Capillary pathology with prominent basement membrane reduplication is the hallmark histopathological feature of scleromyositis.

AIMS: We aim to perform ultrastructural and histopathological analysis of muscle biopsies from a large group of systemic sclerosis (SSc) patients, including some with early/mild SSc features, and examine whether capillary pathology differentiates 'scleromyositis' (SM) from other auto-immune myositis (AIM) subsets. METHODS: Muscle biopsies from a total of 60 SM patients and 43 AIM controls from two independent cohorts were examined by electron microscopy, collagen-4 immunofluorescence (Col4IF) and routine light microscopy. RESULTS: Ultrastructural examination revealed prominent capillary basement membrane (BM) reduplication (4+ layers in >50% of capillaries) in 65% of SM vs 0% of AIM controls (p < 0.001). In SM cases without prominent BM reduplication, capillary dilation was the most distinctive feature, present in 8% of capillaries in SM vs 2% in controls (p = 0.001). Accumulation of ensheathed pericyte processes was another characteristic feature of SM and closely correlated with the degree of BM reduplication (r = 0.833, p < 0.001). On light microscopy, BM marker Col4IF revealed more frequent capillary enlargement in SM than in controls (84% vs 21%, p < 0.001). SM cases were classified as non-inflammatory myopathy (36%), non-specific myositis (33%) or immune-mediated necrotizing myopathy (31%), but despite this histopathological heterogeneity, prominent BM reduplication remained a constant finding. In the 16 SM patients with early/mild SSc features, 63% showed prominent BM reduplication. CONCLUSIONS: These results show that capillary pathology, and in particular prominent capillary BM reduplication, is the hallmark histopathological feature of SM even in patients with early/mild SSc and support the concept of SM as an organ manifestation of SSc and a distinct subset of AIM.

Autoantibody profiles delineate distinct subsets of scleromyositis.

OBJECTIVE: Scleromyositis remains incompletely characterized owing in part to its heterogeneity. The purpose of this study was to explore the role of autoantibody profiles to define subsets of scleromyositis. METHODS: Subjects with scleromyositis from a prospective cohort were divided into three groups based on autoantibody profiles: subjects with SSc-specific autoantibodies (anti-centromere, -topoisomerase 1, -RNA polymerase III, -Th/To, -fibrillarin), subjects with SSc-overlap autoantibodies (anti-PM/Scl, -U1RNP, -Ku) and subjects without SSc-related autoantibodies. Clinical features, laboratory tests and histopathological findings were retrieved and compared between groups. RESULTS: Of 42 scleromyositis subjects (79% female, mean age at diagnosis 55 years, mean disease duration 3.5 years), 8 (19%) subjects had SSc-specific autoantibodies, 14 (33%) SSc-overlap autoantibodies and 20 (48%) had no SSc-related autoantibodies. One-third had no skin involvement, a finding more frequent in the SSc-overlap subjects and those without SSc-related autoantibodies. Proximal and distal weakness was common and head drop/bent spine was found in 50% of the SSc-specific and 35% of the subjects without SSc-related autoantibodies. Of note, the group without SSc-related autoantibodies had the only cases of severe cardiac systolic dysfunction (n = 1) and scleroderma renal crisis (n = 1), as well as three out of the four cancers and three out of the four deaths. CONCLUSION: In this carefully phenotyped series of scleromyositis subjects, absence of SSc-related autoantibodies was common and associated with distinct features and poor prognosis. Future studies are needed to validate these results and possibly identify novel autoantibodies or other biomarkers associated with scleromyositis.

Febuxostat as a novel option to optimize thiopurines' metabolism in patients with inadequate metabolite levels.

OBJECTIVE: To report the use of febuxostat in order to potentiate thiopurines' metabolism in a patient on azathioprine (AZA) therapy with low metabolite 6-thioguanine nucleotides (6-TGN) levels and elevated metabolite 6-methylmercaptopurine (6-MMP) levels. CASE SUMMARY: A 44-year-old woman with a history of anti-signal recognition particle necrotizing myopathy was treated with AZA-allopurinol combination therapy. When she developed an atypical drug-induced hypersensitivity syndrome, allopurinol was replaced by the new xanthine oxidase (XO) inhibitor febuxostat, at a daily dose of 40 mg. Febuxostat-AZA combination was successful with 6-TGN reaching therapeutic levels while 6-MMP levels remained low. After 5 months, she developed similar manifestations that she had presented on AZA-allopurinol combination. Febuxostat and AZA were then stopped. DISCUSSION: AZA and 6-MP are both inactive pro-drugs that undergo a complex metabolic transformation leading to active 6-TGN and potentially hepatotoxic 6-MMP. Some patients with unfavorable thiopurine metabolism might benefit from addition of XO inhibitor allopurinol in order to potentiate 6-TGN and reduce 6-MMP levels. It is likely that febuxostat, via its XO inhibition, would exhibit the same effect on thiopurines' metabolism. CONCLUSION: It has been shown that low dose of febuxostat was able to prevent hypermethylation and to potentiate 6-TGN levels in an AZA-treated patient. Thus, febuxostat could be useful in optimizing thiopurines' metabolism, but more data are needed before this practice can be recommended. The mechanisms by which febuxostat optimizes thiopurines' metabolism remain to be confirmed. Also, the optimal dose of febuxostat for this use remains to be determined.

