Fcγ receptor profile of monocytes and macrophages from rheumatoid arthritis patients and their response to immune complexes formed with autoantibodies to citrullinated proteins.

OBJECTIVE: To analyse Fcγ receptor (FcγR) expression on monocytes and macrophages from rheumatoid arthritis (RA) patients versus healthy controls (HC), and to compare their responses to immune complexes containing RA-specific anti-citrullinated proteins auto antibodies (ACPA). METHODS: Monocytes and monocyte-derived macrophages were obtained from the peripheral blood of 34 RA patients and 69 HC. FcγR expression was studied by flow cytometry. Cells were stimulated with ACPA-containing immune complexes, and tumour necrosis factor alpha (TNFα) was assayed in culture supernatants. RESULTS: Variations distinguished RA from HC monocytes, corresponding to a 5% and 6% decrease in the percentages of monocytes expressing FcγRI and FcγRII, respectively, and a 7% increase in the proportion of FcγRIII-positive monocytes. Although in both HC and RA patients macrophage differentiation was accompanied by a dramatic increase in the percentage of FcγRIII-expressing cells (72% vs 74.5%), the parallel decline in the proportion of FcγRI-positive cells was markedly smaller in RA (7% vs 43%). Monocytes and macrophages from patients were responsive to ACPA-containing immune complexes but TNFα production in both cell types neither differed from that observed with the corresponding cells from HC, nor correlated with FcγR expression or clinical or biological data. In RA as in HC, ACPA-containing immune complexes induced secretions of more TNFα in macrophages than in paired monocytes (ninefold). Finally, the proinflammatory potential of ACPA-containing immune complexes was confirmed in CD14-positive monocyte macrophages from the synovial fluid of four RA patients. CONCLUSIONS: ACPA-containing immune complexes induce TNFα secretion by blood and synovial fluid-derived macrophages from RA patients, fitting with their probable involvement in RA pathophysiology.

Clinical manifestations of anti-synthetase syndrome positive for anti-alanyl-tRNA synthetase (anti-PL12) antibodies: a retrospective study of 17 cases.

OBJECTIVE: To describe the clinical manifestations of the anti-synthetase syndrome (ASS) specifically associated with anti-alanyl-tRNA (anti-PL12) synthetase antibodies. METHODS: In a retrospective study, 17 patients (eight males, nine females, mean age = 60.3 years) with ASS symptoms confirmed by two consecutive tests (cyto-dot and/or immunoblot, or both), with positive results for anti-PL12 antibodies, were included. RESULTS: All patients presented with interstitial lung disease (ILD), which was associated with mild myositis in 41% of the cases. RP and general impairment were common, whereas rheumatic and dermatological symptoms were uncommon. Four patients suffered from SS, and four others had an atypical oesophageal involvement. The long-term course was assessable for 10 patients (follow-up of 41.1 months). Five patients required immunosuppressive drugs. Two patients are waiting for a lung transplant because of disproportionate and refractory pulmonary hypertension. CONCLUSION: The severity of anti-PL12 ASS varied because of the constant pulmonary involvement. ILD was the predominant prognosis factor, which was notable in cases associated with pulmonary hypertension.

Posttraumatic psoriatic osteitis of the frontal bone successfully treated with etanercept. Report of a case.

We report a case of aseptic osteomyelitis of the frontal bone that developed after a local injury in an 8-year-old girl with psoriasis of the scalp as a predisposing factor. Follow-up was 36 years (1972 to 2008). Enthesitis of the forehead muscles was a plausible pathophysiological mechanism. The symptoms responded to anti-inflammatory medications and resolved immediately after the introduction of etanercept therapy. The most interesting feature of this case of psoriatic osteomyelitis is the involvement of a skull bone.

Maffucci syndrome and adrenal cortex tumor.

We report the second known case of Maffucci syndrome associated with an adrenal cortex tumor. Endocrine tumors have been reported in patients with multiple enchondromas, although the underlying mechanism of this combination is unknown. Maffucci syndrome is characterized by abnormalities of several mesodermal derivates. Therefore, routine evaluation for involvement of the adrenal cortex may be warranted to improve our knowledge of this syndrome and of its pathophysiology.

