Predictive risk factors of serious infections in patients with rheumatoid arthritis treated with abatacept in common practice: results from the Orencia and Rheumatoid Arthritis (ORA) registry.

OBJECTIVES: Little data are available regarding the rate and predicting factors of serious infections in patients with rheumatoid arthritis (RA) treated with abatacept (ABA) in daily practice. We therefore addressed this issue using real-life data from the Orencia and Rheumatoid Arthritis (ORA) registry. METHODS: ORA is an independent 5-year prospective registry promoted by the French Society of Rheumatology that includes patients with RA treated with ABA. At baseline, 3 months, 6 months and every 6 months or at disease relapse, during 5 years, standardised information is prospectively collected by trained clinical nurses. A serious infection was defined as an infection occurring during treatment with ABA or during the 3 months following withdrawal of ABA without any initiation of a new biologic and requiring hospitalisation and/or intravenous antibiotics and/or resulting in death. RESULTS: Baseline characteristics and comorbidities: among the 976 patients included with a follow-up of at least 3 months (total follow-up of 1903 patient-years), 78 serious infections occurred in 69 patients (4.1/100 patient-years). Predicting factors of serious infections: on univariate analysis, an older age, history of previous serious or recurrent infections, diabetes and a lower number of previous anti-tumour necrosis factor were associated with a higher risk of serious infections. On multivariate analysis, only age (HR per 10-year increase 1.44, 95% CI 1.17 to 1.76, p=0.001) and history of previous serious or recurrent infections (HR 1.94, 95% CI 1.18 to 3.20, p=0.009) were significantly associated with a higher risk of serious infections. CONCLUSIONS: In common practice, patients treated with ABA had more comorbidities than in clinical trials and serious infections were slightly more frequently observed. In the ORA registry, predictive risk factors of serious infections include age and history of serious infections.

Cutaneous melanoma in patients treated with tumour necrosis factor inhibitors: a retrospective series of 15 patients.

BACKGROUND: Several case reports suggested that tumour necrosis factor-α (TNF) inhibitors might increase the incidence and/or alter the natural course of melanoma towards a more aggressive behaviour. OBJECTIVE: Our objective was to point if history of melanoma in patients exposed to TNF inhibitors could present with a particular pattern at diagnosis or during follow-up. METHODS: We performed a retrospective multicentre study settled in the West part of France to collect and analyse all cases of patients with melanoma who received anti-TNF therapy. RESULTS: Fifteen cases were included. First, 10 patients (mean age: 55.6 years; sex ratio: 1) had a melanoma diagnosed after TNF inhibitors initiation. The mean duration between initiation of treatment and melanoma was 48.7 months. Two patients died of metastatic disease. Second, four patients had a past history of melanoma before anti-TNF therapy (mean duration of treatment: 10.8 months). None experienced a progression of melanoma disease. Last, one woman had a past history of melanoma before and then developed a second melanoma when exposed to biotherapy. CONCLUSION: Our case series does not reveal a distinct profile of melanoma in the patients exposed to TNF inhibitors. Additional prospective trials including larger number of patient are needed to demonstrate the possible link between biological therapy with TNF inhibitors and development of melanoma.

Anti-tumour necrosis factor treatment in patients with refractory systemic vasculitis associated with rheumatoid arthritis.

OBJECTIVE: To assess anti-tumour necrosis factor (anti-TNF) agents in patients with refractory systemic rheumatoid vasculitis (SRV). METHODS: 1200 rheumatologists and internists were asked to provide medical files for patients with anti-TNF agents given as a second-line treatment for active SRV refractory to cyclophosphamide and glucocorticoids. RESULTS: We identified nine cases in which anti-TNF drugs were given for active SRV, despite previous treatment with a mean cumulative dose of 8.4 g of cyclophosphamide in association with high-dose glucocorticoids. The mean prednisone dose before anti-TNF therapy was 29.6 mg/day. After 6 months, six patients were in remission (complete in five, partial in one). The treatment failed in one patient and two patients stopped taking the anti-TNF treatment due to side-effects. Mean prednisone dose was reduced to 11.2 mg/day. Severe infection occurred in three patients. Relapses were observed in two patients. Remission was re-established by reintroducing anti-TNF therapy in one case and increasing the dose in the other. CONCLUSIONS: This study provides evidence of efficacy of anti-TNF therapy in adjunct to glucocorticoids for treating active refractory SRV. Remission was achieved in two-thirds of patients, with a significant decrease in prednisone dose, although there was a high rate of infection in these severely ill patients.

