New-onset vitiligo and progression of pre-existing vitiligo during treatment with biological agents in chronic inflammatory diseases.

BACKGROUND: The development of vitiligo during treatment with biological agents is an unusual event and only a few isolated cases have been reported. OBJECTIVES: To describe the clinical characteristics and evolution of patients developing new-onset vitiligo following initiation of a biological agent for chronic inflammatory disease; and also to report the clinical course of pre-existing vitiligo under biological therapy. METHODS: This nationwide multicentre, retrospective study, carried out between July 2013 and January 2015, describes the characteristics of a large series of 18 patients (psoriasis N = 8, inflammatory rheumatic diseases N = 8, ulcerative colitis N = 1, uveitis N = 1) who developed new-onset vitiligo while receiving a biological agent. RESULTS: TNFα inhibitors were the most common biological agent involved (13/18) while anti-IL-12/23 and anti-IL-17 agents or abatacept were less common (4/18 and 1/18 respectively). Mean duration of biological agent exposure before vitiligo onset was 13.9 ± 16.5 months. Outcome was favourable for most patients (15/17) while maintaining the biological agent. Data were also collected for 18 patients (psoriasis N = 5, inflammatory rheumatic diseases N = 10, inflammatory bowel diseases N = 2, SAPHO N = 1) who had pre-existing vitiligo when treatment with a biological agent started (TNFα inhibitors N = 15, ustekinumab N = 1, rituximab N = 1, tocilizumab N = 1). Vitiligo progressed in seven patients and was stable or improved in eight cases. CONCLUSION: Vitiligo may thus emerge and/or progress during treatment with various biological agents, mainly TNFα inhibitors and could be a new paradoxical skin reaction. De novo vitiligo displays a favourable outcome when maintaining the biological agent, whereas the prognosis seems worse in cases of pre-existing vitiligo.

Safety of surgery after rituximab therapy in 133 patients with rheumatoid arthritis: data from the autoimmunity and rituximab registry.

OBJECTIVE: We used data from the AutoImmunity and Rituximab (AIR) registry to investigate the safety of surgery for patients with rheumatoid arthritis receiving rituximab (RTX) in routine care. METHODS: Data for patients included in the AIR registry and undergoing surgery during the year following an infusion of RTX were reviewed to describe the frequency of postsurgical complications, compare patients with and without complications, and identify factors associated with complications. RESULTS: We examined data for 133 patients with a known date of surgery and at least 1 followup visit, corresponding to 140 procedures, including 94 orthopedic surgeries (67%) and 23 abdominal surgeries (16.5%). The median delay between surgery and the last RTX infusion was 6.4 months (interquartile range 4.3­ 8.7 months), without any difference between patients with and without complications. Nine patients (6.7%) experienced 12 complications (8.5%), including 8 surgical site infections (5.7%) and 1 death due to septic shock. Postoperative complications occurred after 4.3% of abdominal surgeries (1 of 23) and 7.4% of orthopedic surgeries (7 of 95). On univariate analysis, spine surgery was associated with postoperative complications (P = 0.048). CONCLUSION: In common practice, the risk of complications may be more important in case of spine surgery, but does not seem to be linked to the time between the last RTX infusion and surgery.

Eighteen cases of crowned dens syndrome: Presentation and diagnosis.

BACKGROUND AND PURPOSE: Crowned dens syndrome is an ill-known etiology of acute neck pain. METHODS: We carried out a retrospective study of 18 cases of patients with crowned dens syndrome, assessing clinical and radiological features. RESULTS: The results of our study are comparable to data from the literature. The clinical presentation of acute febrile neck pain, occipital headache and multidirectional stiff neck especially affects women aged over 60. No predisposing factor was recognized. However, a history of peripheral joint chondrocalcinosis may reinforce the diagnosis. In more than 50% of cases, laboratory tests showed a marked inflammatory syndrome. The diagnosis was obtained with cervical CT-scan focusing on the C1/C2 joint. This gold standard test was able to show a calcification of the cruciform ligament in connection with deposits of calcium pyrophosphate crystals in almost 80% of cases. Other imaging tests provided little information, including standard radiographs of the cervical spine. MRI can eliminate some differential diagnoses such as infections or neurological emergencies. Complications are infrequent. The standard treatment is based on anti-inflammatory drugs (NSAID, colchicine) or corticosteroids. These treatments are highly effective: a drammatic full recovery of cervical mobility may be observed within 48 hours. In over half of cases, a different diagnosis was initially made, responsible of unnecessary additional tests and treatment. CONCLUSION: A comprehensive consultation, a complete clinical examination and a precise analysis of the imaging will avoid certain investigations and rule out differential diagnoses.

The piriformis muscle syndrome: an exploration of anatomical context, pathophysiological hypotheses and diagnostic criteria.