Aseptic osteomyelitis responding to TNFalpha antagonist therapy in a patient with Crohn's disease.

Aseptic osteomyelitis was diagnosed in a patient with Crohn's disease. This rarely reported manifestation responded to infliximab therapy.

Morquio syndrome: diagnosis in an adult.

Morquio syndrome or mucopolysaccharidosis (MPS) type IV is a rare autosomal recessive disease in which keratan sulfate builds up in cells. There are two variants, A and B, corresponding to deficiencies of two different enzymes. Type A is usually severe, although considerable clinical variability occurs due to the existence of attenuated phenotypes, which may escape diagnosis until adulthood. We illustrate this little known possibility by reporting a case of MPS IV A diagnosed in a 38-year-old woman. We review the clinical and radiological features of this disease, with which pediatricians are more familiar than other physicians. Our case provides an opportunity to emphasize the need for management by a rheumatologist in addition to the standard surgical treatment.

Maintenance of infliximab treatment in ankylosing spondylitis: results of a one-year randomized controlled trial comparing systematic versus on-demand treatment.

OBJECTIVE: Continuous treatment with the anti-tumor necrosis factor alpha (anti-TNFalpha) antibody infliximab is efficacious in ankylosing spondylitis (AS), whereas treatment discontinuation results in disease relapse, with variable delay. This study was undertaken to compare the efficacy of continuous treatment with infliximab with that of a treatment regimen adapted to symptom recurrence. Methotrexate (MTX) in combination with infliximab was also tested. METHODS: Patients with active AS were randomly assigned at week 0 to receive infliximab every 6 weeks (continuous treatment) or upon symptom recurrence (on-demand treatment), following infusions at weeks 4, 6, and 10. Patients in the on-demand group were randomly assigned to receive either MTX in combination with infliximab or infliximab alone. Patients were monitored for 1 year. The primary end point was the proportion of patients who met the ASsessment in AS International Working Group criteria for 20% improvement (ASAS20) at week 58. RESULTS: Of 247 patients, 124 were assigned to receive infliximab every 6 weeks and 123 to receive on-demand treatment. Among the latter, 62 received MTX, and 61 received infliximab alone. A greater proportion of patients receiving infliximab every 6 weeks fulfilled ASAS20 response criteria at week 58 than did patients receiving on-demand treatment (75% versus 46%; P<0.0001). Patients in the continuous treatment group received more infliximab infusions after week 10 than did those in the on-demand group (mean+/-SD 5.8+/-2.2 versus 3.5+/-2; P<0.0001). Addition of MTX did not significantly affect the proportion of patients with an ASAS20 response at week 58, nor the number of infliximab infusions administered. CONCLUSION: These findings indicate that continuous treatment of AS with infliximab is more efficacious than on-demand treatment, and that the addition of MTX to infliximab provides no significant benefit.

An unusual presentation of primary hyperparathyroidism: severe hypercalcemia and multiple brown tumors.

Primary hyperparathyroidism is common, particularly in postmenopausal women. Since the introduction of routine automated serum calcium assays and the development of assays for intact 1-84 parathyroid hormone, the diagnosis is usually made fortuitously in asymptomatic patients or during evaluation for osteoporosis. As a result, many physicians have no experience with the clinical manifestations. Here, we describe the case of a 70-year-old man with bone pain, multiple brown tumors, and severe hypercalcemia (4 mmol/L). The diagnostic pitfalls raised by these symptoms are illustrated.

Whipple disease revealed by musculocutaneous symptoms, with muscle biopsy cultures positive for Tropheryma whipplei.

A patient experienced sudden onset of musculocutaneous symptoms 3 years after being diagnosed with polyarthritis. Biopsies from the duodenum, skin, and muscle established the diagnosis of Whipple disease. Cultures of muscle biopsy specimens grew Tropheryma whipplei. Adequate antibiotic therapy ensured a favorable outcome. To our knowledge, this is the first case in which T. whipplei was recovered from muscle biopsy specimens, confirming the infectious nature of muscle involvement in Whipple disease.