Cysteine and serine proteases of synovial tissue in rheumatoid arthritis and osteoarthritis.

OBJECTIVE: To compare the activities of cathepsin B (EC 3.4.22.1) and L (EC 3.4.22.15), calpain (EC 3.4.22.17), and dipeptidyl peptidase (EC 3.4.14.5 or DPP IV or CD26) in synovial membrane from patients with rheumatoid arthritis (RA), osteoarthritis (OA), and post-traumatic joint injury (PT). METHODS: Forty RA patients were divided into two groups on the basis of surgical procedure: the RAs group comprised 18 patients requiring surgical synovectomy; the RAr group comprised 22 patients requiring a total joint replacement or arthrodesis. A third group (the OA group) comprised 19 OA patients while six patients with post-traumatic joint injury were included in the fourth group (the PT group). Cathepsin and calpain activity was assessed using a Cobas Fara II centrifugal analyser. DPP IV activity was determined kinetically using a fluorogenic substrate. RESULTS: RAs patients were significantly younger than RAr patients, and the mean duration of RA was shorter in the RAs group than in the RAr group. Cathepsin and calpain activity in synovial membrane was higher in RA and OA patients than in the control group, but no statistical difference was observed between RA and OA. However, cathepsin, calpain, and DPP IV synovial activity was significantly higher in the RAs group than in either the OA or the PT group. CONCLUSION: Our results show that proteinase activity tends to be higher in joints with early synovitis in RA, and suggest that these enzymes are not all involved at the same stage of the disease.

[Cutaneous manifestations during treatment with TNF-alpha blockers: 11 cases]. / Manifestations cutanées observées au cours d'un traitement par anti-TNF alpha: 11 observations.

BACKGROUND: TNFalpha blockers have recently extended the therapeutic arsenal available in dermatology. However, dermatologists must be informed of their potential adverse dermatological effects. While the chief adverse effect of TNFalpha blockers is risk of infection, cutaneous adverse effects have not yet been clearly elucidated and publications on this topic are few and far between. The aim of our study is to report various dermatological problems noted during treatment with TNFalpha blockers. PATIENTS AND METHODS: This was a retrospective study of patient files. The study population comprised patients receiving TNFalpha blockers and presenting cutaneous reaction, and seen in the dermatology department between August 2001 and December 2004. RESULTS: Eleven patients were included. The following cutaneous reactions were seen: delayed skin rash (1 case), lupus syndrome (1 case), cutaneous vasculitis (2 cases), palmoplantar pustulosis (2 cases), psoriasis vulgaris (1 case), atopic dermatitis (1 case), lichenoid rash (1 case), purpuric capillaritis (1 case) and melanoma (1 case). DISCUSSION: The cutaneous manifestations seen represented a wide range of different clinical pictures. Dermatologists must be aware of these potential adverse effects. Future improvement of knowledge of the physiopathological mechanisms as well as the institution of prospective cohort studies should provide clearer guidance on the management of such symptoms.

Emergence of Legionella pneumophila pneumonia in patients receiving tumor necrosis factor-alpha antagonists.

BACKGROUND: Patients treated with tumor necrosis factor-alpha (TNF-alpha) antagonists have an increased risk of infection, but infection due to Legionella pneumophila has rarely been described in patients receiving such therapy. METHODS: A registry involving 486 clinical departments in France was designed by a multidisciplinary group (Recherche Axée sur la Tolérance des Biothérapies [RATIO]) to collect data on opportunistic and severe infections occurring in patients treated with TNF-alpha antagonists. All cases are reported to RATIO in accordance with national health authorities and validated by infectious disease experts. The legionellosis rate among patients treated with TNF-alpha antagonists was compared with the rate in France overall. RESULTS: We report a 1-year consecutive series of 10 cases of L. pneumophila pneumonia in France in 2004, including 6 cases treated with adalimumab, 2 treated with etanercept, and 2 treated with infliximab. The median patient age was 51 years (range, 40-69 years). Eight patients were treated for rheumatoid arthritis, 1 was treated for cutaneous psoriasis, and 1 was treated for pyoderma gangrenosum. The median duration of TNF-alpha antagonist treatment at onset of infection was 38.5 weeks (range, 3-73 weeks). Eight patients were receiving concomitant treatment with corticosteroids, and 6 were receiving treatment with methotrexate. The relative risk of legionellosis when receiving treatment with a TNF-alpha antagonist, compared with the relative risk in France overall, was estimated to be between 16.5 and 21.0. We also report a second episode of confirmed legionellosis following the reintroduction of infliximab therapy. CONCLUSIONS: L. pneumophila pneumonia is a potentially severe but curable infection that might complicate anti-TNF-alpha therapy. In patients receiving anti-TNF-alpha who develop pneumonia, legionellosis should be systematically investigated, and first-line antibiotic therapy should be efficient against L. pneumophila.

