tacrolimus and Lung-Diseases--Interstitial

Anti-synthetase syndrome (ASS) is a chronic multisystemic autoimmune disease characterized by detectable anti-aminoacyl-transfer-RNA antibodies. Interstitial lung disease (ILD) in anti-synthetase syndrome patients is often severe and rapidly progressive. Anti-Zo (phenylalanyl) antibody is reported rarely in ASS. Therefore, the appropriate treatment of anti-Zo positive ASS is unclear.. Here we present a case of anti-Zo-positive ASS with rapid progressive ILD (RP-ILD) in a Chinese patient successfully treated with a combination of systemic corticosteroids and tacrolimus.. We reviewed 13 anti-Zo-positive ASS patients (including our case) and summarized clinical features that have some differences with other ASS. Anti-Zo-positive ASS is a rare autoimmune disease with a high burden of ILD, is often severe and rapidly progressive. Corticosteroids with tacrolimus may improve patient outcomes in anti-Zo antibody positive ASS with RP-ILD.

Topics: Autoimmune Diseases; Humans; Ligases; Lung Diseases, Interstitial; Tacrolimus

Interstitial lung disease (ILD) in patients with polymyositis (PM) and dermatomyositis (DM) is often resistant to treatment and life threatening, being recognized as one of the severest complication in these autoimmune disorders. Patients with clinically amyopathic dermatomyositis (CADM) or those with anti-CADM140/MDA5 antibody are especially prone to develop rapidly progressive interstitial pneumonia. We retrospectively analyzed 46 patients with PM/DM admitted to our hospital and identified DM, rapidly progressive disease, honeycomb lung, CADM and extensive ILD as risk factors for recurrence or death. In the presence of two or more risk factors, the sensitivity and specificity for the prediction of death or relapse were 81.3% and 76.7%, respectively. Calcineurin inhibitors have been widely used as induction and maintenance therapy for PM/DM-associated ILD. Recently we reported the benefit of tacrolimus on the disease-free survival and event-free survival of the patients with PM/DM-associated ILD. Among those patients treated with tacrolimus, poor prognostic factors for death, recurrence or severe adverse event were identified as acute progression of the disease, honeycomb lung, forced vital capacity (FVC) less than 80% and having DM. The potential effectiveness of an intensive therapy protocol with triple therapy that comprises high-dose corticosteroids, calcineurin inhibitors and cyclophosphamide has been reported.

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Cyclophosphamide; Cyclosporine; Dermatomyositis; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Prognosis; Retrospective Studies; Tacrolimus

The purpose of this study is to examine the efficacy and safety of tacrolimus (FK506) in the management of polymyositis (PM)/dermatomyositis (DM). The Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, and China National Knowledge Infrastructure (CNKI) were searched to find articles published between May 1980 and April 2015 concerning tacrolimus therapy in PM/DM. The initial search yielded 107 articles. In the end, eight studies met our inclusion criteria and involved a total of 134 patients who received tacrolimus therapy for DM/PM. All studies were non-randomized. Oral tacrolimus of 0.075 mg/kg/day or 1.0-3.5 mg/d was administered twice daily or once daily together with glucocorticoids (GCs). According to comprehensive analysis of the studies, 93.3 % (42/45) and 64.7 % (11/17) of patients showed improvement in muscle strength and physical function status. The creatine kinase (CK) levels of 100 % (68/68) of patients decreased. The average dosage of GCs was reduced from 33.8 to 11.5 mg/day in PM/DM patients after the addition of tacrolimus. In the subject population, 65 patients had interstitial lung disease (ILD). After treatment, the forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) improved or stabilized in 89.3 % (25/28) and 81.3 % (13/16) of patients, respectively. The commonly adverse events were nephrotoxicity, hypomagnesemia, tremors, and hypertension, but they were slight among these patients. Current evidence appears to support the use of tacrolimus in refractory PM/DM and PM/DM-ILD patients. Tacrolimus seems to be a safe drug that improves both muscle strength and lung function, and it is well tolerated by patients. However, this conclusion should be confirmed by large-sample, randomized controlled studies.

