical and histological features, with more than 50 previously independent entities included under this umbrella term, [START_REF] Kahn | The SAPHO-Syndrome[END_REF] such as chronic recurrent multifocal osteomyelitis (CRMO), anterior chest wall syndrome and sternocostoclavicular hyperostosis. Despite the acronym, osteitis and hyperostosis constitute the hallmarks of SAPHO syndrome. The diagnosis can be made in the absence of cutaneous signs, which if they present, usually occur within 2 years from the onset of bone symptoms, although the interval may be in excess of 20 years. [START_REF] Hayem | SAPHO syndrome: A long-term follow-up study of 120 cases[END_REF] The currently accepted diagnostic criteria for SAPHO syndrome is based on fulfilling at least one of the following parameters originally determined by Kahn et al in 1994: [START_REF] Kahn | The SAPHO-Syndrome[END_REF] 1) Multifocal osteitis with or without skin manifestations 2) Sterile acute or chronic joint inflammation associated with either pustules from psoriasis (usually palmoplantar) or severe acne (conglobata or fulminans)

3) Sterile osteitis in the presence of any of the above skin manifestations. SAPHO syndrome is rare with no accurate incidence data. It is of indeterminate aetiology, although some authors believe that an antigenic trigger, related to low grade Proprionobacterium acnes infection, may be contributory. [START_REF] Kotilainen | Propioni-bacterium acnes isolated from sternal osteitis in a patient with SAPHO syndrome[END_REF] Others regard SAPHO to be an additional member of the seronegative spondyloarthropathies, [START_REF] Kilursu | A study of musculoskeletal manifestations in 12 patients with SAPHO Syndrome[END_REF][START_REF] Benhamou | Synovitis-acne-pustulosis-hyperostosisosteomyelitis syndrome (SAPHO): a new syndrome among the spondyloarthropathies?[END_REF] in view of common findings such as sacroiliitis and vertebral body involvement which occurs in about 50% of patients, [START_REF] Kahn | The SAPHO-Syndrome[END_REF][START_REF] Kilursu | A study of musculoskeletal manifestations in 12 patients with SAPHO Syndrome[END_REF] the higher prevalence of the HLA-B27 antigen (in 33%), [START_REF] Chamot | Le syndrome acnè pustulose hyperostose ostèite (SAPHO) -Resultats d'une enquète nationale[END_REF][START_REF] Kahn | The SAPHO-Syndrome[END_REF][START_REF] Benhamou | Synovitis-acne-pustulosis-hyperostosisosteomyelitis syndrome (SAPHO): a new syndrome among the spondyloarthropathies?[END_REF] and the association with extra-articular manifestations such as inflammatory bowel disease, [START_REF] Kahn | Enterocolopathies chroniques et syndrome SAPHO[END_REF][START_REF] Schilling | Chronic recurrent multifocal osteomyelitis in association with chronic inflammatory bowel disease: entheropathic CRMO[END_REF][START_REF] Bousvaros | Chronic recurrent multifocal osteomyelitis associated with chronic inflammatory bowel disease in children[END_REF][START_REF] Schilling | Orphanet Encyclopedia[END_REF] enthesopathies, uveitis and psoriasis. [START_REF] Kahn | The SAPHO-Syndrome[END_REF][START_REF] Benhamou | Synovitis-acne-pustulosis-hyperostosisosteomyelitis syndrome (SAPHO): a new syndrome among the spondyloarthropathies?[END_REF][START_REF] Kahn | Enterocolopathies chroniques et syndrome SAPHO[END_REF][START_REF] Schilling | Chronic recurrent multifocal osteomyelitis in association with chronic inflammatory bowel disease: entheropathic CRMO[END_REF] CRMO, which is the commonest presentation of SAPHO syndrome, was found to affect 49% of patients in one cohort consisting of 173 SAPHO patients. [START_REF] Schilling | Orphanet Encyclopedia[END_REF] CRMO is a clinicopathological diagnosis whereby sterile osteomyelitis (osteitis) is the key feature. The acronym is misleading. It is not necessarily chronic, recurrent nor multifocal in adults, although this is usually the case in children. [START_REF] Schilling | Orphanet Encyclopedia[END_REF] CRMO is usually chronic with a relapsing and remitting course, although a subacute course before permanent remission may be observed. It typically affects multiple sites in children, [START_REF] Chamot | Le syndrome acnè pustulose hyperostose ostèite (SAPHO) -Resultats d'une enquète nationale[END_REF][START_REF] Kahn | The SAPHO-Syndrome[END_REF] although unifocal CRMO, especially when affecting the clavicle, is a recognized entity in adults. [START_REF] Schilling | Orphanet Encyclopedia[END_REF] It is often described in children and young adults, and is rare in adults when the literal terminology is applied.