Lack of efficacy of a third tumour necrosis factor alpha antagonist after failure of a soluble receptor and a monoclonal antibody.

OBJECTIVE: Some studies have highlighted the potential benefits of switching from infliximab to etanercept, or after failure of one or the other treatment. To our knowledge, no study has assessed the potential benefits of using the three anti-TNF-alpha agents that are currently available. The objective of this retrospective study was to assess the response to treatment in RA patients who had received the three anti-TNF-alpha agents, namely infliximab, etanercept and adalimumab. METHODS: Among a cohort of 364 patients undergoing biological treatments since the year 2000, 284 had been treated with only one anti-TNF-alpha agent. Our assessment focused on the records of 70 patients who had received at least two anti-TNF-alpha agents. Twenty of the 70 patients had received all three anti-TNF-alpha agents (infliximab, etanercept and adalimumab). Effectiveness was assessed using the 28-joint Disease Activity Score (DAS28), and adverse events were reported for each anti-TNF-alpha treatment. RESULTS: Of the 70 patients who had received two anti-TNF-alpha agents, 32 had switched from an antibody to a soluble receptor; 45% of them had a good clinical response to the soluble receptor. Thirty patients had switched from a soluble receptor to an antibody; 45% of them had a good clinical response to the antibody. Only eight patients had switched from an antibody to another antibody with an efficiency score of 33%. Of the 20 patients who had received three anti-TNF-alpha agents, seven had stopped receiving the third anti-TNF-alpha agent due to lack of effectiveness. In this group of non-responders to the third anti-TNF-alpha treatment, all patients except one had stopped receiving the two previous anti-TNF-alpha agents, without adverse events, for lack of effectiveness. These patients were deemed resistant to anti-TNF-alpha therapy. CONCLUSIONS: Resistance to anti-TNF-alpha agents is rare. The lack of effectiveness of a soluble receptor and of one of the anti-TNF-alpha antibodies predicts the lack of effectiveness of the third anti-TNF-alpha treatment.

The usefulness of bone remodelling markers in predicting the efficacy of pamidronate treatment in SAPHO syndrome.

OBJECTIVES: Pamidronate has recently been used in SAPHO syndrome due to its anti-osteoclastic effect. The aim of this study is to determine the usefulness of bone remodelling markers for determining the efficacy of pamidronate treatment. METHODS: Thirteen patients with SAPHO syndrome were treated with pamidronate. The treatment evaluation was done using a visual analogue scale (VAS) and also erythrocyte sedimentation rate, C-reactive protein, serum crosslaps (sCTX) and osteocalcin initially and after 3 months. A relevant clinical response was defined as an improvement in VAS of at least 40%. RESULTS: At 3 months, 7 of 13 patients had a good clinical response, as previously defined. Five of the seven patients maintained the good response over 6 months. Before the first perfusion 6 of the 13 patients had increased sCTX (upper 3250 pmol/l). In this small cohort we tried to analyse whether the increase in bone remodelling markers was associated with a good clinical response. In the responders group the mean levels of sCTX and osteocalcin at baseline were 6783.17 and 24.66, respectively, and in the non-responders group the levels were 2152 and 11.8, respectively. There was a significant difference in sCTX between the responders and the non-responders (P = 0.0044). CONCLUSION: Infusion of pamidronate is effective in SAPHO in some patients. Increased sCTX might be a prognostic marker for a good clinical response but results have to be confirmed in a larger cohort.

