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.

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.

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.

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.

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.

[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.

[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.

[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.

Molecular mechanisms involved in the association of HLA-DR4 and rheumatoid arthritis.

Susceptibility to developing rheumatoid arthritis (RA) maps to a highly conserved amino acid motif located in the third hypervariable region of different HLA-DRB1 chains. This motif, namely QKRAA, QRRAA, or RRRAA, helps the development of RA by an unknown mechanism. The QKRAA motif predisposes to more severe disease than the QRRAA or RRRAA motifs. The QKRAA motif carries particular properties: it is a strong B- and T-cell epitope, it shapes the T cell repertoire, it is overrepresented in protein databases, and it is a binding motif for bacterial and human 70-kDa heat-shock proteins. In this article, we propose different models to explain how the QKRAA motif might contribute to RA.

The association of HLA-DM genes with rheumatoid arthritis in Eastern France.

In this study, the polymorphisms of the HLA DMA and DMB genes in patients with rheumatoid arthritis (RA) were examined.DMA and DMB typing was performed in 120 white RA patients from eastern France and 100 healthy controls, using PCR-SSO (sequence specific oligonucleotide probes) method for DMA determination and PCR-RFLP (restriction fragment length polymorphism) method for DMB typing. All patients and controls had been HLA DRB1* genotyped.DMA*0103 was found significantly increased in RA patients (RA vs. controls: 18.3% vs. 4%) (p(corr) = 0.004; OR: 5.39; CI: 1.67-19.23). A decreased frequency of DMA*0102 was also observed in the RA group (RA vs. controls: 18.3% vs. 31%), but not significantly. There were no differences in the prevalence of DMB alleles between RA and controls. The patients and the controls were then stratified according to the expression of the HLA DRB1* RA-linked alleles (DRB1*01 and *04) and this allowed us to find no linkage disequilibrium between DMA*0103 and DRB1*01 or *04 alleles. Finally, most DMA*0103 patients were positive for rheumatoid factors and had extraarticular involvement such as subcutaneous nodules. Thus, our results suggest that DMA*0103 could be an additional genetic factor for RA susceptibility in French whites.

HLA-DRB1 motifs and heat shock proteins in rheumatoid arthritis.

Susceptibility to develop Rheumatoid arthritis (RA) maps to a highly conserved amino acid motif expressed in the third hypervariable region of different HLA-DRB1 alleles. This motif, namely QKRAA, QRRAA or RRRAA helps the development of RA by an unknown mechanism. In the past ten years, we have extensively studied the unique properties of the QKRAA motif of HLA-DRB1*0401 and have found: (1) That it can constitute B and T cell epitopes on many infectious agents; (2) That it can shape the T cell repertoire; (3) That it is overrepresented in protein databases; (4) That it constitutes a binding motif for the highly conserved family of 70 kD heat shock proteins. This may cause abnormal trafficking of HLA-DRB1*0401 in B cells and/or abnormal T cell responses to bacterial and human 70 kD heat shock proteins in people who express HLA-DRB1*0401.

Current guidelines for the drug treatment of ankylosing spondylitis.

Ankylosing spondylitis (AS) is a systemic inflammatory rheumatic disease involving spinal and sacroiliac joints. This condition is responsible for back pain, stiffness and discomfort. Several drugs are currently available in the management of AS, and may be divided into 3 groups. The first includes nonsteroidal anti-inflammatory drugs (NSAIDs), which are the main drug group used in AS because they reduce pain and stiffness in most patients. Several NSAIDs are available but phenylbutazone is considered the NSAID of choice in AS. However, other NSAIDs give similar beneficial results and the medication of preference in specific to each patient. All NSAIDs share common gastrointestinal toxicity, and they should be administered during periods of flare-up of the disease. The second drug group that has been used in the treatment of patients with AS comprises analgesics, muscle relaxants and low dose corticosteroids. They can be considered as adjuvant therapy. These drugs are helpful when NSAIDs are poorly tolerated or ineffective. Second-line treatments or disease modifying antirheumatic drugs (DMARDs) are included in the third group. These drugs are required in cases of longstanding severe or refractory AS. Sulfasalazine has proven to be effective in such cases, leading to improvement in clinical and laboratory indices of disease activity. Beneficial results are mainly evident in patients with AS who have peripheral disease involvement. Other medications (such as methotrexate or gold salts, for instance) require properly designed controlled studies to evaluate their effectiveness in the treatment of this disorder, while immunosuppressive agents have little to offer in the management of patients with AS and require further studies. Some specific clinical features are observed in AS: enthesopathy may be treated with local injection of corticosteroids; sacroiliac joint pain may be managed by corticosteroid injection performed under fluoroscopic control or guided by computed tomography. The management of patients with AS includes some other procedures such as patient education, rest, a programme of physical exercise and physiotherapy. In parallel with pharmacotherapy, these procedures are of great importance in reducing stiffness and spinal ankylosis, and thus improve the patient's quality of life.

