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Background/objective Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Interstitial lung disease (ILD) is an extra-articular manifestation of RA. We investigated incidence rates of ILD in patients with RA, receiving tofacitinib 5 or 10 mg twice daily, and identified potential risk factors for ILD. Methods This post hoc analysis comprised a pooled analysis of patients receiving tofacitinib 5 or 10 mg twice daily or placebo from 2 phase (P)1, 10 P2, 6 P3, 1 P3b/4, and 2 long-term extension studies. Interstitial lung disease events were adjudicated as "probable" (supportive clinical evidence) or "possible" (no supportive clinical evidence) compatible adverse events. Incidence rates (patients with events per 100 patient-years) were calculated for ILD events. Results Of 7061 patients (patient-years of exposure = 23,393.7), 42 (0.6%) had an ILD event; median time to ILD event was 1144 days. Incidence rates for ILD with both tofacitinib doses were 0.18 per 100 patient-years. Incidence rates generally remained stable over time. There were 17 of 42 serious adverse events (40.5%) of ILD; for all ILD events (serious and nonserious), 35 of 42 events (83.3%) were mild to moderate in severity. A multivariable Cox regression analysis identified age 65 years or older (hazard ratio 2.43 [95% confidence interval, 1.13-5.21]), current smokers (2.89 [1.33-6.26]), and Disease Activity Score in 28 joints-erythrocyte sedimentation rate score (1.30 [1.04-1.61]) as significant risk factors for ILD events. Conclusions Across P1/2/3/4/long-term extension studies, incidence rates for ILD events were 0.18 following tofacitinib treatment, and ILD events were associated with known risk factors for ILD in RA.

Raynaud phenomenon (RP) in connective tissue disease (CTD) can be resistant to oral vasodilator therapy, resulting in uncontrollable digital ischemia. Intravenous (IV) prostanoids are often used, but the benefit can be transient and not all patients respond. Selexipag is an orally active selective IP-type prostanoid receptor agonist used in pulmonary arterial hypertension. We describe 2 patients where selexipag significantly reduced digital ischemia after failure of other oral vasodilating agents. Subject 1 with undifferentiated CTD had impressive healing of her fingers (Figure 1) and subject 2 with systemic sclerosis (SSc) had a …

To describe the phenotypic characteristics and natural history of patients with autoimmune forms of interstitial lung disease (ILD). Retrospective, descriptive, single-center study of patients with autoimmune forms of ILD evaluated between February 2008 and August 2014. All data were extracted from the electronic medical record. Longitudinal changes in forced vital capacity (FVC%) and diffusion capacity for carbon monoxide (DLco%) in percent predicted were analyzed and time-to-event analyses for death were performed using Cox regression. Of the entire cohort (n = 243), systemic sclerosis (SSc)-associated ILD (n = 88, 36%), interstitial pneumonia with autoimmune features (IPAF, n = 56, 23%), rheumatoid arthritis (RA)-associated ILD (n = 42, 17%), and idiopathic inflammatory myopathy (IIM)-associated ILD (n = 26, 11%) were the most common phenotypes. The SSc-ILD, IIM-ILD, and IPAF groups had similar features: average age in the mid-50s, strongly female predominant and more likely to have nonspecific interstitial pneumonia (NSIP). In contrast, RA-ILD patients were older, gender balanced, more likely to be past smokers and were UIP predominant. Adjusted longitudinal lung function was stable during a median follow-up period of nearly 4 years and the independent predictors for death were older age (p = 0.003), male sex (p = 0.019), and lower FVC (p =

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.

Objective To describe the clinical phenotype and natural history of a cohort of patients with interstitial pneumonia with autoimmune features (IPAF). Methods A retrospective, single center study of 56 patients with IPAF evaluated between February 2008 and August 2014. All clinical data were extracted from the electronic medical record and longitudinal changes in forced vital capacity (FVC) were analyzed with mixed-effects, piecewise linear regression models that considered time as a continuous factor. Results All patients fulfilled classification criteria for IPAF. The majority were women (71%) and never smokers (68%). The most frequently identified clinical features were Raynaud's phenomenon (39%), distal digital fissuring (29%), Gottron's sign (18%) and inflammatory arthropathy (16%). The most frequently identified serologies were antinuclear antibody (ANA) (48%), anti-Ro (SSA) (43%) and anti-tRNA-synthetase antibodies (36%). Nonspecific interstitial pneumonia (NSIP) (57.1%) followed by NSIP with organizing pneumonia (18%) were the most common radiologic patterns, while usual interstitial pneumonia was identified in only 9%. All but one patient was treated with immunosuppression: prednisone (82%) and mycophenolate mofetil (76%) were the most frequently used agents. During a follow-up period of 284.9 ± 141.3 days, modeled longitudinal FVC% was stable (slope = 0.69/year) and no deaths were observed in the cohort. Conclusions In this single center study, patients with IPAF were predominately non-smoking women with high-resolution computed tomography scans that suggested NSIP. Their pulmonary physiology was stable, and during limited follow-up, no deaths were observed. Prospective and multi-center studies are needed to better inform our understanding of IPAF.