Anti-SMN autoantibodies in mixed connective tissue disease are associated with a severe systemic sclerosis phenotype.

OBJECTIVES: The survival of motor neuron (SMN) complex has an essential role in the assembly of small nuclear ribonucleoproteins (RNP). Recent reports have described autoantibodies (aAbs) to the SMN complex as novel biomarkers in anti-U1RNP+ myositis patients. The aim of this study was to compare phenotypic features of anti-U1RNP+ mixed connective tissue disease (MCTD) patients with and without anti-SMN aAbs. METHODS: A retrospective MCTD cohort was studied. Addressable laser bead immunoassay was used to detect specific anti-SMN aAbs with <300 mean fluorescence intensity (MFI) as normal reference range, 300-999 MFI as low-titre and ≥1000 MFI as high-titre positivity. Comparison of clinical features between anti-SMN+ and anti-SMN- subgroups used two-tailed Fisher's exact test, and logistic regression analyses. RESULTS: Sixty-six patients were included. Median age at MCTD diagnosis was 40.6 years, and duration of follow-up was 12 years. Based on the highest available titre, 39 (59%) were anti-SMN+: 10 (26%) had low titre and 29 (74%) had high titre. Anti-SMN+ patients had a higher frequency of fingertip pitting scars (anti-SMN+ 23% vs anti-SMN- 4%, p=0.04), lower gastrointestinal (GI) involvement (26% vs 4%, p=0.04), and myocarditis (16% vs 0%, p=0.04). The combined outcome of pitting scars and/or lower GI involvement and/or myositis and/or myocarditis was highest among high-titre anti-SMN+ patients: adjusted OR 7.79 (2.33 to 30.45, p=0.002). CONCLUSIONS: Anti-SMN aAbs were present in 59% of our MCTD cohort. Their presence, especially at high-titres, was associated with a severe systemic sclerosis (scleroderma) phenotype including myositis, myocarditis and lower GI involvement.

Myositis with prominent B cell aggregates may meet classification criteria for sporadic inclusion body myositis.

The objective of this study was to report the clinical, serological and pathological features of patients with autoimmune myositis other than dermatomyositis, who displayed both muscle weakness on physical examination and prominent B cell aggregates on muscle pathology, defined as ≥ 30 CD20+ cells/aggregate. Specifically, the presence of a brachio-cervical inflammatory myopathies or a sporadic inclusion body myositis (sIBM) phenotype was recorded. Over a three-year period, eight patients were identified from two university neuropathology referral centers. Seven of 8 (88%) patients had an associated connective tissue disease (CTD): rheumatoid arthritis (n=3), systemic sclerosis (n=2), Sjögren's syndrome (n=1) and systemic lupus erythematosus (n=1), while one patient died on initial presentation without a complete serological and cancer investigation. A brachio-cervical phenotype, i.e. neck weakness, proximal weakness more than distal and shoulder abduction weakness greater than hip flexors, was seen in two patients (25%), while one patient had both proximal and diaphragmatic weakness. In contrast, an IBM-like clinical phenotype was seen in the last five patients (63%), who either had finger flexor weakness and/or quadriceps weakness ≤ 4 on the manual muscle testing MRC-5 scale. Although these 5 patients met at least one set of classification criteria for sIBM, an integrated clinico-sero-pathological approach argued against a diagnosis of sIBM. In summary, in a weak patient with myositis plus an associated CTD and lymphoid aggregates at muscle pathology, B cell predominant aggregates may represent a morphological biomarker against a diagnosis of sIBM.

In inflammatory myopathies, dropped head/bent spine syndrome is associated with scleromyositis: an international case-control study.

BACKGROUND: Some myopathies can lead to dropped head or bent spine syndrome (DH/BS). The significance of this symptom has not been studied in inflammatory myopathies (IM). OBJECTIVES: To assess the significance of DH/BS in patients with IM. METHODS: Practitioners from five IM networks were invited to report patients with IM suffering from DH/BS (without other known cause than IM). IM patients without DH/BS, randomly selected in each participating centre, were included as controls at a ratio of 2 to 1. RESULTS: 49 DH/BS-IM patients (DH: 57.1%, BS: 42.9%) were compared with 98 control-IM patients. DH/BS-IM patients were older (65 years vs 53 years, p<0.0001) and the diagnosis of IM was delayed (6 months vs 3 months, p=0.009). Weakness prevailing in the upper limbs (42.9% vs 15.3%), dysphagia (57.1% vs 25.5%), muscle atrophy (65.3% vs 34.7%), weight loss (61.2% vs 23.5%) and loss of the ability to walk (24.5% vs 5.1%) were hallmarks of DH/BS-IM (p≤0.0005), for which the patients more frequently received intravenous immunoglobulins (65.3% vs 34.7%, p=0.0004). Moreover, DH/BS-IM patients frequently featured signs and/or complications of systemic sclerosis (SSc), fulfilling the American College of Rheumatology/European Alliance of Associations for Rheumatology criteria for this disease in 40.8% of the cases (vs 5.1%, p<0.0001). Distribution of the myopathy, its severity and its association with SSc were independently associated with DH/BS (p<0.05). Mortality was higher in the DH/BS-IM patients and loss of walking ability was independently associated with survival (p<0.05). CONCLUSION: In IM patients, DH/BS is a marker of severity and is associated with SSc (scleromyositis).