Rat bite fever mimicking rheumatoid arthritis.

We report a case of Streptobacillus moniliformis polyarthritis mimicking a rheumatoid arthritis, in a pet shop employee. In culture of fluid joint growth a curious Gram-negative bacillus was identified by polymerase chain reaction as Streptobacillus moniliformis. The outcome was good after surgical debridment and rifampin-clindamycin combination during 4 weeks.

[Dropped head syndrome: report of two cases]. / Le syndrome de la tête tombante: à propos de deux cas.

PURPOSE: The dropped head syndrome is characterized by an abnormal bending of the head to the body, mainly affecting old people. It corresponds to an alteration of the cervical extensor muscles, revealing in some cases a neuromuscular disease. In some cases, the etiology of this syndrome remains unknown. EXEGESIS: We report here two cases with dropped head syndrome. The first clinical case concerned a 78-year old man, presenting a dropped head syndrome revealing a myasthenia. The syndrome disappeared with specific therapy. The second clinical case was a dropped head syndrome developed in the context of severe depressive syndrome in a 71-year old woman. The etiological screening did not reveal any underlying disease. Counteracting the syndrome was successfully obtained with early physiotherapy. CONCLUSION: The dropped head syndrome can reveal a general disease such as myasthenia or amyotrophic lateral sclerosis. Therefore, investigation needs first to eliminate underlying diseases. If no etiology is found, the dropped head syndrome is considered of an unknown neuromuscular origin or a psychosomatic disease. In this latter case, physiotherapy may be beneficial.

Evaluation of anti-citrullinated filaggrin antibodies as hallmarks for the diagnosis of rheumatic diseases.

BACKGROUND: Anti-filaggrin antibodies (AFA) are among the most specific antibodies for rheumatoid arthritis, so procedures for their detection should be included in early biological diagnoses. AFA can be detected by indirect immunofluorescence (anti-keratin antibodies, AKA) or by new enzyme immunoassays (EIA). Their comparative performance needs to be established. OBJECTIVE: To compare these technical procedures to optimise the serological diagnosis of rheumatoid arthritis. METHODS: Results obtained using AKA and EIA were compared in 271 sera from 140 patients with rheumatoid arthritis at various stages, 98 patients with other autoimmune diseases, and 33 healthy subjects. EIA were successively undertaken with citrullinated linear filaggrin peptide (home made EIA) or cyclic citrullinated peptide (CCP2, commercial kits). Rheumatoid factor (RF) was assessed by EIA in all patients. RESULTS: Anti-CCP2 kits showed the best sensitivity and specificity (65% and 96%, respectively). Among the 140 patients with rheumatoid arthritis, those with very recent disease (less than six months' duration, n = 21) were studied as a separate group. In this group, the sensitivity of anti-CCP2 kits decreased to approximately 50%. Nevertheless this assay remained the most accurate when compared with AKA or home made EIA using linear filaggrin peptides. The combination of anti-CCP2 and RF only slightly increased the sensitivity of the diagnosis of very early rheumatoid arthritis. CONCLUSIONS: Kits using citrullinated cyclic peptides (CCP2) were more suitable than either AKA or EIA using linear filaggrin peptides for the diagnosis of early rheumatoid disease.

Axial osteomalacia with sacroiliitis and moderate phosphate diabetes: report of a case.

We report a new case of axial osteomalacia diagnosed in a 51-year-old white Caucasian male, made particular by its association with sacroiliitis, positive HLA-B27 antigen, and also moderate phosphate diabetes responsible for a decreased appendicular bone mass. The diagnosis was suspected when X-ray evaluation showed increased density and coarse trabeculation mainly involving the pelvis and spine. Dual energy X-ray absorptiometry confirmed the elevated bone density at the lumbar spine (T score: +1.92) contrasting with a decreased bone mass at the femoral neck (T score: -2.33). The diagnosis was confirmed by histomorphometry of the iliac crest showing marked thickening of the cortices (2190 microns +/- 0.574, N = 780 +/- 40) and an increased trabecular bone volume (33.24%, N = 14 +/- 3). Osteoid parameters were also markedly increased with an osteoid volume of 2.1% (N = 1.2 +/- 0.5) and a mean osteoid thickness of 28.7 microns (N = 13 +/- 2.5), with a normal bone fluoride content (0.082%, N < 0.10). Bone resorption as assessed on bone biopsy and by the measurement of markers of bone remodeling (serum procollagen type I C-terminal telopeptide and 24 hr urinary cross-laps to creatinine ratio) was increased. This latter finding was not necessarily due to axial osteomalacia and could be the consequence of moderate phosphate diabetes. The patient was treated with calcitriol which was promptly discontinued due to gastrointestinal symptoms and replaced by calcidiol without any significant effect on the low back pain.