Introduction.Interstitial lung disease (ILD) is 1 possible manifestation of the idiopathic inflammatory myopathies (IIM). Occasionally, patients presenting with ILD are mistakenly diagnosed with idiopathic interstitial pneumonia (IIP), but after multidisciplinary evaluation, their ILD is determined to be because of antisynthetase syndrome (SynS) or myositis spectrum of disease.Methods.We used retrospective analytic methods to identify patients with ILD evaluated at the National Jewish Health between February 2008 and August 2014 and believed initially to have IIP but ultimately diagnosed with SynS or myositis spectrum of disease.Results.The cohort included 33 patients; most were white women with a mean age at presentation of 55 years. Their pulmonary physiologic impairment was moderate. In 31 cases, the ILD pattern by thoracic high-resolution computed tomography scan was nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), or a combination of the 2. Surgical lung biopsy was performed in 21 patients; NSIP was the most common pattern. Less than one-third of the cohort had positive antinuclear antibodies. Two-thirds had positive SSA. All patients had either myositis-specific or myositis-associated autoantibody. Most had subtle extrathoracic symptoms or signs of SynS; 12 had an elevated serum creatine phosphokinase, but none had clinical evidence of myositis. None met the Peter and Bohan classification criteria for polymyositis/dermatomyositis.Conclusion.Among patients who present with presumed IIP, a multidisciplinary evaluation that includes the integration of clinical evaluations by rheumatologists and pulmonologists, morphologic (both histopathologic and radiographic) data, and serologic features is helpful in the detection of occult SynS or the myositis spectrum of disease.

Systemic lupus erythematosus (SLE) can affect all compartments of the thorax, either as part of the systemic disease or due to pulmonary infection as a consequence of the immunosuppressive effects of the disease itself or the drugs used to treat it. Infection must be rigorously excluded when lung disease is evident. This chapter focuses on all the pulmonary manifestations of SLE and provides the authors' views on best management while acknowledging that there is no true evidence base for any of the recommendations due to the absence of any controlled studies of pulmonary disease in SLE or its treatment.

In this report, we describe a patient with the unusual concomitant presentation of an acute exacerbation of systemic sclerosis-associated interstitial lung disease with the development of anti-neutrophil cytoplasmic antibody-associated active renal vasculitis. Systemic sclerosis is a connective tissue disease characterized by systemic autoimmunity and organ fibrosis and vasculopathy. Interstitial lung disease is identified in the majority of patients with systemic sclerosis and may have varying degrees of severity. Patients with systemic sclerosis-associated interstitial lung disease rarely develop acute exacerbations of interstitial lung disease. An overlap of systemic vasculitis has been reported to occur in patients with systemic sclerosis – yet this too is a rare occurrence. This case is unique in that it demonstrates the concomitant presentation of these rare clinical scenarios and serves to highlight the importance of a comprehensive and multidiscciplinary approach to the evaluation of patients in general, and systemic autoimmune patients in particular.