Scleromyositis: A distinct novel entity within the systemic sclerosis and autoimmune myositis spectrum. Implications for care and pathogenesis.

Systemic sclerosis and autoimmune myositis are both associated with decreased quality of life and increased mortality. Their prognosis and management largely depend on the disease subgroups. Indeed, systemic sclerosis is a heterogeneous disease, the two predominant forms of the disease being limited and diffuse scleroderma. Autoimmune myositis is also a heterogeneous group of myopathies that classically encompass necrotizing myopathy, antisynthetase syndrome, dermatomyositis and inclusion body myositis. Recent data revealed that an additional disease subset, denominated "scleromyositis", should be recognized within both the systemic sclerosis and the autoimmune myositis spectrum. We performed an in-depth review of the literature with the aim of better delineating scleromyositis. Our review highlights that this concept is supported by recent clinical, serological and histopathological findings that have important implications for patient management and understanding of the disease pathophysiology. As compared with other subsets of systemic sclerosis and autoimmune myositis, scleromyositis patients can present with a characteristic pattern of muscle involvement (i.e. distribution of muscle weakness) along with multisystemic involvement, and some of these extra-muscular complications are associated with poor prognosis. Several autoantibodies have been specifically associated with scleromyositis, but they are not currently integrated in diagnostic and classification criteria for systemic sclerosis and autoimmune myositis. Finally, striking vasculopathic lesions at muscle biopsy have been shown to be hallmarks of scleromyositis, providing a strong anatomopathological substratum for the concept of scleromyositis. These findings bring new insights into the pathogenesis of scleromyositis and help to diagnose this condition, in patients with subtle SSc features and/or no autoantibodies (i.e. "seronegative" scleromyositis). No guidelines are available for the management of these patients, but recent data are showing the way towards a new therapeutic approach dedicated to these patients.

Myositis with prominent B-cell aggregates causing shrinking lung syndrome in systemic lupus erythematosus: a case report.

BACKGROUND: Shrinking lung syndrome (SLS) is a rare manifestation of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and diaphragmatic weakness in a dyspneic patient. Chest wall dysfunction secondary to pleuritis is the most commonly proposed cause. In this case report, we highlight a new potential mechanism of SLS in SLE, namely diaphragmatic weakness associated with myositis with CD20 positive B-cell aggregates. CASE PRESENTATION: A 51-year-old Caucasian woman was diagnosed with SLE and secondary Sjögren's syndrome based on a history of pleuritis, constrictive pericarditis, polyarthritis, photosensitivity, alopecia, oral ulcers, xerophthalmia and xerostomia. Serologies were significant for positive antinuclear antibodies, anti-SSA, lupus anticoagulant and anti-cardiolopin. Blood work revealed a low C3 and C4, lymphopenia and thrombocytopenia. She was treated with with low-dose prednisone and remained in remission with oral hydroxychloroquine. Seven years later, she developed mild proximal muscle weakness and exertional dyspnea. Pulmonary function testing revealed a restrictive pattern with small lung volumes. Pulmonary imaging showed elevation of the right hemidiaphragm without evidence of interstitial lung disease. Diaphragmatic ultrasound was suggestive of profound diaphragmatic weakness and dysfunction. Based on these findings, a diagnosis of SLS was made. Her proximal muscle weakness was investigated, and creatine kinase (CK) levels were normal. Electromyography revealed fibrillation potentials in the biceps, iliopsoas, cervical and thoracic paraspinal muscles, and complex repetitive discharges in cervical paraspinal muscles. Biceps muscle biopsy revealed dense endomysial lymphocytic aggregates rich in CD20 positive B cells, perimysial fragmentation with plasma cell-rich perivascular infiltrates, diffuse sarcolemmal upregulation of class I MHC, perifascicular upregulation of class II MHC, and focal sarcolemmal deposition of C5b-9. Treatment with prednisone 15 mg/day and oral mycophenolate mofetil 2 g/day was initiated. Shortness of breath and proximal muscle weakness improved significantly. CONCLUSION: Diaphragmatic weakness was the inaugural manifestation of myositis in this patient with SLE. The spectrum of myologic manifestations of myositis with prominent CD20 positive B-cell aggregates in SLE now includes normal CK levels and diaphragmatic involvement, in association with SLS.

Optimizing Thiopurine Therapy with a Xanthine Oxidase Inhibitor in Patients with Systemic Autoimmune Diseases: A Single-Centre Experience.