Rheumatologic manifestations of pachydermoperiostosis and preliminary experience with bisphosphonates.

OBJECTIVE: Pachydermoperiostosis is manifested by finger clubbing, hypertrophic skin changes, and periosteal bone formation. We describe 5 cases revealed primarily by their rheumatologic manifestations. Also reported are preliminary experiences on the use of intravenous pamidronate as a treatment. METHODS: This is a retrospective study including the analysis of clinical manifestations, laboratory results and morphological examinations gathered from patients' medical records. We evaluated efficacy of treatment with 1 mg/kg iv pamidronate in the 3 new cases. RESULTS: Before treatment with iv pamidronate, the patients' global assessment was poor (twice) and very poor (once). The physician's global assessment was poor in 3 patients. After treatment with iv pamidronate, 2 patients had significant improvement. Physician and patient global assessments were very good, good, and moderate. No side effects were observed. All biological variables were within normal ranges at 12 month followup visit. CONCLUSION: Pachydermoperiostosis must be recognized by the rheumatologist, since it can present symptomatically through articular manifestations. When conventional treatment modalities fail, iv pamidronate might be useful.

Lack of CD80 expression by fibroblast-like synoviocytes leading to anergy in T lymphocytes.

OBJECTIVE: To investigate whether contact with HLA-DR+, but CD80-, fibroblast-like synoviocytes (FLS) in the presence of antigen leads to the induction of anergy in, rather than stimulation of, T cells. METHODS: Cell surface expression of activation and costimulatory markers on FLS were studied by flow cytometry. Functional changes were investigated by T cell proliferation to tuberculin purified protein derivative or allogeneic responses to FLS, in the presence or absence of DAP3.B7 cells, a human CD80-transfected mouse fibroblast cell line. Induction of anergy was investigated by a 2-stage culture system. T cells were cocultured with allogeneic FLS in the primary culture, rested, and restimulated in the secondary culture by FLS in the presence or absence of DAP3.B7 cells or interleukin-2 (IL-2). RESULTS: Direct contact between T cells and FLS caused up-regulation of CD69 on T cells and HLA-DR on FLS in both the allogeneic and autologous cultures. The addition of DAP3.B7 cells to FLS-T cell cocultures restored the depressed allogeneic responses of T cells. The allogeneic response by T cells to FLS in the presence of DAP3.B7 cells could be completely inhibited by blocking CD80 with CTLA-4 Ig. Indirect evidence that T cells cocultured with FLS were anergic was the up-regulation of CD25, negligible T cell proliferation, and the restoration of proliferation by the addition of exogenous IL-2. Direct evidence of anergy was obtained when T cells from the primary cultures with FLS remained unresponsive to secondary culture with FLS even in the presence of DAP3.B7 cells. In contrast, primary culture of T cells with FLS plus DAP3.B7 cells initiated a good allogeneic response in all subsequent cultures. CONCLUSION: It is possible that T cells within the synovium may be anergized by contact with HLA-DR+ CD80- FLS.

Arthritis, tenosynovitis, fasciitis, and bursitis due to sea urchin spines. A series of 12 cases in Réunion Island.