Therapeutic advances in ankylosing spondylitis.

Ankylosing spondylitis (AS) is a systemic inflammatory rheumatic disease involving spinal and sacroiliac joints. This condition is responsible for back pain, stiffness, but also loss of functional capacity with socio-economic consequences. The management of AS includes patient education, rest, a programme of regular physical exercise, together with the use of NSAIDs. Second-line treatments are required in cases of severe or refractory AS, however only sulfasalazine has proven to benefit AS patients with peripheral arthritis. In spite of this management, the disease may not be adequately controlled, mainly for patients with refractory axial disease, enthesopathy or extra-articular features. Thus, new innovative treatments are needed for AS. It is likely that the new NSAIDs or COX-2 specific inhibitors will certainly take the place of the conventional NSAIDs, with regard to their superior tolerability. Methotrexate is a therapeutic option for AS treatment, but its usefulness in this disease remains to be established in adequate controlled studies. Finally, the TNF-alpha targeting drugs, namely thalidomide and the anti-TNF-alpha mAb, infliximab, have given promising results in the treatment of severe and/or refractory AS patients, however further controlled studies are required. In addition, the long-term use (efficacy and tolerability) of these two agents deserves attention.

Crohn's disease associated with seropositive rheumatoid arthritis.

We report two cases of rheumatoid arthritis (RA) associated with Crohn's disease (CD). The first case was a 60-year-old man with longstanding CD who next developed a seropositive, nodular RA. This patient also had bilateral sacroiliitis, but without positive HLA B27. The second was a 65-year-old female with a 15-year history of seropositive RA who presented secondarily a CD. No sacroiliitis or nodules were found in this patient. Both patients were DR1 (DRB1* 0101). Gold salts were only given in the second case and were stopped many years before the gastrointestinal symptoms. A similar case report has been previously described consisting in an ulcerative colitis complicating a seronegative HLA-B27 RA with sacroiliitis. The gastrointestinal involvement in RA may be broad and includes many causes: drug-induced colitis (including gold enterocolitis) vasculitis and amyloidosis located in the gut, associated bowel disease such as collagenous colitis, and also infectious agents. In addition, erosive polyarthritis associated with gastrointestinal manifestations can present a problem in the differential diagnosis between RA and an enteropathic arthritis. Finally, the coexistence by chance of inflammatory bowel disease and RA is suggested by the low occurrence of these two conditions in the same patient.

Erosive polyarthritis and Crohn's disease. A case with HLA DRB1 determination.

The authors report the case of a 49-year-old woman with an asymmetrical, seronegative and peripheral polyarthritis with erosions, who subsequently developed Crohn's disease. She was diagnosed as having an erosive Crohn polyarthritis as no evidence of rheumatoid arthritis was found. However, the patient was homozygote for DR4 and the HLA DRB1 oligotyping was 0401/0404. This corresponds to two susceptibility alleles for rheumatoid arthritis responsible for the severity of this disease. Erosive polyarthritis is rarely encountered in inflammatory bowel diseases. The underlying mechanism of the erosions in these conditions is unknown but granulomatous synovitis with contiguous erosive bone changes has been reported. HLA DR has not been previously reported in erosive Crohn polyarthritis. The homozygosity for DR4 with DRB1*0401/0404 subtypes suggests that DR4 could contribute to the erosive course in this patient. This question is of interest, and HLA DR must be further studied in inflammatory bowel diseases with erosive arthritic manifestations.

