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 as...

The objective of this study was to determine the prevalence, mutual associations, clinical manifestations, and diagnoses associated with serum autoantibodies, as detected using recently available immunoassays, in patients with autoimmune myositis (AIM). Sera and clinical data were collected from 100 patients with AIM followed longitudinally. Sera were screened cross-sectionally for 21 autoantibodies by multiplex addressable laser bead immunoassay, line blot immunoassay, immunoprecipitation of in vitro translated recombinant protein, protein A assisted immunoprecipitation, and enzyme-linked immunosorbent assay. Diagnoses were determined using the Bohan and Peter classification as well as recently proposed classifications. Relationships between autoantibodies and clinical manifestations were analyzed by multiple logistic regression. One or more autoantibodies encompassing 19 specificities were present in 80% of the patients. The most common autoantibodies were anti-Ro52 (30% of patients), antiKu (23%), anti-synthetases (22%), anti-U1RNP (15%), and antifibrillarin (14%). In the presence of autoantibodies to Ku, synthetases, U1RNP, fibrillarin, PM-Scl, or scleroderma autoantigens, at least one more autoantibody was detected in the majority of sera and at least two more autoantibodies in over one-third of sera. The largest number of concurrent autoantibodies was six autoantibodies. Overall, 44 distinct combinations of autoantibodies were counted. Most autoantibodies were unrestricted to any AIM diagnostic category. Distinct clinical syndromes and therapeutic responses were associated with anti-Jo-1, anti-fibrillarin, anti-U1RNP, antiRo, anti-Ro52, and autoantibodies to scleroderma autoantigens. We conclude that a significant proportion of AIM patients are characterized by complex associations of autoantibodies. Certain myositis autoantibodies are markers for distinct overlap syndromes and predict therapeutic outcomes. The ultimate clinical features, disease course, and response to therapy in a given AIM patient may be linked to the particular set of associated autoantibodies. These results provide a rationale for patient profiling and its application to therapeutics, because it cannot be assumed that the B-cell response is the same even in the majority of patients in a given diagnostic category.

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.

SummaryBackground and objectives ANCA-associated vasculitis (AAV) is treated with potent immunosuppressive regimens. This study sought to determine risk factors associated with infections during first-intention therapy.Design, setting, participants, & measurements This retrospective study involved two separate cohorts of consecutive cases of AAV seen from 2004 to 2011 at two university hospitals. The following were assessed: vasculitis severity; therapy; and periods with no, moderate (lymphocyte count, 0.3-1.03 10 9 /L), or severe (lymphocyte count # 0.3310 9 /L) lymphopenia and neutropenia (neutrophil count # 1.5310 9 /L).Results One hundred patients had a mean age of 57615 years and a Birmingham vasculitis activity score of 7.763.6. Therapy consisted of pulse methylprednisolone (59%), cyclophosphamide (85%), methotrexate (6%), and plasmapheresis (25%) in addition to oral corticosteroids. During follow-up, 53% of patients experienced infection and 28% were hospitalized for infection (severe infection). Only 18% experienced neutropenia, but 72% and 36% presented moderate and severe lymphopenia for a total duration of ,0.1%, 73%, and 8% of the treatment follow-up, respectively. Lower initial estimated GFR, longer duration of corticosteroid use, and presence of lymphopenia were risk factors of infections. The rate was 2.23 events/person-year in the presence of severe lymphopenia compared with 0.41 and 0.19 during periods with moderate or no lymphopenia (P,0.001). Similarly, the rate of severe infections was 1.00 event/person-year with severe lymphopenia and 0.08 and 0.10 with moderate and no lymphopenia (P,0.001). This association remained independent of other risk factors.Conclusions Lymphopenia is frequent during the treatment of AAV, and its severity is associated with the risk of infectious complications.

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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 × 10 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 × 10 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.

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