BACKGROUND: Thiopurines are a mainstay of therapy for autoimmune diseases. However, up to 20% to 30% of patients experience overproduction of the methylated metabolites, known as 6-MMP, to the detriment of the active metabolite, 6-thioguanine nucleotide (6-TGN). These patients, commonly referred to as "shunters", are predisposed to thiopurine resistance and hepatotoxicity. In patients with inflammatory bowel diseases, the combination of thiopurine with a xanthine oxidase inhibitor (XOI) is used to reverse this skewed metabolism and to prevent treatment failure or hepatotoxicity. Data on the use of this strategy for patients with other diseases are limited. OBJECTIVES: To investigate and describe the use of thiopurine-XOI combination therapy in shunters with systemic autoimmune diseases. METHODS: Shunters treated in the study hospital between January 1, 2005, and December 31, 2015, were identified using the hospital's laboratory database, and clinical data were collected retrospectively. For each patient with optimization of thiopurine therapy, clinical and laboratory data were assessed over a 6-month period. RESULTS: Thirty-four patients were identified as shunters; for 14 of these patients, thiopurine therapy was optimized with an XOI. In these 14 patients, the median dose of azathioprine was reduced from 1.95 to 0.78 mg/kg with combination therapy. In addition, median 6-TGN level increased from 135 to 385 pmol/8 × 108 erythrocytes (p = 0.001); furthermore, 6-TGN levels rose to above 235 pmol/8 ×108 erythrocytes for 11 of the 14 patients. Conversely, the median 6-MMP level decreased from 6267 to 271 pmol/8 × 108 erythrocytes (p = 0.001). Except for a 12% increase in mean corpuscular volume, no clinically significant changes in blood count were recorded. Notable infections were reported in 3 patients, and 1 patient had to discontinue treatment because of cytopenia. After 6 months, median prednisone daily dose was reduced by 74%, from 16.7 mg to 4.4 mg (p = 0.005), and 4 patients had been weaned off corticosteroids. Of the 14 patients, 11 (79%) were in full remission, and 2 (14%) were in partial remission. CONCLUSION: Optimizing thiopurine therapy with an XOI may be a safe and effective strategy for patients with systemic autoimmune diseases.

CONTEXTE: Les thiopurines sont des piliers de l'intervention thérapeutique contre les maladies auto-immunes. Cependant, 20 % à 30 % des patients surproduisent des métabolites méthylés (connus sous le nom 6-MMP), au détriment du métabolite actif, le nucléotide 6-thioguanine (6-TGN). Ces patients, communément appelés « courts-circuiteurs ¼ sont prédisposés à résister à la thiopurine et à l'hépatotoxicité. Pour les patients ayant des maladies inflammatoires intestinales, on utilise la combinaison de thiopurine avec une xanthine oxydase inhibitrice (XOI) afin d'inverser ce métabolisme anormal et prévenir l'échec du traitement ou l'hépatotoxicité. Les données concernant l'adoption de cette stratégie pour les patients atteints d'autres maladies sont limitées. OBJECTIFS: Étudier et décrire l'utilisation de la thérapie combinée de thiopurine et de XOI pour les « courts-circuiteurs ¼ ayant des maladies auto-immunes systémiques. MÉTHODES: Les « courts-circuiteurs ¼ traités dans l'hôpital où s'est déroulée l'étude entre le 1er janvier 2005 et le 31 décembre 2015 ont été identifiés à l'aide de la base de données du laboratoire de l'hôpital et les données cliniques ont été recueillies de manière rétrospective. L'évaluation des données cliniques et de laboratoire de chaque patient bénéficiant d'une optimisation de la thérapie par la thiopurine a porté sur six mois de traitement. RÉSULTATS: Trente-quatre patients ont été identifiés comme « courts-circuiteurs ¼ et 14 d'entre eux ont bénéficié d'une optimisation de la thérapie par la thiopurine à l'aide d'une XOI. Ces derniers ont subi une thérapie de combinaison qui a fait passer la dose moyenne d'azathioprine de 1,95 à 0,78 mg/kg. De plus, le niveau moyen de 6-TGN est passé de 135 à 385 pmol/8 × 108 érythrocytes (p = 0,001). En outre, 11 des 14 patients ont vu le niveau de 6-TGN passer à plus de 235 pmol/8 ×108 érythrocytes. Inversement, le niveau moyen de 6-MMP est passé de 6267 à 271 pmol/8 × 108 érythrocytes (p = 0,001). À l'exception d'une augmentation de 12 % du volume corpusculaire moyen, aucun changement clinique important dans la numération globulaire n'a été noté. Trois patients ont développé des infections notables et l'un d'eux a dû arrêter le traitement à cause d'une cytopénie. Après six mois, la dose moyenne quotidienne de prednisone a été réduite de 74 %, pour passer de 16,7 mg à 4,4 mg (p = 0,005), et quatre patients ont été sevrés des corticostéroïdes. Sur les 14 patients, 11 (79 %) ont été déclarés en rémission totale et 2 (14 %) en rémission partielle. CONCLUSION: L'optimisation de la thérapie par la thiopurine associée à une XOI pourrait être sécuritaire et constituer une stratégie efficace pour les patients ayant une maladie auto-immune systémique.

Trigeminal neuralgia in systemic sclerosis.

OBJECTIVES: Although trigeminal neuralgia (TN) has been associated with systemic sclerosis (SSc), there is a paucity of evidence and pathophysiological processes remain unknown. We undertook a nested case-control study to identify associations between TN and SSc in a large multi-centered cohort and identify possible pathophysiological links. METHODS: Data were derived from a longitudinal cohort of 1652 SSc subjects. Cases with a physician-reported diagnosis of TN were identified at baseline visit (prevalent) and during follow-up (incident). Each case was matched on study visit to four SSc patients without TN. Sociodemographic, clinical and serological characteristics of cases and controls were compared. RESULTS: At enrolment, 43/1652 (2.6%) subjects had a history of TN. During follow-up, an additional 36 subjects developed TN over 6193 person-years of observation (incidence rate 5.8 per 1000 person-years). Cases were identified and matched to 172 and 144 controls, respectively. Compared to controls, prevalent cases had more inflammatory myositis (24.4% versus 5.2%, p<0.001) and inflammatory arthritis (46.5% versus 30.2%, p = 0.043). Incident cases also had more inflammatory myositis (19.4% versus. 6.3%, p = 0.033) and inflammatory arthritis (50.0% versus. 16.2%, p<0.001) compared to controls. There was a trend towards more interstitial lung disease in prevalent (32.6% versus 23.8%, p = 0.241) and incident (55.6% versus 40.6%, p = 0.105) cases compared to controls. CONCLUSION: This study provides novel evidence for a clinical association linking TN, inflammatory myositis, inflammatory arthritis and possibly interstitial lung disease. In addition to ischemia, we propose that TN in SSc could also be a consequence of inflammatory and possibly fibrotic processes.