UNLABELLED: Arthritis, tenosynovitis, and bursitis due to sea urchin spine injuries have unique pathological features and run a chronic course until the spines are removed. Of the 40 cases of sea urchin spine-related clinical symptoms published to date, only 12 had osteoarticular symptoms. PATIENTS AND METHODS: We studied 12 cases with osteoarticular symptoms seen in Réunion Island from 1994 to 1998. There were nine cases of arthritis and one case each of tenosynovitis, fasciitis, and bursitis. The nine males and three females had an age range of 9 to 50 years. RESULTS: The injury was at the knee in six cases, the foot in three, and the hand in three. The time from injury to lesion development ranged from two days to two and a half months. Laboratory tests were normal apart from evidence of mild inflammation in three of the arthritis cases. The spine was visible on plain radiographs in eight cases. Histology was done in seven patients and consistently showed a typical foreign body granuloma. Removal of the spine with synovectomy was performed in 11 cases and consistently ensured a full recovery. DISCUSSION: The clinical manifestations and management in our patients were compared to those in earlier reports. The differential diagnosis of laboratory test, radiographic, and histologic findings is reviewed. Pathogenic hypotheses and the immunogenic effect of the protein sheath that surrounds sea urchin spines are discussed. CONCLUSION: The diagnosis of these frequently under-recognized lesions rests on a careful history and on converging histologic, radiologic, and clinical findings.

Causes of osteoporosis in males. A review of 160 cases.

BACKGROUND: The discovery of osteoporosis in a male requires a careful search for a cause. OBJECTIVE: To evaluate etiologic factors in male osteoporosis. PATIENTS AND METHODS: Males admitted to our department for osteoporosis were included if they had a nontrauma-related vertebral or peripheral fracture and/or a spinal or femoral neck bone mineral density value 2.5 standard deviations or more below the mean in young subjects. The study was retrospective from 1990 to 1995 and prospective from 1996 to 1997. During the prospective part of the study, each subject underwent a standardized battery of laboratory tests including renal tubular function parameters. Causes identified during these two periods were compared. RESULTS: Of the 160 patients included in the study, 28.1% had idiopathic osteoporosis, 22.5% had alcoholic osteoporosis, 19.4% had glucocorticoid-induced osteoporosis, 12.5% had osteoporosis due to moderate idiopathic proximal tubule dysfunction, and 8.8% had senile osteoporosis. The proportion of patients with idiopathic osteoporosis was 30% (23/76) during the retrospective part of the study and 26% (21/84) during the prospective part (nonsignificant difference). Moderate idiopathic proximal tubule dysfunction was found in 2.6% (2/76) and 21.4% (18/84) of patients during these two parts of the study, respectively, a difference ascribable to the routine determination of tubule function parameters during the second part of the study. CONCLUSION: An exhaustive search for a cause decreases the proportion of male osteoporosis cases that remain idiopathic. In our study, only 28% of cases were classified as idiopathic, a term that probably indicates involvement of multiple interrelated factors.

[Osteoporotic vertebral crush fractures with severe neurologic manifestations. Apropos of 6 cases]. / Tassements vertébraux ostéoporotiques avec complications neurologiques sévères. A propos de six observations.

Osteoporotic vertebral crush fractures with neurologic complications are rarely reported in the literature. We report six new cases particularly severe in which death occurred in two cases. The study group included four women and two men with a mean age of 75 years (range: 72-79). Vertebral collapse causing neurological deficit was T5, T9, T11 in two cases, L1 and L3. The mean number of vertebral collapses was three per patient (range: 1-9). Back pain appeared without traumatism 6 weeks before admission (range: 1-24). Neurological complications appeared 2.5 weeks after back pain (range: 1-8). One patient suffered from a paraplegia, three from a paraparesia with bladder dysfunction (n = 1). In one case there was a severe weakness of the levator muscles of the foot and in another a L3 femoral neuralgia with severe bowel and bladder dysfunction. X-rays demonstrated backwards displacement of the posterior cortex in three cases, an intravertebral vacuum phenomenon in two cases and a heterogeneous appearance suggesting a malignancy in two cases. Computed tomography, performed in four patients and tomography in one patient, demonstrated fragmentation of the vertebral body in all the cases and vacuum phenomenon in four cases. Magnetic resonance imaging performed in four cases has confirmed the absence of epiduritis and a compression due to bony structures in two cases. A vertebral biopsy was performed in three cases. Osteoporosis was observed in all the cases and in two cases there was also an osteonecrosis. Surgical treatment was performed in three cases and conservative medical treatment in the other cases. After surgical treatment we have observed an absence of improvement of neurological complications in one case, an improvement in another and finally a full recovery in the last case. After conservative treatment we have noted in two cases an absence of improvement of neurological complications and in one case an improvement of neurological deficit. Two patients died (one after medical treatment and another after surgical treatment).