INTRODUCTION: The piriformis muscle syndrome (PMS) has remained an ill-defined entity. It is a form of entrapment neuropathy involving compression of the sciatic nerve by the piriformis muscle. Bearing this in mind, a medical examination is likely to be suggestive, as a classical range of symptoms corresponds to truncal sciatica with frequently fluctuating pain, initially in the muscles of the buttocks. PATHOPHYSIOLOGICAL HYPOTHESES: The piriformis muscle is biarticular, constituting a bridge in front of and below the sacroiliac joint and behind and above the coxo-femoral joint. It is essentially a lateral rotator but also a hip extensor, and assumes a secondary role as an abductor. Its action is nonetheless conditioned by the position of the homolateral coxo-femoral joint, and it can also function as a hip medial rotator, with the hip being flexed at more than 90°. The main clinical manoeuvres are derived from these types of biomechanical considerations. For instance, as it is close to the hip extensors, the piriformis muscle is tested in medial rotation stretching, in resisted contraction in lateral rotation. On the other hand, when hip flexion surpasses 90°, the piriformis muscle is stretched in lateral rotation, and we have consequently laid emphasis on the manoeuvre we have termed Heel Contra-Lateral Knee (HCLK), which must be prolonged several tens of seconds in order to successfully reproduce the buttocks-centred and frequently associated sciatic symptoms. CONCLUSION: A PMS diagnosis is exclusively clinical, and the only objective of paraclinical evaluation is to eliminate differential diagnoses. The entity under discussion is real, and we favour the FAIR, HCLK and Freiberg stretching manoeuvres and Beatty's resisted contraction manoeuvre.

Piriformis muscle syndrome: diagnostic criteria and treatment of a monocentric series of 250 patients.

OBJECTIVES: Piriformis Muscle Syndrome (PMS) is caused by sciatic nerve compression in the infrapiriformis canal. However, the pathology is poorly understood and difficult to diagnose. This study aimed to devise a clinical assessment score for PMS diagnosis and to develop a treatment strategy. MATERIAL AND METHODS: Two hundred and fifty patients versus 30 control patients with disco-radicular conflict, plus 30 healthy control subjects were enrolled. A range of tests was used to produce a diagnostic score for PMS and an optimum treatment strategy was proposed. RESULTS: A 12-point clinical scoring system was devised and a diagnosis of PMS was considered 'probable' when greater or equal to 8. Sensitivity and specificity of the score were 96.4% and 100%, respectively, while the positive predictive value was 100% and negative predictive value was 86.9%. Combined medication and rehabilitation treatments had a cure rate of 51.2%. Hundred and twenty-two patients (48.8%) were unresponsive to treatment and received OnabotulinumtoxinA. Visual Analogue Scale (VAS) results were 'Very good/Good' in 77%, 'Average' in 7.4% and 'Poor' in 15.6%. Fifteen of 19 patients unresponsive to treatment underwent surgery with 'Very good/Good' results in 12 cases. CONCLUSIONS: The proposed evaluation score may facilitate PMS diagnosis and treatment standardisation. Rehabilitation has a major role associated in half of the cases with botulinum toxin injections.

Adiponectin in autoimmune diseases.

Adiponectin is the most abundant adipokine circulating in the organism. Different molecular forms of adiponectin exist: low, middle and high molecular isoforms, as well as globular adiponectin, all of which have different biological properties. Adiponectin is considered a key adipokine in metabolic diseases such as type 2 diabetes, metabolic syndrome and related complications, especially cardiovascular diseases. In these metabolic conditions, circulating adiponectin is reduced. It is now well known that adiponectin has beneficial effects on endothelial cells and endothelial function and is also cardioprotective. Unlike metabolic diseases, systemic autoimmune and chronic inflammatory joint diseases are characterized by increased production of adiponectin. There is evidence to suggest that adiponectin may be related to disease activity and/or severity in different conditions such as rheumatoid arthritis, systemic lupus erythematosus and osteoarthritis. Since adiponectin has been found to display both pro and anti-inflammatory activities, controversial findings have been observed on the role of total adiponectin in systemic autoimmune and inflammatory joint diseases. Thus, the relative contribution of each adiponectin isoform to the inflammatory response and joint and/or tissue damage requires further study.

[TNFα blocking agents and sarcoidosis: an update]. / Agents anti-TNFα et sarcoïdose.