Topics: Dermatomyositis; Drug Therapy, Combination; Glucocorticoids; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Polymyositis; Tacrolimus; Treatment Outcome

To highlight recent advances in understanding the clinical spectrum, pathogenesis, and treatment of interstitial lung disease associated with inflammatory myositis and the antisynthetase syndrome.. In recent years, serologic tests to identify the less common antisynthetase antibodies and the anti-MDA-5 antibody have become commercially available. As a result, several large, retrospective analyses have illustrated both the pulmonary and non-pulmonary features associated with the antisynthetase syndrome and myositis-related interstitial lung disease. Notably, there is now a better appreciation for the heterogeneity of these syndromes and the prognostic value in accurately identifying the associated autoantibodies. Human cytokine profiling and murine models of muscle inflammation suggest that tRNA synthetases themselves may act to trigger an initial innate immune response, thus offering new insights into the pathophysiology of these diseases. Finally, although randomized clinical trials in patients with myositis-associated interstitial lung disease have not occurred, new observational studies suggest that cyclosporine, tacrolimus, and rituximab may be effective treatment options.. Recent research has provided a better understanding of the phenotype and prognosis that define interstitial lung disease in the setting of myositis and the antisynthetase syndrome. Although several therapeutic agents demonstrate promise, randomized trials are needed in order to establish the best clinical approach in these patients. Furthermore, additional research into the pathophysiology of this disease will be necessary to develop newer, more targeted therapeutics.

Topics: Antibodies, Monoclonal, Murine-Derived; Cyclosporine; Humans; Immunologic Factors; Lung Diseases, Interstitial; Myositis; Prognosis; Rituximab; Tacrolimus; Treatment Outcome

We contacted and analyzed the data of 18 lung transplant recipients who had had children. The complications we detected included: hypertension (50%), diabetes mellitus (21%), preeclampsia (13%), infection (21%), rejection (30%), loss of graft function (23%) and a lower percentage of live births than in transplant recipients of other organs. Other aspects to keep in mind are: the potential risk for fetal alterations (caused by drugs used as prophylaxis against rejection crossing the placental barrier); greater risk for infection and alterations in drug levels due to changes in metabolism typical of pregnancy and postpartum period. We describe the two cases in Spain of female lung transplant recipients who have had children after transplantation. Although pregnancy in these cases can have a similar evolution as in non-transplanted women, doctors should recommend their transplanted patients to avoid becoming pregnant, while explaining the high risk of both fetal and maternal morbidity and mortality after transplantation.

Topics: Adult; Cardiomyopathies; Female; Graft Rejection; Heart Defects, Congenital; Heart-Lung Transplantation; Humans; Hypertension; Hypertension, Pulmonary; Immunosuppressive Agents; Infant, Newborn; Infant, Premature, Diseases; Lung Diseases, Interstitial; Lung Transplantation; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Complications, Infectious; Pregnancy in Diabetics; Pregnancy Outcome; Pregnancy, High-Risk; Spain; Survivors; Tacrolimus

It is well known that a certain percentage of patients with polymyositis and dermatomyositis (PM/DM) is corticosteroid resistant. Established and novel approaches to steroid-resistant PM/DM are discussed in this review. Methotrexate (MTX) is a first-line treatment in the case that steroid therapy fails. Azathioprine and cyclophosphamide also fall into this category. Cyclosporine, a specific inhibitor of calcineurin, has been reported almost as effective as MTX. Tacrolimus, also a calcineurin inhibitor, and mycophenolate mofetil could be additional alternatives for the treatment. Several clinical trials have demonstrated that high-dose intravenous immunoglobulin is promising. Recently favorable data have been published using intravenous high-dose pulse cyclophosphamide or cyclosporine for the poorly prognostic interstitial pneumonitis or pulmonary fibrosis accompanied with PM/DM.

Topics: Animals; Anti-Inflammatory Agents; Azathioprine; Cyclophosphamide; Cyclosporine; Dermatomyositis; Drug Resistance; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Lung Diseases, Interstitial; Methotrexate; Mycophenolic Acid; Polymyositis; Steroids; Tacrolimus

The efficacy of combination therapy with corticosteroids and CNI, TAC and CsA, for PM/DM-ILD has been described retrospectively. However, it remains unknown which CNI treatment regimens, TAC or CsA regimens, are more effective as initial treatments for patients with PM/DM-ILD.. We conducted a prospective multicentre, open-label, randomized, 52-week phase 2 trial. Patients with PM/DM-ILD were randomly allocated to receive PSL plus TAC (TAC group) or PSL plus CsA (CsA group). The primary endpoint was PFS rate in the intention-to-treat population at 52 weeks. The secondary endpoints were OS rate at 52 weeks, changes in pulmonary function tests from baseline to 52 weeks and AE.. Fifty-eight patients were randomly assigned to the TAC group (n = 30) and the CsA group (n = 28). The PFS rates at 52 weeks were 87% in the TAC group and 71% in the CsA group (P = 0.16). The OS rates at 52 weeks were 97% in the TAC group and 93% in the CsA group (P = 0.50). The %FVC at 52 weeks in the per-protocol populations significantly increased in both groups. None of the patients discontinued the treatment due to AE.. PSL plus TAC treatment may achieve a better short-term PFS rate compared with PSL plus CsA treatment. Further studies must be conducted to evaluate the long-term efficacy and safety of such treatment.

