Incidence Rates of Interstitial Lung Disease Events in Tofacitinib-Treated Rheumatoid Arthritis Patients: Post Hoc Analysis From 21 Clinical Trials.

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.

Clinical Characteristics and Natural History of Autoimmune Forms of Interstitial Lung Disease: A Single-Center Experience.

OBJECTIVE: To describe the phenotypic characteristics and natural history of patients with autoimmune forms of interstitial lung disease (ILD). METHODS: 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. RESULTS: 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 = < 0.001). CONCLUSIONS: The predominant phenotypes of autoimmune ILD were SSc-ILD, IPAF, RA-ILD, and IIM-ILD. In contrast to the other subsets, those with RA-ILD may be older, gender balanced, with more smoking history, and higher proportion of UIP. Longitudinal lung function was stable among the groups and younger age, female gender, and better lung function were associated with improved survival.

Current approach to connective tissue disease-associated interstitial lung disease.

PURPOSE OF REVIEW: To review current approaches to the complex intersection of interstitial lung disease (ILD) with the spectrum of connective tissue disease (CTD). RECENT FINDINGS: There is a growing appreciation that the approach to CTD-associated ILD (CTD-ILD) can be enhanced by a multidisciplinary evaluation that often incorporates the rheumatologist. Determining that ILD is associated with an established CTD requires the exclusion of alternative causes and thorough assessments of the clinical features of both the CTD and ILD. The detection of occult CTD in patients with presumed 'idiopathic' disease requires careful attention to the demographic profile, historical clues, subtle physical examination findings, specific autoantibody positivity, radiologic, and histopathologic features. A comprehensive treatment program for CTD-ILD should address comorbid conditions and consider implementation of adjunctive therapeutic strategies. Pharmacologic intervention for CTD-ILD is reserved for those with progressive, clinically significant disease and typically involves use of immunosuppressive therapies. SUMMARY: A multidisciplinary approach can be helpful for CTD-ILD. Further research and controlled trials are needed to determine how to best manage the diverse spectrum of CTD-ILD.

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.

Rituximab for the treatment of connective tissue disease-associated interstitial lung disease.

OBJECTIVE: To describe our experience with rituximab (RTX) as treatment for a diverse spectrum of chronic connective tissue disease-associated interstitial lung disease (CTD-ILD). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

A Multidisciplinary Evaluation Helps Identify the Antisynthetase Syndrome in Patients Presenting as Idiopathic Interstitial Pneumonia.

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.

Clinical features and natural history of interstitial pneumonia with autoimmune features: A single center experience.

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.

Assessment and management of connective tissue disease-associated interstitial lung disease.

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.

Management of connective tissue disease-associated interstitial lung disease.

A thorough, often multidisciplinary assessment to determine extrathoracic versus intrathoracic disease activity and degrees of impairment is needed to optimize the management of connective tissue disease (CTD)-associated interstitial lung disease (ILD). Pharmacologic intervention with immunosuppression is the mainstay of therapy for all forms of CTD-ILD, but should be reserved for those that show clinically significant and/or progressive disease. The management of CTD-ILD is not yet evidence based and there is a need for controlled trials across the spectrum of CTD-ILD. Nonpharmacologic management strategies and addressing comorbidities or aggravating factors should be included in the comprehensive treatment plan for CTD-ILD.