Pseudo Felty's syndrome. A polyclonal disease with a favorable prognosis. Report of two cases with Southern blot analysis of TCR.

The authors report two patients with large granular lymphocyte (LGL) expansion associated with rheumatoid arthritis corresponding to pseudo Felty's syndrome. These cells have natural killer and T cell surface antigen markers. LGL are a heterogeneous population and expansion of these cells is responsible for leukemia, which is generally a monoclonal proliferation. It has been suggested that Epstein-Barr virus (EBV) is a putative agent in this leukemia. No EBV DNA was found with a polymerase chain reaction analysis in the lymphocyte DNA of our two patients. Some cases of pseudo Felty's syndrome have exhibited a monoclonal pattern on Southern blot analysis of the T cell receptor. On the contrary, our two cases showed a polyclonal pattern with TCR beta chain Southern blot analysis. This fact, associated with the mild course seen in both over more than twenty years, suggest that pseudo Felty's syndrome is a disease with a good prognosis.

Marked elevation of serum N-acetyl-beta-D-hexosaminidase activity in rheumatoid rheumatoid arthritis.

OBJECTIVE: To study N-acetyl-beta-D-hexosaminidase (NAHase) activity in the sera of rheumatoid arthritis (RA) patients and to determine its source. METHODS: NAHase activity in the serum and synovial fluid of RA patients was measured with p-nitrophenyl beta-N-acetylglucosaminide as substrate. The p-nitrophenol released was measured spectrophotometrically in an ELISA reader. Rabbit articular chondrocytes in primary culture were stimulated with interleukin-1 beta (IL-1 beta). RESULTS: Serum NAHase activity was higher in 35% of the RA patients than in healthy patients. The median activity was about twice that of the serum of healthy volunteers. RA patients with high serum NAHase activity also had more joint destruction (85%) than those with normal NAHase activity (57%, p < 0.05), but their inflammatory status was similar. The source of NAHase in RA was investigated by assaying it in RA synovial fluids (SF) and measuring its release from articular chondrocytes in primary culture. NAHase activity was detected in all 23 RA SF, at a median concentration that was 2 times that of the serum. NAHase activity in the medium of articular chondrocytes was stimulated by IL-1 beta (p < 0.005 compared to unstimulated cells), suggesting that cartilage is a source of serum and SF NAHase activity. CONCLUSION: The serum concentration of the matrix hydrolase, NAHase, is higher in destructive RA than in inflammatory RA.

Fibromyalgia developed after administration of gonadotrophin-releasing hormone analogue.

We report the case of a woman treated with a gonadotrophin-releasing hormone analogue for endometriosis who developed typical clinical features of fibromyalgia, with widespread musculoskeletal pain, sleep difficulties, neuropsychological complaints and tender points on clininal examination. The gonadotrophin-releasing hormone analogue treatment probably induced disturbances in the neuroendocrine system and the secretion of neurotransmitters, and may be suspected to be the cause of this case of fibromyalgia.

Tenosynovitis due to Mycobacterium avium intracellulare and Mycobacterium chelonei: report of two cases with review of the literature.

Atypical mycobacteria can induce soft tissue infections such as tenosynovitis. We observed one case of finger flexor tendon tenosynovitis infected with Mycobacterium avium intracellulare and one case of knee and ankle arthritis with lateral peroneal tendon tenosynovitis due to M. chelonei. In the first patient, a tenosynovectomy only was performed leading to resolution of the infection. The second patient was immunocompromised as a result of corticosteroid therapy and the mycobacterial infection was treated with tenosynovectomy and multidrug chemotherapy. This patient died from infectious pneumonitis. Previously reported cases of infectious tenosynovitis due to these atypical mycobacteria are reviewed.