Histopathological features of systemic sclerosis-associated myopathy: A scoping review.

BACKGROUND: Scleromyositis (SM) is an emerging subset of myositis associated with features of systemic sclerosis (SSc) but it is currently not recognized as a distinct histopathological subset by the European NeuroMuscular Center (ENMC). Our aim was to review studies reporting muscle biopsies from SSc patients with myositis and to identify unique histopathological features of SM. METHODS: A scoping review was conducted and included all studies reporting histopathological findings in SSc patients with myositis searching the following databases: PubMed, MEDLINE, EMBASE, CINAHL and EBM-Reviews. Clinical, serological, and histopathological data were extracted using a standardized protocol. RESULTS: Out of 371 citations, 77 studies that included 559 muscle biopsies were extracted. Fifty-seven percent (n = 227/400) had inflammatory infiltrates, predominantly T cells, which were endomysial (49%), perimysial (42%) and perivascular (41%). Few studies (18%, n = 8/44) evaluated the presence of B-cells. Myofiber atrophy was present in 48% (n = 104/218) of biopsies, and was predominantly perifascicular in 19% (n = 6/31), with necrosis reported in 56% (n = 162/290) of cases. Sarcolemmal MHC-I upregulation was found in 72% (n = 64/89) of biopsies. Non-specified C5b-9 deposition was described in 39% of muscle biopsies (n = 28/72). Neurogenic features were present in 23% (n = 44/191); endomysial fibrosis was reported in 35% (n = 120/340); and rimmed vacuoles were observed in 32% (n = 11/34) of biopsies. Capillaropathy, such as capillary dropout and/or ultrastructural endothelial abnormalities, was reported in 33% (n = 43/129) of cases. Reported ENMC categories were mainly polymyositis (21%), non-specific myositis (19%), immune-mediated necrotizing myopathy (16%), and dermatomyositis (8%). Histopathological features were analyzed according to serological subtypes in 28 studies, including anti-PM-Scl (n = 48), -Ku (n = 23) and -U1RNP (n = 90). Most of these biopsies demonstrated inflammatory infiltrates (range 49-85%) as well as MHC-I expression (range 63-81%). Necrosis was associated with anti-Ku (85%) and anti-U1RNP (73%), while anti-Ku was also associated with neurogenic features and rimmed vacuoles in 57% and 25% of cases, respectively. CONCLUSION: Our review suggests that SM is characterized by heterogeneous pathological features using definitions included in current histopathological criteria. Whether a distinct histopathological signature exists in SM remains to be determined. SSc-specific and SSc-associated autoantibodies may help define more homogeneous histopathological subsets.

Colour Doppler ultrasound and the giant cell arteritis probability score for the diagnosis of giant cell arteritis: a Canadian single-centre experience.

OBJECTIVES: The aim was to compare the accuracy of colour Doppler ultrasonography (CDUS) and temporal artery biopsy (TAB) to establish the final diagnosis of GCA and to determine how the GCA probability score (GCAPS) performs as a risk stratification tool. METHODS: Descriptive statistics were performed on a retrospective cohort of patients referred to our vasculitis referral centre between 1 July 2017 and 1 October 2020 for suspected GCA. CDUS, TAB, centre-specific TAB (vasculitis centre vs referring hospitals) and GCAPS were compared against the final diagnosis of GCA as determined by a GCA expert; CDUS was also compared with TAB results. RESULTS: Data from 198 patients were included: 60 patients with GCA and 138 patients without GCA. Sixty-two patients had a TAB. Using the final diagnosis by a GCA expert as a reference, the sensitivity, specificity, positive predictive value and negative predictive value were 93.3%, 98.5%, 96.6% and 97.1% for CDUS and 69.2%, 100%, 100% and 81.8% for TAB, respectively. The false-negative rate was 6.7% for CDUS and 30.8% for TAB. False-negative TAB mostly occurred when performed in referring hospitals (57.1%) as opposed to our vasculitis centre (21.1%). With a cut-off at 9.5 points, sensitivity for GCAPS was 98.3% and specificity 74.3%. CONCLUSION: CDUS of the temporal and axillary arteries showed a high sensitivity and specificity and helped to diagnose GCA in patients with negative TAB. We validated that GCAPS is a useful clinical tool, with a score of <9.5 making the diagnosis of GCA improbable.

Recognising the spectrum of scleromyositis: HEp-2 ANA patterns allow identification of a novel clinical subset with anti-SMN autoantibodies.