Topics: Cyclosporine; Dermatomyositis; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Prednisolone; Prospective Studies; Retrospective Studies; Tacrolimus

Interstitial pneumonia is common and has high short-term mortality in patients with PM and DM despite glucocorticoid (GC) treatment. Retrospective studies suggested that the early use of immunosuppressive drugs with GCs might improve its short-term mortality.. A multicentre, single-arm, 52-week-long clinical trial was performed to test whether the initial combination treatment with tacrolimus (0.075 mg/kg/day, adjusted for the target whole-blood trough levels between 5 and 10 ng/ml) and GCs (0.6-1.0 mg/kg/day of prednisolone followed by a slow taper) improves short-term mortality of PM/DM-interstitial pneumonia patients. The primary outcome was overall survival. We originally intended to compare, by using propensity-score matching, the outcome data of clinical trial patients with that of historical control patients who were initially treated with GCs alone.. The 52-week survival rate with the combination treatment (N = 26) was 88.0% (95% CI, 67.3, 96.0). Safety profiles of the combination treatment were consistent with those known for tacrolimus and high-dose GCs individually. Serious adverse events occurred in 11 patients (44.0%), which included four opportunistic infections. Only 16 patients, including only 1 deceased patient, were registered as historical controls, which precluded meaningful comparative analysis against the clinical trial patients.. Our study provided findings which suggest that initial treatment with tacrolimus and GCs may improve short-term mortality of PM/DM-interstitial pneumonia patients with manageable safety profiles. This was the first prospective clinical investigation conducted according to the Good Clinical Practice Guideline of the International Conference on Harmonization for the treatment of this potentially life-threatening disease.. ClinicalTrials.gov, http://clinicaltrials.gov, NCT00504348.

Topics: Adult; Aged; Cause of Death; Comorbidity; Dermatomyositis; Disease-Free Survival; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Japan; Kaplan-Meier Estimate; Lung Diseases, Interstitial; Male; Middle Aged; Outcome Assessment, Health Care; Polymyositis; Prospective Studies; Respiratory Function Tests; Risk Assessment; Survival Rate; Tacrolimus

Herein, we report the case of a 67-year-old man with severe coronavirus disease (COVID-19) pneumonia and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine breakthrough infection during immunosuppressive therapy for connective tissue disease-related interstitial lung disease (CTD-ILD). The patient received glucocorticoids combined with tacrolimus as maintenance therapy. His serum anti-SARS-CoV-2-immunoglobulin G (IgG) antibody levels were extremely low at the onset of COVID-19 pneumonia, even after the second dose of SARS-CoV-2 mRNA vaccine (BNT162b2). After treatment for COVID-19 pneumonia, the levels of anti-SARS-CoV-2-IgG antibodies increased. These results indicated a lack of the ability to produce neutralising antibodies from immune cells despite the booster vaccination. Therefore, we suggest that advanced-age patients with CTD-ILD receiving immunosuppressive therapy with polypharmacy require consistent personal protection, vaccination of close caregivers, increased awareness, and booster vaccination. Moreover, we recommend that tacrolimus should be withdrawn for a while after vaccination under controlled conditions.

Topics: Aged; Antibodies, Viral; BNT162 Vaccine; Breakthrough Infections; Connective Tissue Diseases; COVID-19; COVID-19 Vaccines; Humans; Immunoglobulin G; Immunosuppression Therapy; Lung Diseases, Interstitial; Male; SARS-CoV-2; Tacrolimus

To examine the association between MTX, LEF and tacrolimus use and the progression of RA-associated interstitial lung disease (ILD).. The Korean RA-ILD cohort prospectively enrolled patients with RA-associated ILD at multiple centres from 2015 to 2018 and followed up with them for 3 years. ILD progression was defined by any of the followings: a decrease of ≥10% in forced vital capacity, a decrease of ≥15% in the diffusing capacity of the lung for carbon monoxide, or death from respiratory failure.. Of 143 patients, 64 patients experienced ILD progression during a median follow-up period of 33 months. The use of MTX [adjusted hazard ratio (aHR), 1.06; 95% CI, 0.59, 1.89], LEF (aHR, 1.75; 95% CI, 0.88, 3.46) and tacrolimus (aHR, 0.94; 95% CI, 0.52, 1.72) did not increase the risk of ILD progression. However, the association between LEF use and the risk of ILD progression was significant in subgroups with poor lung function (aHR, 8.42; 95% CI, 2.61, 27.15). Older age, male sex, a shorter RA duration, higher RA disease activity and extensive disease at baseline were independently associated with ILD progression.. None of the three treatments increased the risk of RA-associated ILD progression, except for LEF, which increased the risk of ILD progression in patients with severe ILD. The appropriate use of conventional synthetic disease-modifying antirheumatic drugs considering RA disease activity and ILD severity would be important for the management of RA-associated ILD.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Leflunomide; Lung Diseases, Interstitial; Male; Methotrexate; Tacrolimus