Extrasynovial ultrasound abnormalities in the psoriatic finger. Prospective comparative power-doppler study versus rheumatoid arthritis.

We prospectively compared power Doppler ultrasound findings in 25 fingers with rheumatoid arthritis (RA) and 25 fingers with psoriatic arthritis (PsA). Erosive synovitis and tenosynovitis were seen in both groups. Extrasynovial changes were found in 21/24 (84%) fingers with PsA versus none of the fingers with RA. Of the 21 PsA fingers exhibiting extrasynovial changes, 15 (15/25, 60%) also had synovial changes. The extrasynovial changes reflected enthesitis or soft tissue inflammation, with the main patterns being capsular enthesophyte, juxtaarticular periosteal reaction, enthesopathy at the site of deep flexor tendon insertion on the distal phalanx, and subcutaneous soft tissue thickening of the finger pad or entire finger. In four fingers, ultrasonograhy showed pseudotenosynovitis, an underrecognized abnormality characterized by diffuse inflammation of the digital soft tissues. Pseudotenosynovitis may play a pivotal role in dactylitis (sausage digit), which is defined as diffuse uniform swelling of the entire finger. Our findings suggest that inflammation of the fibrous skeleton of the finger may lead to the clinical and radiological features that distinguish PsA from RA of the finger.

Acitretin-induced enthesitis in a patient with psoriatic arthritis.

A patient with psoriatic arthritis and cutaneous psoriasis took acitretin for 10 years to treat his skin lesions. Radiographs disclosed exuberant ossifications in several entheses. Their features were not typical for psoriatic arthritis but were consistent with acitretin-induced hyperostosis. Retinoids are known to induce hyperostosis, most notably when they are used in high dosages and over long periods. The concomitant presence of two conditions affecting the entheses may explain the exuberant nature of the ossifications in our patient.

Pathology and clinico-pathologic correlations in spondyloarthropathies.

The term "spondyloarthritis" encompasses a variety of conditions that manifest as inflammation of the synovial membranes and entheses. The synovial inflammation lacks specificity and shares many features with rheumatoid synovitis. The hallmark of spondyloarthritis is inflammation of the entheses, which manifests as a combination of hyperostosis, osteitis, and periostitis. The entheses include not only the sites where tendons, ligaments, and joint capsules attach to bone, but also other fibrous structures such as the amphiarthroses (pubic symphysis, manubriosternal symphysis, and discovertebral junctions) and the diarthro-amphiarthroses (sacroiliac area, chest wall joints, and tips of the fingers and toes). This vast entheseal territory is the target selectively involved in patients with spondyloarthropathy.

Spondyloarthropathy with entheseal pain. A prospective study in 33 patients.

OBJECTIVES: To identify objective features individualizing spondyloarthropathy with isolated entheseal pain and distinguishing this condition from fibromyalgia. PATIENTS AND METHODS: Thirty-three patients presenting with entheseal pain were studied prospectively. The diagnoses were psoriatic arthritis in six patients and ankylosing spondylitis in seven patients; among the 20 remaining patients, in whom entheseal pain was the only symptom, 11 responded to nonsteroidal antiinflammatory drugs (NSAIDs) and were diagnosed with entheseal spondyloarthropathy whereas the nine unresponsive patients were diagnosed with fibromyalgia. A physical examination, laboratory tests, plain radiographs, and radionuclide scan and resonance imaging (MRI) scan of a painful enthesis were done in each patient. RESULTS: Among the 11 patients with entheseal spondyloarthropathy, two experienced inflammatory joint symptoms during the 4-6-month follow-up and three patients had radionuclide scanning and MRI evidence of entheseal inflammation similar to that in nine patients with definite spondyloarthropathy (ankylosing spondylitis or psoriatic arthritis). The feature that best discriminated between entheseal spondyloarthropathy and fibromyalgia was responsiveness to NSAIDs. CONCLUSION: These preliminary data suggest that isolated entheseal pain may indicate spondyloarthropathy in some patients. The imaging methods used in this study lacked sensitivity for enthesitis, which may therefore have been missed in some patients. The development of bone and joint ultrasonography may provide additional insights into the entheseal abnormalities present in patients with isolated entheseal pain.