OBJECTIVE: To describe systemic sclerosis (SSc) with myopathy in patients without classic SSc-specific and SSc-overlap autoantibodies (aAbs), referred to as seronegative scleromyositis. METHODS: Twenty patients with seronegative scleromyositis diagnosed by expert opinion were analysed retrospectively for SSc features at myositis diagnosis and follow-up, and stratified based on HEp-2 nuclear patterns by indirect immunofluorescence (IIF) according to International Consensus of Autoantibody Patterns. Specificities were analysed by protein A-assisted immunoprecipitation. Myopathy was considered an organ involvement of SSc. RESULTS: SSc sine scleroderma was a frequent presentation (45%) at myositis diagnosis. Myositis was the most common first non-Raynaud manifestation of SSc (55%). Lower oesophagal dysmotility was present in 10 of 11 (91%) investigated patients. At follow-up, 80% of the patients met the American College of Rheumatology/EULAR SSc classification criteria. Two-thirds of patients had a positive HEp-2 IIF nuclear pattern (all with titers ≥1/320), defining three novel scleromyositis subsets. First, antinuclear antibody (ANA)-negative scleromyositis was associated with interstitial lung disease (ILD) and renal crisis. Second, a speckled pattern uncovered multiple rare SSc-specific aAbs. Third, the nuclear dots pattern was associated with aAbs to survival of motor neuron (SMN) complex and a novel scleromyositis subset characteriszed by calcinosis but infrequent ILD and renal crisis. CONCLUSIONS: SSc skin involvement is often absent in early seronegative scleromyositis. ANA positivity, Raynaud phenomenon, SSc-type capillaroscopy and/or lower oesophagal dysmotility may be clues for scleromyositis. Using HEp-2 IIF patterns, three novel clinicoserological subsets of scleromyositis emerged, notably (1) ANA-negative, (2) ANA-positive with a speckled pattern and (3) ANA-positive with nuclear dots and anti-SMN aAbs.

Statin-induced anti-HMGCR myopathy: successful therapeutic strategies for corticosteroid-free remission in 55 patients.

OBJECTIVE: To describe successful therapeutic strategies in statin-induced anti-HMGCR myopathy. METHODS: Retrospective data from a cohort of 55 patients with statin-induced anti-HMGCR myopathy, sequentially stratified by the presence of proximal weakness, early remission, and corticosteroid and IVIG use at treatment induction, were analyzed for optimal successful induction and maintenance of remission strategies. RESULTS: A total of 14 patients achieved remission with a corticosteroid-free induction strategy (25%). In 41 patients treated with corticosteroids, only 4 patients (10%) failed an initial triple steroid/IVIG/steroid-sparing immunosuppressant (SSI) induction strategy. Delay in treatment initiation was independently associated with lower odds of successful maintenance with immunosuppressant monotherapy (OR 0.92, 95% CI 0.85 to 0.97, P = 0.015). While 22 patients (40%) presented with normal strength, only 9 had normal strength at initiation of treatment. CONCLUSION: While corticosteroid-free treatment of anti-HMGCR myopathy is now a safe option in selected cases, initial triple steroid/IVIG/SSI was very efficacious in induction. Delays in treatment initiation and, as a corollary, delays in achieving remission decrease the odds of achieving successful maintenance with an SSI alone. Avoiding such delays, most notably in patients with normal strength, may reset the natural history of anti-HMGCR myopathy from a refractory entity to a treatable disease.

Rationale, study design, and descriptive data of the Lucky Bone™ Fracture Liaison Service.

The study design of a multidisciplinary Fracture Liaison Service (2-year follow-up) aiming to optimize fragility fracture management in an outpatient setting is presented. Patient characteristics, investigation, and treatment initiation data at baseline were recorded. Results corroborate the care gap in osteoporosis management, reinforcing the need for secondary fracture prevention programs. PURPOSE: This paper describes the study design, implementation, and baseline characteristics of a multidisciplinary Fracture Liaison Service (FLS) in Quebec (Canada). METHODS: A FLS was implemented as a prospective cohort study. After identification, fracture risk was assessed and patients were started on treatment or referred, according to guidelines and risk assessment. Thereafter, patients were systematically followed over 2 years. Clinical data (fractures, bone density, blood testing (bone turnover markers), quality of life, physical disability) as well as administrative data (pharmacological, health services, hospitalization) was collected. Baseline descriptive data was analyzed and presented. RESULTS: Of 542 recruited participants, 532 underwent baseline assessment (85.7% female, mean age 63.4 years). Overall, 29.7% of participants either withdrew from the study or were lost to follow-up. Almost 27% were referred to a specialist, while > 70% received anti-osteoporosis medication prescriptions through the FLS at baseline. Mean femoral T-score was - 1.6 ± 1.0 and vertebral T-score was - 1.7 ± 1.4. Nearly 19% of subjects reported being under anti-osteoporosis medication at the time of incident fracture. Thirty-three percent of participants reported a prior fracture history, of which 29.7% reported being given anti-osteoporosis therapy. Most fracture sites were to the wrist and ankle, while < 19% were hip/femur or vertebral fractures. CONCLUSIONS: These results highlight the important care gap in fragility fracture management and reinforce the need for secondary fracture prevention programs. This prospective study will allow the evaluation of key performance indicators for outpatient clinic-based FLS, such as medication usage, by combining prospective clinical and administrative data.