Insufficient evidence exists regarding the efficacy of Janus kinase inhibitors (JAKis), a class of targeted synthetic disease-modifying anti-rheumatic drugs (tsDMARDs), in the treatment of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD). Herein, we present a case of RA-ILD refractory to previous treatments that exhibited favorable response to upadacitinib. A 69-year-old man, former smoker, was diagnosed with RA-ILD based on persistent symmetric polyarthritis, elevated C-reactive protein levels and erythrocyte sedimentation rate, reduced diffusing capacity for carbon monoxide/alveolar volume (D

Topics: Aged; Arthritis, Rheumatoid; Dyspnea; Humans; Lung Diseases, Interstitial; Male; Methotrexate; Prednisolone; Tacrolimus

With expansion of the COVID-19 pandemic, reports of post-COVID-19 interstitial lung disease (ILD) have been emerging. However, there are few reports regarding treatment. Some reports indicate that corticosteroids are effective for post-COVID-19 ILD, but the use of long-term corticosteroid carries risks of side effects. We administered tacrolimus to an elderly patient with post-COVID-19 ILD who suffered a respiratory failure relapse during steroid tapering. The respiratory status improved with tacrolimus in the post-acute phase, but pulmonary fibrosis progressed in the late phase. Tacrolimus may be effective for treating post-COVID-19 ILD in the post-acute phase, but it does not halt progression of pulmonary fibrosis.

Topics: Aged; COVID-19; Humans; Lung; Lung Diseases, Interstitial; Pandemics; SARS-CoV-2; Tacrolimus

The calcineurin inhibitor tacrolimus has been approved in Japan for the treatment of interstitial pneumonia (IP) in patients with polymyositis (PM) and dermatomyositis (DM). Postmarketing surveillance was initiated to examine long-term outcomes of immunosuppressive regimens containing tacrolimus in real-world settings.. Observational, prospective, postmarketing surveillance is ongoing in 179 patients with PM/DM-associated IP initiating treatment with tacrolimus. We report interim findings after 2 years of follow-up. Cumulative overall survival was assessed using Kaplan-Meier analysis. Potential prognostic factors for mortality were assessed by univariate Cox proportional hazards analysis.. A total of 170 patients were included in this analysis. At the time of starting treatment with tacrolimus, almost all patients were receiving corticosteroids (98.8%), and cyclophosphamide was additionally used in 42 patients (24.7%). Forty-nine patients (28.8%) discontinued tacrolimus during follow-up, mainly due to loss to follow-up, patient death, and adverse events. Mean (SD) oral corticosteroid dose decreased from 32.4 (21.6) mg/day at baseline to 7.6 (4.2) mg/day at 2 years. Overall survival at 2 years was 90.3%; corresponding progression-free survival was 62.5%. Factors found to be associated with all-cause mortality included diagnosis of clinically amyopathic DM (hazard ratio [HR] 9.04, 95% CI 1.18-69.51 vs PM), ferritin level 500 to < 1500 ng/mL (HR 8.61, 95% CI 2.51-29.45 vs < 500 ng/mL), and presence of antimelanoma differentiation-associated gene 5 antibodies (HR 8.16, 95% CI 1.03-64.47 vs absence).. Immunosuppressive regimens containing tacrolimus appear useful for the management of IP in patients with PM/DM. [ClinicalTrials.gov: NCT02159651].

Topics: Adrenal Cortex Hormones; Dermatomyositis; Humans; Immunosuppressive Agents; Japan; Lung Diseases, Interstitial; Polymyositis; Prospective Studies; Retrospective Studies; Tacrolimus

The high-dose glucocorticosteroid (GC) treatment is the first choice for dermatomyositis complicated with interstitial lung disease (DM-ILD) but patients are resistant to the high-dose GC monotherapy. Besides, the high dose of GC, the secondary immunosuppressive agent(s) is necessary but there is controversy for the selection of immunosuppressive agent(s). The objectives of the study were to analyze the efficacy of different therapeutic options for DM-ILD to identify the optimal therapy. A total of 60 patients had received intravenous 1.0-2.0 mg/ kg/day prednisolone for DM-ILD. In severe conditions, patients had received oral 1 to 3 mg/day tacrolimus (TAC), 500 mg/ m2/month cyclophosphamide (CY), and/or 1 g/ day methylprednisolone pulse (TI cohort, n = 24). In severe conditions, patients had received 1 g/day methylprednisolone pulse and 2-3 mg/ kg/day cyclosporine A (CsA) and/or 500 mg/ m2/month CY (existing historical treatment; CT cohort, n = 36). Patients of the TI cohort did not receive CsA. Patients in the CT cohort were received CY in significantly fewer numbers than those of the TI cohort during treatment (P = .0112). A total of 11 (46%) patients from the TI cohort and 14 (39%) patients from the CT cohort were developed relapsed. At the end of the 30-months, higher numbers of patients of the TI cohort had an event(s) free survival than those of the CT cohort (7 (29%) vs 2 (6%), P = .0229). Also, higher numbers of patients of the TI cohort had survived irrespective of an event(s) than those of the CT cohort (21 (87%) vs 22 (61%), P = .0399). Patients of the TI cohort had developed herpes zoster (2 (8%)) and cytomegalovirus (4 (17%)) infections. Patients of the CT cohort developed renal dysfunction (10 (28%)). Hyperglycemia, hyperlipidemia, and fracture (GC-related toxicities) were also reported in both cohorts and these toxicities were fever in the TI cohort. The addition of TAC to high doses GC with CY is an ideal treatment for severe conditions of DM-ILD (Level of Evidence: III; Technical Efficacy Stage: 4).