Increased production of TNFα by alveolar macrophages and involvement of TNFα in granuloma formation suggest that this cytokine is involved in the pathophysiology of sarcoidosis. The three available TNFα blocking agents have been tested in sarcoidosis refractory to corticosteroids or immunosuppressive drugs. Data are available from isolated case reports or limited series of patients treated in open label trials with favourable issue with anti-TNFα monoclonal antibodies. Two randomized placebo controlled studies evaluated the efficacy of infliximab in pulmonary and extra-pulmonary sarcoidosis, showing that infliximab improves significantly extra-pulmonary disease. There is no significant difference between infliximab and placebo in the treatment of pulmonary manifestations. Etanercept showed no efficacy for treating ocular sarcoidosis in a controlled trial and for pulmonary disease in an open label trial. Paradoxical cases of proven sarcoidosis have been reported in patients receiving anti-TNFα agents for chronic inflammatory rheumatic diseases. A literature review identified 28 cases, including 16 with etanercept, eight with infliximab and four with adalimumab. Although these cases were mainly reported with etanercept, paradoxical sarcoidosis has been reported with the three available anti-TNFα agents, suggesting a class effect. Changes in the cytokine balance may be involved in these cases of induced sarcoidosis, which must be known by the clinician.

Spinal cord compression complicating aseptic spondylodiscitis in ankylosing spondylitis.

Aseptic spondylodiscitis is a well recognized complication of ankylosing spondylitis. Neurological complications of such discovertebral lesions are uncommon. We report a new case with a diagnosis of T12-L1 spondylodiscitis which developed ten years after a spinal cord compression. Such neurological complications of aseptic spondylodiscitis may be explained by proliferative epidural tissue without predominant inflammatory infiltrates and also the development of new bone reaction, suggesting the contribution of mechanical factors.

HLA-DRB1*0404 is strongly associated with high titers of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis.

OBJECTIVE: To test whether the presence of RA associated HLA-DRB1*0101, HLA-DRB1*0401 and HLA-DRB1*0404 alleles individually influences anti-cyclic citrullinated peptide antibodies (anti-CCP) production. METHODS: The frequency of anti-CCP antibodies was calculated in the sera of 260 RA patients expressing either two (double dose genotypes SE+/SE+), one (single dose genotypes SE+/SE-) or no RA associated HLA-DR alleles (SE-/SE-). Anti-CCP antibodies titers were also determined. RESULTS: RA associated HLA-DR alleles are not mandatory for production of anti-CCP. We found that 68% of SE-/SE- patients were anti-CCP positive. There was no significant difference in anti-CCP between SE negative patient (SE-/SE-) and patients expressing at least one SE (SE+/SE+ and SE+/SE-) (p=0.140). We observed no statistical difference in anti-CCP between RA patients expressing one or two SE (82% vs. 77%, p=0.577). Among SE+/SE-patients, HLA-DRB1*0404 was associated with anti-CCP with a statistically significant difference compared with SE negative patients (90% anti-CCP positive, p=0.02). HLA-DRB1*0404 was also associated with high titers of anti CCP with a statistically significant difference compared with HLA-DRB1*0401 and HLA-DRB1*0101 patients (p=0.025). CONCLUSIONS: The RA-associated HLA-DRB1*0404 allele was the most strongly associated with the presence of anti-CCP in RA sera. Moreover, HLA-DRB1*0404 patients had higher titers of anti CCP than patients with other RA associated HLA-DR alleles.

Sarcoidosis occuring during anti-TNF-alpha treatment for inflammatory rheumatic diseases: report of two cases.

Anti-TNF-alpha agents have been tried in cases of refractory sarcoidosis, giving favourable results. Thus, the occurrence of a granulomatous disease in a patient receiving such drug seems paradoxical. We describe 2 patients with inflammatory rheumatic disease, the first with ankylosing spondylitis, the second with rheumatoid arthritis, under anti-TNF-alpha treatment (infliximab and etanercept respectively) who developed non-caseating granulomas of the lungs and lymph nodes consistent with the diagnosis of sarcoidosis. Limited and various similar cases have been reported. It is generally considered that these granulomatous diseases are related to the anti-TNF-alpha agent.

Characteristics and survival of 26 patients with paraneoplastic arthritis.

OBJECTIVE: To date, only a few series of patients with paraneoplastic arthritis have been published. The charts of patients with cancer-associated arthritis were collected in order to describe characteristics of this rheumatism. METHODS: A questionnaire was created for this study and validated by experts based on specific criteria of inclusion and exclusion. Histology of neoplasia was included. RESULTS: In all, 16 males and 10 females with a mean (range) age of 57.5 years (28-85) were recruited from 17 nationwide centres in France. Patients presented with symmetric polyarthritis involving wrists and hands (85%) and extra-articular symptoms were frequent (84%). There was no specific biologic or radiographic feature. The mean (range) delay between the diagnosis of rheumatism and neoplasia was 3.6 months (0-21.2). Tumours were usually diagnosed after articular symptoms occurred (88.5%). Twenty patients had a solid cancer, and six a haematological malignancy. Adenocarcinoma of the lungs was the most frequent type of solid cancer (60%). Tumours were diagnosed at an early stage, which may explain the good median survival of 1.21 years (range 0.64-present) with a mean follow-up of 1.9 years (range 0.16-10). The percentage of articular symptoms resolution was significantly higher in patients with solid tumours, as compared to patients with haemopathy (p = 0.007). In cases of tumour relapse, rheumatic symptoms did not recur for 75% of patients. CONCLUSIONS: Underlying neoplasia should be considered in male patients with new onset polyarthritis, smokers, and particularly in patients chronically ill. Additional investigations should then be performed to diagnose cancer at an early stage.