Metabolite monitoring to guide thiopurine therapy in systemic autoimmune diseases.

6-Thioguanine nucleotide (6-TGN) is the active metabolite of thiopurine drugs azathioprine and 6-mercaptopurine. 6-Methylmercaptopurine (6-MMP) is an inactive and potentially hepatotoxic metabolite. A subgroup of patients (shunters) preferentially produce 6-MMP instead of 6-TGN, therefore displaying thiopurine resistance and risk for hepatotoxicity. Outside inflammatory bowel disease literature, few data exist regarding individualized thiopurine therapy based on metabolite monitoring. This study sought to describe metabolite monitoring in patients receiving weight-based thiopurine for systemic autoimmune diseases. Patients were enrolled using a laboratory database, and data were retrospectively collected. The correlation between the highest thiopurine dose (mg/kg) and the 6-TGN concentration (pmol/8 × 108 erythrocytes) was estimated with Pearson's correlation coefficient. Seventy-one patients with various systemic autoimmune conditions were enrolled. The correlation between the thiopurine dose and the 6-TGN level was weak for the overall patient sample (r = 0.201, p = 0.092) and for the subgroup of non-shunters (r = 0.278, p = 0.053). Subjects with 6-MMP levels >5700 pmol/8 × 108 erythrocytes had more hepatic cytolysis compared to subjects with 6-MMP <5700, OR = 4.36 (CI 95% 1.18-16.13, p = 0.027). Twenty-two patients (31%) were identified as shunters. Six shunters developed hepatotoxicity, five of which had 6-MMP concentration >5700. Eleven non-shunters had hepatotoxicity, one of which had 6-MMP >5700. Thiopurine metabolite monitoring shows wide variability in 6-TGN levels among patients treated with weight-based thiopurine for systemic autoimmune diseases. Thirty-one percent of the patients in our series fulfilled the shunter definition. Thiopurine metabolite monitoring and dose adjustment to improve maintenance of remission and avoid hepatotoxicity should be studied prospectively.

Atorvastatin-induced necrotizing autoimmune myositis: An emerging dominant entity in patients with autoimmune myositis presenting with a pure polymyositis phenotype.

The general aim of this study was to evaluate the disease spectrum in patients presenting with a pure polymyositis (pPM) phenotype. Specific objectives were to characterize clinical features, autoantibodies (aAbs), and membrane attack complex (MAC) in muscle biopsies of patients with treatment-responsive, statin-exposed necrotizing autoimmune myositis (NAM). Patients from the Centre hospitalier de l'Université de Montréal autoimmune myositis (AIM) Cohort with a pPM phenotype, response to immunosuppression, and follow-up ≥3 years were included. Of 17 consecutive patients with pPM, 14 patients had a NAM, of whom 12 were previously exposed to atorvastatin (mean 38.8 months). These 12 patients were therefore suspected of atorvastatin-induced AIM (atorAIM) and selected for study. All had aAbs to 3-hydroxy-3-methylglutaryl coenzyme A reductase, and none had overlap aAbs, aAbs to signal recognition particle, or cancer. Three stages of myopathy were recognized: stage 1 (isolated serum creatine kinase [CK] elevation), stage 2 (CK elevation, normal strength, and abnormal electromyogram [EMG]), and stage 3 (CK elevation, proximal weakness, and abnormal EMG). At diagnosis, 10/12 (83%) patients had stage 3 myopathy (mean CK elevation: 7247 U/L). The presenting mode was stage 1 in 6 patients (50%) (mean CK elevation: 1540 U/L), all of whom progressed to stage 3 (mean delay: 37 months) despite atorvastatin discontinuation. MAC deposition was observed in all muscle biopsies (isolated sarcolemmal deposition on non-necrotic fibers, isolated granular deposition on endomysial capillaries, or mixed pattern). Oral corticosteroids alone failed to normalize CKs and induce remission. Ten patients (83%) received intravenous immune globulin (IVIG) as part of an induction regimen. Of 10 patients with ≥1 year remission on stable maintenance therapy, IVIG was needed in 50%, either with methotrexate (MTX) monotherapy or combination immunosuppression. In the remaining patients, MTX monotherapy or combination therapy maintained remission without IVIG. AtorAIM emerged as the dominant entity in patients with a pPM phenotype and treatment-responsive myopathy. Isolated CK elevation was the mode of presentation of atorAIM. The new onset of isolated CK elevation on atorvastatin and persistent CK elevation on statin discontinuation should raise early suspicion for atorAIM. Statin-induced AIM should be included in the differential diagnosis of asymptomatic hyperCKemia. Three patterns of MAC deposition, while nonpathognomonic, were pathological clues to atorAIM. AtorAIM was uniformly corticosteroid resistant but responsive to IVIG as induction and maintenance therapy.

Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: analysis of 100 French Canadian patients.