Topics: Cyclophosphamide; Cyclosporine; Dermatomyositis; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Methylprednisolone; Retrospective Studies; Tacrolimus

The efficacy of tofacitinib (TOF) in the early diagnosis of melanoma differentiation-associated gene 5 (MDA5)-related interstitial lung disease (ILD) has been described. However, whether TOF exposure is associated with a reduced 1-year mortality rate remains undetermined.. Patients diagnosed with MDA5-ILD receiving TOF or tacrolimus (TAC) treatment were included. A Cox proportional hazards model, which was adjusted for age, sex, smoking history, anti-MDA5 antibody titers, and concurrent use of other steroid-sparing agents, was performed to compare all-cause mortality and to investigate the risk factors predicting 1-year mortality rates in the 2 treatment groups.. During the study period, 26 patients were treated with TOF and 35 were treated with TAC. The 6-month (38.5% vs 62.9%;. Our observational study showed that TOF use might have a potential effect on improving the outcomes of MDA5-ILD. Future clinical trials are needed to assess the long-term efficacy and tolerability of TOF.

Topics: Autoantibodies; Dermatomyositis; Humans; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Melanoma; Retrospective Studies; Tacrolimus

To examine the efficacy of tacrolimus on top of glucocorticoids (GCs) in the management of idiopathic inflammatory myopathies-associated interstitial lung disease (IIM-ILD) and further assess the therapeutic benefit and safety of low-dose pirfenidone followed above treatments.. The retrospective study comprised 250 patients with IIM-ILD hospitalized in Tongji Hospital from 2014 to 2020. Demographic data, survival outcomes, and recurrence rates over the 1-year follow-up period were retrospectively analyzed. These patients were divided into two groups based on treatment with tacrolimus alone or other conventional immunosuppressants. Endpoints were compared by adjusted Cox regression model using inverse probability of treatment weighting to minimize treatment bias and potential confounders. For the prospective study, IIM-ILD patients treated with tacrolimus alone or tacrolimus combined with low-dose pirfenidone were enrolled from 2018 to 2020. Clinical characteristics, survival outcomes and multifarious assessment scales were followed up at baseline, 3, 6 and 12 months. The primary endpoint was 12-month survival rate and the secondary endpoints included respiratory-related events, adverse events, exacerbation in HRCT findings and laboratory parameters during therapy courses, and changes in respiratory function.. For the retrospective study, tacrolimus group (n=93) had a significantly higher survival rate (weighted HR=0.330, p=0.002) and a lower relapse rate (weighted HR=0.548, p=0.003) compared with patients treated with other types of immunosuppressant (n=157) after adjustment. The prospectively enrolled 34 IIM-ILD patients were treated with tacrolimus (n=12) or tacrolimus combined with low-dose pirfenidone (n=22). After 12 months of treatment with tacrolimus, patients in the prospective cohort showed significant improvements in cardio-pulmonary function, disease activity, muscle strength, and mental scale from baseline. Subgroup analysis indicated that patients with tacrolimus and pirfenidone combination therapy showed lower chest HRCT scores (p=0.021) and lower respiratory-related relapse rates than those in tacrolimus monotherapy group (log-rank p=0.0029). The incidence rate of drug-associated adverse events (AEs) was comparable between two groups and none of the patients discontinued the treatment due to severe AEs.. Tacrolimus is well-tolerated and effective in the treatment of IIM-ILD. Furthermore, low-dose pirfenidone add-on treatment seems result in favorable improvements in pulmonary involvements for IIM-ILD patients.. http://www.chictr.org.cn, identifier ChiCTR2100043595.