Characteristically, the condition has a predilection for the anterior chest wall in 65-90%, with medial clavicle involvement being the clinical hallmark. [START_REF] Schilling | The SAPHO syndrome-Clinical and radiological differentiation and classification on the basis of 86 cases[END_REF] The vertebrae are the second most commonly affected site (30%), followed by the diaphyses of long bones, mandible and iliac bones (in 10%). [START_REF] Schilling | The SAPHO syndrome-Clinical and radiological differentiation and classification on the basis of 86 cases[END_REF] The number of affected areas reduce with increasing age. [START_REF] Schilling | Orphanet Encyclopedia[END_REF] Technetium scintigraphy is useful for screening affected sites. On X-ray and CT imaging, the affected bone is often enlarged (hyperostosed) and sclerotic due to inflammation. MRI may reveal bone marrow oedema and synovitis. Histologically, a periosteal reaction from leukocyte infiltration, along with increased osteolytic and osteoblastic activity resembling Paget's disease may be observed. [START_REF] Reith | Osseous manifestations of SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis) syndrome[END_REF][START_REF] Kahn | SAPHO syndrome[END_REF] Absence of bacterial cells is obligatory. With clinical features that vary between children and adult CRMO, [START_REF] Kahn | The SAPHO-Syndrome[END_REF][START_REF] Kahn | SAPHO syndrome[END_REF] SAPHO syndrome is regarded by Kahn to be the adult version of CRMO. [START_REF] Kahn | The SAPHO-Syndrome[END_REF] The occurrence of SAPHO syndrome in a middle-aged patient with ulcerative colitis, as reported in our case, is very rare. In Germany, where the condition has been well recognized, the incidence of CRMO is estimated at 0.04%, [START_REF] Schilling | Orphanet Encyclopedia[END_REF] with the enteropathic variant reported to affect 9% of CRMO patients. [START_REF] Schilling | Chronic recurrent multifocal osteomyelitis in association with chronic inflammatory bowel disease: entheropathic CRMO[END_REF] However, enteropathic SAPHO are typically reported in children and young adults, with the majority of cases occurring in conjunction with Crohn's disease. Only 20-25% of enteropathic variants are associated with ulcerative colitis. [START_REF] Schilling | Chronic recurrent multifocal osteomyelitis in association with chronic inflammatory bowel disease: entheropathic CRMO[END_REF] The overall picture is of CRMO, usually preceding gastrointestinal disease for as long as 5 years in children. [START_REF] Kahn | Enterocolopathies chroniques et syndrome SAPHO[END_REF] Skin lesions are present in 40% of cases, [START_REF] Kahn | Enterocolopathies chroniques et syndrome SAPHO[END_REF] with palmoplantar pustulosis being the commonest lesion. [START_REF] Schilling | Chronic recurrent multifocal osteomyelitis in association with chronic inflammatory bowel disease: entheropathic CRMO[END_REF] Schilling and Marker-Hermann proposed that the pathogenesis of enteropathic SAPHO may be similar to that of enteropathic spondyloarthropathies, and hypothesized that the disorder may be driven by a common antigen inappropriately activating T-cells within lymphoid tissues of the skin-gut-bone axis. [START_REF] Schilling | Chronic recurrent multifocal osteomyelitis in association with chronic inflammatory bowel disease: entheropathic CRMO[END_REF] However, unlike spondyloarthropathies, most patients with enteropathic SAPHO are HLA-B27 negative.

Furthermore, although the role of the synovium in autoimmune disease has been well explored, there is poor understanding why bone should be affected. With regard to our patient, we believe that chronic inflammation within the gut from her 20 year history of colitis may have resulted in abnormal bowel permeability, thereby allowing the abnormal trafficking of lymphocytes from gut mucosa target other tissues. However, no in vitro pathological model exists of enteropathic SAPHO, and its mechanisms remain to be elucidated. Due to the rarity of the condition, the clinical presentation and course of enteropathic SAPHO in adults is also poorly understood.

Currently, no specific treatment exists for SAPHO syndrome. Due to the lack of patient numbers, there have been no randomized placebo-controlled trials. Traditionally, NSAIDs, sulfasalazine and corticosteroids have been tried with varying degrees of success. Azithromycin, which has been beneficial for acne, has been reported to provide rapid osteoarticular relief in over 50% of patients, [START_REF] Schilling | Azithromycin: an anti-inflammatory effect in chronic recurrent multifocal osteomyelitis? A preliminary report[END_REF] and are used by some authorities as first line. [START_REF] Schilling | Orphanet Encyclopedia[END_REF] Infliximab, which has confirmed efficacy in seronegative spondyloarthropathies, may have a role especially in SAPHO associated with Crohn's disease, although its evidence is confined to case reports. Recently, nasal calcitonin has found favour in paediatric patients. However, intravenous pamidronate has now become the cornerstone of treatment for SAPHO syndrome given its safety profile and efficacy. In one series, it has induced complete remission in 60% and partial remission in 30% of patients. [START_REF] Amital | SAPHO syndrome treated with pamidronate: an open-label study of 10 patients[END_REF] Bisphosphonates were initially introduced based on their efficacy in other conditions where bone becomes dysregulated, such as in Paget's disease, which shares histological similarities to CRMO. They act by inducing osteoclastic apoptosis and exert an anti-inflammatory effect within bone by modulating cytokine concentrations. [START_REF] Amital | SAPHO syndrome treated with pamidronate: an open-label study of 10 patients[END_REF] Better understanding of SAPHO and its enteropathic variant is crucial for the treatment of the condition, which may carry a chronic course with prolonged morbidity.

Conclusion

We present a 39 year old patient with ulcerative colitis with a rare diagnosis of enteropathic SAPHO syndrome predominantly affecting the right clavicle, with good response to pamidronate therapy.

Recognition of this condition is important, as the condition is often chronic, and treatment options are available. It can occur, but is often undiagnosed, in the absence of cutaneous manifestations. Knowledge of the condition may help to differentiate it from a malignant process and avoid repeated bone biopsies.