Our objective was to improve the currently imperfect classifications of idiopathic inflammatory myopathies (IIM). In clinical practice, overlap features are common in IIM. This provided a rationale for positioning overlap clinical features at the core of a new classification system. We conducted a longitudinal study of 100 consecutive adult French Canadian patients with IIM. Clinical and laboratory data were obtained by retrospective chart review. Sera were analyzed for autoantibodies (aAbs) by protein A-assisted immunoprecipitation and double immunodiffusion. Overlap aAbs encompassed aAbs to synthetases, systemic sclerosis-associated aAbs, anti-signal recognition particle (SRP) and anti-nucleoporins. Patients were classified both at IIM diagnosis, based on data at presentation, and at the end of follow-up, based on cumulative findings. Three classifications were used: 1) the Bohan and Peter original classification, 2) a new version of that classification as modified by us, and 3) a novel clinicoserologic classification. As investigators were blinded to aAb results, the modified classification is strictly a clinical classification. Its core concept is the attribution of diagnostic significance to the presence of overlap features, that is, their presence resulted in a diagnosis of overlap myositis (OM). This approach allowed direct comparison with the original Bohan and Peter classification. By integrating aAb results to the modified classification, we also defined the clinicoserologic classification, which allowed to examine the added value of aAbs to diagnostic, therapeutic and prognostic stratification. Whereas polymyositis (PM) was the most common IIM according to the original classification, accounting for 45% of the cohort at diagnosis, its frequency fell to 14% with the modified classification. Conversely, while the frequency of myositis associated with connective tissue disease was 24% according to the original classification, the frequency of OM was 60% when using the modified classification. At last follow-up, the frequency of PM fell further to only 9%, while the frequency of OM rose to 67%. Systemic sclerosis was the most common connective tissue disease associated with IIM, accounting for 42.6% of OM patients and 29% of the cohort. The frequencies of overlap aAbs in the cohort and in OM patients were 48% and 70.5% (n =48/68), respectively. The presence of overlap aAbs at IIM diagnosis identified additional OM patients unrecognized by the modified classification. The sensitivity of the modified classification for OM at diagnosis was 87%, suggesting that clinicians may rely on the modified classification for identification of most OM patients, while awaiting results of aAb assays. The new classifications predicted the response to prednisone and IIM course. Using stringent definitions, IIM was classified as responsive or refractory after an adequate initial corticosteroid therapy, and the disease course as monophasic or chronic after a single adequate trial of prednisone. PM was always chronic and was associated with the highest rate (50%) of refractoriness to initial corticosteroid treatment. Dermatomyositis was almost always chronic (92% rate); however, its responsiveness to initial corticosteroid treatment was high (87%). OM was almost always responsive to corticosteroids (89%-100% rates). When OM patients were divided according to aAb subsets, anti-synthetase, SRP, or nucleoporin aAbs were markers for chronic myositis, whereas aAbs to U1RNP, Pm-Scl, or Ku were markers for monophasic myositis. We conclude that the original Bohan and Peter classification should be abandoned as it leads to misclassification of patients. Much of IIM is composed of OM. The proposed modified and clinicoserologic classifications have diagnostic, prognostic, and therapeutic value.

An autoimmune myositis-overlap syndrome associated with autoantibodies to nuclear pore complexes: description and long-term follow-up of the anti-Nup syndrome.

Autoimmune myositis encompasses various myositis-overlap syndromes, each being identified by the presence of serum marker autoantibodies. We describe a novel myositis-overlap syndrome in 4 patients characterized by the presence of a unique immunologic marker, autoantibodies to nuclear pore complexes. The clinical phenotype was characterized by prominent myositis in association with erosive, anti-CCP, and rheumatoid factor-positive arthritis, trigeminal neuralgia, mild interstitial lung disease, Raynaud phenomenon, and weight loss. The myositis was typically chronic, relapsing, and refractory to corticosteroids alone, but remitted with the addition of a second immunomodulating drug. There was no clinical or laboratory evidence for liver disease. The prognosis was good with 100% long-term survival (mean follow-up 19.5 yr).By indirect immunofluorescence on HEp-2 cells, sera from all 4 patients displayed a high titer of antinuclear autoantibodies (ANA) with a distinct punctate peripheral (rim) fluorescent pattern of the nuclear envelope characteristic of nuclear pore complexes. Reactivity with nuclear pore complexes was confirmed by immunoelectron microscopy. In a cohort of 100 French Canadian patients with autoimmune myositis, the nuclear pore complex fluorescent ANA pattern was restricted to these 4 patients (4%). It was not observed in sera from 393 adult patients with systemic sclerosis (n = 112), mixed connective tissue disease (n = 35), systemic lupus (n = 94), rheumatoid arthritis (n = 45), or other rheumatic diseases (n = 107), nor was it observed in 62 normal adults.Autoantibodies to nuclear pore complexes were predominantly of IgG isotype. No other IgG autoantibody markers for defined connective tissue diseases or overlap syndromes were present, indicating a selective and highly focused immune response. In 3 patients, anti-nuclear pore complex autoantibody titers varied in parallel with myositis activity, suggesting a pathogenic link to pathophysiology. The nuclear pore complex proteins, that is, nucleoporins (nup), recognized by these sera were heterogeneous and included Nup358/RanBP2 (n = 2 patients), Nup90 (n = 1), Nup62 (n = 1), and gp210 (n = 1). Taken together the data suggest that nup autoantigens themselves drive the anti-nup autoimmune response. Immunogenetically, the 4 patients shared the DQA1*0501 allele associated with an increased risk for autoimmune myositis.In conclusion, we report an apparent novel subset of autoimmune myositis in our population of French Canadian patients with connective tissue diseases. This syndrome is recognized by the presence of a unique immunologic marker, autoantibodies to nuclear pore complexes that react with nups, consistent with an "anti-nup syndrome."