Topics: Glucocorticoids; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Prospective Studies; Recurrence; Retrospective Studies; Tacrolimus

Immunosuppressive therapy is the main treatment for patients with interstitial lung diseases (ILD) secondary to dermatomyositis (DM). Microbial colonization or infection might be very common for these patients. However, the relationship between immunotherapy and microorganism isolates are not fully understood in these patients.. This study retrospectively analyzed on the clinical features in DM-ILD patients who had positive microbiological results during immunosuppressive therapy in our hospital.. Patients were divided into two groups, according to the result of microbiological study. Comparisons in infection-related data in various contexts were carried out.. Occurrence of positive isolates in DM-ILD patients may relate to higher inflammatory markers CRP, lower CD4 + T cells counts, high concentration of serum FK-506, and longer hospital stay.

Topics: Autoantibodies; Dermatomyositis; Humans; Immunosuppression Therapy; Lung Diseases, Interstitial; Prognosis; Retrospective Studies; Tacrolimus

We retrospectively compared the therapeutic effects of combination therapy with prednisolone (PSL) and oral tacrolimus (TAC) or azathioprine (AZA) on progressive interstitial pneumonia with systemic sclerosis (SSc-PIP).. The effects of PSL (0.2-0.5 mg/kg/day) and TAC (3 mg/day) or AZA (1-2 mg/kg/day) therapies (n = 18) were evaluated for short (12 months) and long (36 months or more) periods.. In the short period, IP improved in 6 and 5 patients and was stable in 12 and 13 patients in the TAC and AZA groups, respectively. In the long period, 11 patients were followed up in the TAC group and 12 in the AZA group. IP improved in 4 and 2 patients and was stable in seven and nine in the TAC and AZA groups, respectively. The rates of evolution of total fibrosis score, and those corrected by disease duration for the long period, in the TAC group were significantly lower than those in the AZA group (p = .017 and .025, respectively).. The inhibitory effect of PSL and TAC combination therapy on the progression of fibrosis in SSc-PIP may be superior to that of PSL and AZA in the long period.

Topics: Azathioprine; Drug Therapy, Combination; Fibrosis; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Prednisolone; Retrospective Studies; Scleroderma, Systemic; Tacrolimus; Treatment Outcome

A 62-year-old Japanese man with swollen fingers and walking difficulty due to myalgia and muscle weakness in proximal limb muscles was admitted to our hospital. Serum creatine kinase was remarkably increased (7,380 U/l) and rapidly progressing interstitial pneumonia developed. Muscle biopsy showed necrotic and regenerating fibers without mononuclear infiltration and fibrosis. Anti-Th/To antibodies were detected in the serum, and anti-Th/To antibody-positive systemic sclerosis was diagnosed. Anti-Th/To antibody-positive sclerosis-associated myopathy has not yet been reported in the literature. The present case suggests that anti-Th/To antibody-positive systemic sclerosis can be accompanied by immune-mediated necrotizing myopathy and be effectively treated with immunotherapy comprising corticosteroids, tacrolimus and immunoglobulin.

Topics: Adrenal Cortex Hormones; Autoantibodies; Autoantigens; Humans; Immunoglobulins; Immunotherapy; Lung Diseases, Interstitial; Male; Middle Aged; Muscle, Skeletal; Muscular Diseases; Necrosis; Scleroderma, Systemic; Skin; Tacrolimus

Interstitial lung disease (ILD) accompanied by anti-melanoma differentiation-associated gene 5 (anti-MDA-5)-positive dermatomyositis (DM) is often rapidly progressive and associated with poor prognosis. Because there is no established treatment, we undertook this study to prospectively evaluate the efficacy and safety of a combined immunosuppressive regimen for anti-MDA-5-positive DM patients with ILD.. Adult Japanese patients with new-onset anti-MDA-5-positive DM with ILD (n = 29) were enrolled at multiple study centers from 2014 to 2017. They were treated with a regimen of high-dose glucocorticoids (GCs), tacrolimus, and intravenous cyclophosphamide (IV CYC). Plasmapheresis was used if a patient's condition worsened after the regimen started. The primary end point was 6-month survival, which was compared between this group of patients and a historical control group (n = 15) consisting of anti-MDA-5-positive DM patients with ILD who received step-up treatment (high-dose GC and stepwise addition of immunosuppressant). Secondary end points were 12-month survival rate, adverse events, and changes in laboratory data.. The combined immunosuppressive regimen group showed significantly higher 6-month survival rates than the step-up treatment group (89% versus 33%; P < 0.0001). Over a period of 52 weeks, improvements in anti-MDA-5 titers, serum ferritin levels, vital capacity, and chest high-resolution computed tomography scores were observed. The combined immunosuppressive regimen group received IV CYC nearly 20 days earlier with shorter intervals and tended to receive plasmapheresis more often than patients undergoing step-up treatment. Cytomegalovirus reactivation was frequently observed over 52 weeks.. A combined immunosuppressive regimen is effective for anti-MDA-5-positive DM patients with ILD. Plasmapheresis can be used for additional effect in intractable disease. Patients should be carefully monitored for opportunistic infections during treatment.