[Hypercalcemia of double origin: association of multiple myeloma and ectopic parathyroidal adenoma]. / Une hypercalcémie d'origine double: association myélome et adénome parathyroïdien ectopique.

INTRODUCTION: Multiple myeloma and primary hyperparathyroidism are two causes of hypercalcemia. This association has already been described to be not casual, despite their link is still unknown. OBSERVATION: We describe a 68 years old woman, without notable background, was admitted for low back pain. Biology showed an IgG Kappa multiple myeloma (stade 3) and an hypercalcemia without renal failure. Hypercalcemia was difficult to control with bisphosphonate and calcitonin. At first, there was also an hypophosphoremia and a high parathormone level (287 pg/ml). Imaging showed spread myeloma impairment and a right paramediastinal tissular mass. Biopsy diagnosed an ectopic parathyroidal adenoma. DISCUSSION: Multiple myeloma and primary hyperparathyroidism can be associated. They are often revealed by an hypercalcemia difficult to control or refractory to the treatment. Hypophosphoremia can suggest the diagnosis of hyperparathyroidism. Both this observation and litterature (about twenty case reports) suggest that this double diagnosis should be systematicly evoked and explored by an assay of parathormone and a seric proteins electrophoresis in all hypercalcemia. CONCLUSION: Multiple myeloma and parathyroidal adenoma should be both explored in all hypercalcemia, because they can be associated.

[Anti TNF-alpha treatment of a refractory polymyositis]. / Traitement d'une polymyosite réfractaire par anti TNF-alpha.

INTRODUCTION: Anti TNF-alpha agents may represent a possibility of treatment in cases of refractory polymyositis. CASE REPORT: We report a case of polymyositis refractory to corticosteroids and immunosuppressive agents in whom adjunction of infliximab led to a mild and transient improvement, and a secondary improvement after discontinuation of the treatment. DISCUSSION: In the reported cases of polymyositis treated with infliximab or etanercept a short-term response was seen in 9 out of 11 cases. Adverse events of the treatment are mentioned, and should be taken into account in the decision of treatment.

[The immunogenetics of ankylosing spondylitis]. / Immunogénétique de la spondylarthrite ankylosante.

BACKGROUND: Ankylosing spondylitis (AS) is an inflammatory rheumatic disease with axial involvement but its physiopathology remains unexplained. This latter combines genetic and environmental factors as well as an abnormal immune response. CURRENT TOPICS AND IMPORTANT RESULT: This review addresses the different aspects of AS immunogenetic. A genetic background in AS is suggested by familial cases, concordance rate in twins and transmission of the disease in siblings. Ankylosing spondylitis is strongly associated with the expression of the HLA Class I antigen, B27, but also with other genes not yet identified since currently, only chromosomic area have been linked to AS. Studies of candidate genes or genome screening allow to determine these chromosomic regions. HLA-B27 is directly associated with the disease physiopathology as suggested by animal models of rats transgenic for human HLA-B27 and beta2 microglobulin. This HLA molecule have original biological properties, in particular a slow heavy chain folding and the formation of heavy chain homodimers without light chain. However, HLA B27 is a functional molecule and assumes its property of presenting peptide of 9 amino acids to CD8+ T cells. Interaction modelling studies between HLA B27 and peptides have identified peptide and peptide groove amino acid sequences, with the identification of critical positions on the HLA B27 molecule for the peptide interaction. Original biochemical properties of HLA-B27 include diminished bacterial antigen response and CD4+ T lymphocyte stimulation. Innate immunity is also of interest in AS, as suggested by the presence of macrophage and polymorphonuclear neutrophils in AS synovitis, as well as the contribution of Toll-like receptors. FUTURE PROSPECTS AND PROJECTS: Thus in AS, the inflammatory process and then the clinical consequences may be explained by the involvement of HLA-B27, a bacterial antigen presentation, an abnormal immune response and the contribution of innate immunity, T CD4+ but also T CD8+ cells. The original molecular structures of HLA-B27 are certainly involved in this complex physiopathology, but their direct influence on the disease remains to be precised.