Detection of antibodies to deiminated recombinant rat filaggrin by enzyme-linked immunosorbent assay: a highly effective test for the diagnosis of rheumatoid arthritis.

OBJECTIVE: To assay antifilaggrin autoantibodies, we developed an enzyme-linked immunosorbent assay (ELISA) using a "citrullinated" recombinant rat filaggrin. Our objectives were to assess its value for diagnosing rheumatoid arthritis (RA) and to compare the results with those obtained using 4 other reference methods for detection of antifilaggrin autoantibodies, including the commercially available ELISA that uses a modified "citrullinated" synthetic peptide derived from the sequence of human filaggrin (CCP-ELISA). METHODS: We analyzed 711 sera from patients with well-characterized rheumatic diseases, including 240 patients with RA. Antifilaggrin autoantibodies were detected by an ELISA using a recombinant rat filaggrin deiminated in vitro as immunosorbent (ArFA-ELISA). The results considered were the differences between the optical densities obtained on deiminated and nondeiminated proteins. Antibodies to rat esophagus epithelium were detected by indirect immunofluorescence, while antibodies to human filaggrin were detected by immunoblotting and by a recently described ELISA using a deiminated recombinant human filaggrin. Finally, CCP-ELISA was performed according to the manufacturer's recommendations. RESULTS: At the titer thresholds allowing diagnostic specificities of 0.95, 0.985, and 0.99 to be reached, the diagnostic sensitivities of the ArFA-ELISA were 0.76, 0.67, and 0.65, respectively. At these 3 thresholds, the sensitivities were significantly higher than those of the 4 other tests. Despite incomplete overlapping of the 5 tests, the high diagnostic performance of the ArFA-ELISA allows us to propose this test to replace all the other methods for antifilaggrin autoantibody detection. CONCLUSION: ArFA-ELISA appears to be the most efficient test among those available for the detection of antifilaggrin autoantibodies, in terms of diagnostic accuracy for RA. Its diagnostic performance in early RA and its prognostic value are currently under evaluation.

Myeloma and monoclonal gammopathy of uncertain significance associated with acquired von Willebrand's syndrome. Seven new cases with a literature review.

OBJECTIVES: Acquired von Willebrand's syndrome (AvWS) is an uncommon complication of monoclonal gammopathy of uncertain significance (MGUS) or myeloma. We investigated clinical and laboratory test abnormalities, pathophysiological hypotheses, and treatment options in this poorly known condition. PATIENTS: Five patients with MGUS and two with myeloma who met classic criteria for acquired von Willebrand's syndrome were included in this retrospective study. RESULTS: Acquired von Willebrand's syndrome was diagnosed before the gammopathy in five of the seven patients. The severity of the bleeding events was chiefly dependent on the degree of von Willebrand's factor deficiency and on the presence or absence of gastrointestinal tract angiodysplasia. Bleeding event severity was similar in patients with nonmalignant and malignant disease. An antibody that inhibited von Willebrand's factor was detected in all seven patients. Clotting returned to normal after treatment of the malignancy in one of the two patients with myeloma. In patients with MGUS, treatment is warranted only when bleeding occurs or before surgery. Von Willebrand's factor concentrates were of limited efficacy because of their short half-life. Intravenous immunoglobulins had a longer-lasting effect (about 3 weeks); this treatment was used on a regular basis in two patients with recurrent bleeding. CONCLUSIONS: A diagnosis of von Willebrand's syndrome in adulthood should prompt a search for a monoclonal gammopathy. In patients with gammopathies, simple clotting tests ensure the diagnosis of acquired von Willebrand's syndrome.