Topics: Adult; Autoantibodies; Cyclophosphamide; Dermatomyositis; Disease Progression; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Interferon-Induced Helicase, IFIH1; Japan; Lung Diseases, Interstitial; Male; Prospective Studies; Survival Rate; Tacrolimus; Treatment Outcome

Rapidly progressive interstitial lung disease (RP-ILD) with poor prognosis often accompanies anti-melanoma differentiation-associated gene 5 (MDA5)-positive DM. Combined immunosuppressive therapy, including glucocorticoids, calcineurin inhibitors and intravenous cyclophosphamide (IVCY) is reportedly effective in DM with RP-ILD, but some patients remain resistant to therapy. We examined the utility of plasma exchange (PE) in such intractable cases and investigated the prognostic factors of the disease.. Thirty-eight anti-MDA5-positive DM-ILD patients who received the combined immunosuppressive therapy were retrospectively reviewed. Their serum cytokines were evaluated by multiplex assay before treatment. The patients were divided into two groups: those who achieved remission without exacerbation of respiratory dysfunction (n = 25, group A) and those who progressed to hypoxemia during the treatment (n = 13, group B).. PE was carried out in eight group B patients, but none of group A. Five of the eight treated with PE survived, while the five untreated patients died (P =0.04). Higher neutrophil lymphocyte ratio, higher serum ferritin, hypoxemia, high-resolution computed tomography (HRCT) score before treatment and increase of Krebs von Lungen-6 (KL-6) in the first 4 weeks of the treatment were the prognostic factors for disease progression. Serum cytokines such as IL-1, IL-6, IL-8, IL-10, IL-12p70, IL-18 and sCD163 levels were higher in group B than group A.. PE should be an effective adjuvant treatment in anti-MDA5-positive DM with RP-ILD. Assessment of basal laboratory tests or monocyte/macrophage-derived cytokines and the increase of KL-6, HRCT score and hypoxemia may help us to predict intractable cases and to make early treatment decisions regarding PE in anti-MDA5-positive DM.

Topics: Adult; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Autoantibodies; Cyclosporine; Dermatomyositis; Drug Resistance; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Interferon-Induced Helicase, IFIH1; Interferons; Interleukins; Japan; Lung Diseases, Interstitial; Male; Middle Aged; Plasma Exchange; Receptors, Cell Surface; Tacrolimus

Anti-melanoma differentiation-associated gene 5 (MDA5) antibodies are frequently detected in amyopathic dermatomyositis with rapidly progressive interstitial lung disease (RP-ILD). However, the presence of anti-MDA5 antibodies in other connective tissue diseases is not well known. We herein report a case of rheumatoid arthritis complicated with refractory anti-MDA5 antibody-positive ILD. A 75-year-old Japanese woman was referred to our hospital for refractory ILD. Serological testing was positive for anti-MDA5 antibody without any muscle or skin lesions. Immunosuppressive therapy (prednisolone and tacrolimus) ameliorated her symptoms as well as ILD. Anti-MDA5 antibody-positive ILD, as well as dermatomyositis with RP-ILD, can occur in patients with rheumatoid arthritis.

Topics: Aged; Arthritis, Rheumatoid; Autoantibodies; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Prednisolone; Radiography; Tacrolimus; Tomography, X-Ray Computed

We assessed the efficacy and safety of combination therapy with glucocorticoids and high-trough level tacrolimus (TAC) for the treatment of acute/subacute interstitial pneumonia (A/SIP) in patients with dermatomyositis (DM).. Eleven DM-A/SIP patients were enrolled. The combination therapy with glucocorticoids and TAC was started as early as possible after DM-A/SIP was diagnosed. We monitored the trough concentration of TAC. In the initial 3 months, we maintained the trough concentration of TAC at relatively high levels within a range of 15-20 ng/mL. Then, we decreased the TAC doses stepwise to keep the trough concentration at 10-15 ng/mL in the next 3 months and 5-10 ng/mL as a maintenance dose.. Seven patients had clinically amyopathic DM. Six patients were positive for anti-aminoacyl-tRNA synthetase antibody and two were positive for anti-melanoma differentiation-associated gene 5 antibody. Ten patients survived for the period of the 24-week follow up. One patient died under a tentative diagnosis of viral encephalitis at 4 months after the treatment. In the 10 surviving patients, interstitial pneumonia improved in eight patients and was not worse in two patients. Clinical examinations, including the Krebs von den Lungen-6 levels, % forced vital capacity, and chest computed tomography score, were significantly improved by this combination therapy. Although grade 1 and 2 renal damage occurred in 4 and 2 patients, respectively.. The present findings suggest that early therapeutic intervention by a combination with glucocorticoids and initial high-trough level TAC is effective for DM-A/SIP although consideration of the risks of infection and renal damage is required.