To describe our experience with rituximab (RTX) as treatment for a diverse spectrum of chronic connective tissue disease-associated interstitial lung disease (CTD-ILD).Twenty-four subjects with CTD-ILD were included. All had pulmonary function testing before and after their first RTX infusion. Each subject was evaluated in a multidisciplinary autoimmune and ILD outpatient clinic. Data were extracted by retrospective review of complete medical records.Most subjects were middle-aged white women with rheumatoid arthritis (RA) (n=15) and a nonspecific interstitial pneumonia (NSIP) pattern on high-resolution chest computed tomography scans (n=17). Sixteen subjects received a corticosteroid-sparing agent at the time of RTX initiation; mostly mycophenolate mofetil (n=8). RTX administration was not associated with corticosteroid-sparing effects: 13 subjects were on prednisone at the time of the initial RTX cycle, and 9 remained on prednisone at 6 months after (mean daily dosage 10.2±16.2 mg before vs. 5.6±11.0 mg after, p=0.27). RTX had no appreciable effect on pulmonary physiology; however, individual trajectories for percentage predicted forced vital capacity (FVC%) were highly variable. The underlying CTD (RA vs. non-RA) and ILD pattern did not appear to affect response to RTX. Among 14 subjects who received multiple RTX cycles, FVC% trajectories were variable: FVC% increased in eight and declined in six. Respiratory infections were the most common post-RTX adverse event.In this small, retrospective study of chronic CTD-ILD, RTX was not associated with changes in FVC% or corticosteroid-sparing effects. Controlled, prospective studies are needed to more confidently define the effects of RTX in CTD-ILD.

The intersection of the connective tissue diseases (CTD) and the interstitial lung diseases (ILD) is complex. Although often considered as a single entity, "CTD-ILD" actually reflects a heterogeneous spectrum of diverse CTDs and a variety of patterns of interstitial pneumonia. The evaluation of patients with CTD that develop ILD, or the assessment for underlying CTD in those presenting with presumed "idiopathic" ILD can be challenging and these evaluations can be optimized by effective multidisciplinary collaboration. When a diagnosis of CTD-ILD is confirmed, careful and thorough assessments to determine extra- versus intra-thoracic disease activity, and degrees of impairment are needed. Pharmacologic intervention with immunosuppression is the mainstay of therapy for all forms of CTD-ILD, but should be reserved only for those that demonstrate clinically significant and/or progressive disease. The management of CTD-ILD is not yet evidence based and there is a desperate need for controlled trials across the spectrum of CTD-ILD. Non-pharmacologic management strategies and addressing comorbidities or aggravating factors should be part of a comprehensive treatment plan for individuals with CTD-ILD.

T lymphocytes isolated from the blood of 24 newly diagnosed and 2 relapsed patients with non-Hodgkin's malignant lymphomas were studied for helper/suppressor activity in cocultures with allogeneic tonsilar B lymphocytes stimulated with pokeweed mitogen. The IgA, IgG, and IgM secretion was measured by double-antibody radioimmunoassay. In 85% of patients with B lymphomas their T lymphocytes produced a severalfold increase in immunoglobulin secretion when compared with age-matched healthy controls. By contrast in two cases of T lymphoma, suppression of immunoglobulin secretion was observed. The ratio of “T helper”/“T suppressor” lymphocytes, as measured with monoclonal antibodies ( OKT 4 OKT 8 ), were similar for patients and controls, and concanavalin A-induced suppression was equally good. However, small numbers of patient T lymphocytes provided good help, while control cells failed in these higher dilutions. Possible explanations of the increased helper activity of “nonmalignant” T lymphocytes in B lymphomas as related to clinical features and the pathogenesis of B- versus T-cell malignancies are discussed.

To identify lymphoid cells bearing receptors for both sheep erythrocytes (sE) and complement (C′), a combined rosette assay was developed using uncoated sE and chicken erythrocytes coated with antibody and complement (cEAC′). Cells with both receptors were present in low percentages in the blood of normal individuals. Tissues and/or blood from 543 patients with various diseases were studied using the combined rosette assay. Large numbers of malignant cells were found to carry receptors for both C′ and sE in four patients with lymphoproliferative malignancies. Two were children with lymphoma who had mediastinal masses. The other two were adults with chronic lymphocytic leukemia; their cells also carried surface immunoglobulin and Fc receptors. In these four patients double or multiple receptor lymphocytes may represent a clonal proliferation of subsets of lymphocytes present in small numbers under normal conditions. An increase in double receptor lymphocytes was rare in the non-neoplastic conditions studied and seen only in children. Double receptor lymphocytes may represent an immature or “stem” cell lymphocyte subset.

Canine Endotoxin Shock: Protection against a Lethal Dose of Endotoxin following an Infusion of Histamine

A pedigree with a variety of rare immunologic and endocrine abnormalities was studied for immunogenetic associations. HLA genotyping, plus the presence of an HLA B/D recombinant reveal that all affected share an HLA region of a single sixth chromosome, including the A and B, but not the D region. Suppressor cell assays of the proband indicate that one manifestation of the genetic defect is suppression of B-lymphocytc immunoglobulin production. (Supported by ACS grant IN-13)