Topics: Acute Disease; Adult; Aged; Dermatomyositis; Drug Monitoring; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Middle Aged; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors; Treatment Outcome

Clinically amyopathic dermatomyositis with anti-Melanoma Differentiation-Associated gene 5 (MDA5) antibody often presents with severe interstitial lung disease. Although serum ferritin level is known to reflect interstitial lung disease activity, there are few case reports describing this association.. A 58-year-old man was referred to our outpatient clinic with a 3-week history of cough and respiratory distress. He had erythema over the V area of the neck and a Gottron's sign. Chest computed tomography revealed diffuse ground-glass opacities and reticular shadows in both lungs. Test for anti-MDA5 antibody was positive. After admission, he received triple combination therapy (methylprednisolone pulse therapy, tacrolimus, and cyclophosphamide). However, his respiratory condition worsened as the serum ferritin level increased. Despite no apparent deterioration on chest radiography, he ultimately died due to respiratory failure.. In this case, triple combination therapy was not effective for the patient's respiratory condition. The serum ferritin level was correlated with disease activity and was more useful than chest radiography for monitoring clinical status.

Topics: Anti-Inflammatory Agents; Cyclophosphamide; Dermatomyositis; Disease Progression; Drug Therapy, Combination; Fatal Outcome; Ferritins; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Methylprednisolone; Middle Aged; Severity of Illness Index; Tacrolimus

We retrospectively investigated efficacy and safety of combination therapy with prednisolone (PSL) and tacrolimus (TAC) for progressive interstitial pneumonitis with systemic sclerosis (SSc-PIP).. We studied 11 patients with SSc-PIP who received combination therapy with PSL (0.5 mg/kg/d) and TAC (3 mg/d).. Baseline Hugh-Jones grades were I, II, III, and IV in 2, 6, 2, and 1 patients, respectively. Krebs von den Lungen-6 (KL-6) values were elevated to 914 (range 300-2614) U/mL. % Diffusing capacity of carbon monoxide (%DLco) remarkably decreased to 47.4 (range 9.7-64.4) %. All patients were alive at 1 year after therapy. In response to treatment, interstitial pneumonia (IP) improved in three patients, stable in seven patients, and deteriorated in one patient. Total ground-glass opacity (GGO) score improved (p = .005). No significant changes occurred in values of KL-6, % forced vital capacity (%FVC), and %DLco. Presently, all seven patients who could be followed up were alive. IP improved in three patients and stable in four patients. Total GGO score improved (p = .016). KL-6, %FVC, and %DLco did not change. Mild cytomegalovirus or herpes zoster infection occurred in two patients. Grade I renal injuries were observed in three and one patient at 1 year and present, respectively.. Combination therapy with PSL and TAC appeared to be well tolerated and effective in suppressing the disease activity of SSc-PIP.

Topics: Administration, Oral; Adult; Aged; Disease Progression; Drug Therapy, Combination; Female; Humans; Japan; Lung Diseases, Interstitial; Male; Middle Aged; Prednisolone; Respiratory Function Tests; Retrospective Studies; Scleroderma, Systemic; Severity of Illness Index; Tacrolimus; Vital Capacity

Interstitial lung disease (ILD) is a significant complication of Sjögren syndrome (SS) associated with increased morbidity and mortality. The mainstay of treatment remains corticosteroid administration, with or without additional immunosuppressive therapies. Preliminary studies in SS have shown benefit in glandular and serologic parameters following treatment with the CTLA4 immunoglobulin fusion protein abatacept. Topical tacrolimus has been effective for ocular symptoms in SS, but systemic therapy has not been reported. We describe the first case, to our knowledge, of the successful use of a combination of systemic tacrolimus and abatacept in severe refractory SS and related ILD.

Topics: Abatacept; Female; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Middle Aged; Respiratory Function Tests; Rituximab; Sjogren's Syndrome; Tacrolimus

A 56-year-old Japanese woman with muscle weakness, increased creatine kinase and aldolase levels, and characteristic cutaneous lesions was diagnosed with anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 antibody)-positive dermatomyositis. She also had interstitial lung disease (ILD). After corticosteroid and tacrolimus combination therapy was started, bicytopenia and elevated serum ferritin and transaminase emerged. Because the bone marrow tissues were hypoplastic with hemophagocytes, she was diagnosed with concomitant autoimmune-associated hemophagocytic syndrome (HPS). Intravenous cyclophosphamide pulse therapy and plasmapheresis were performed. The laboratory findings indicated improved abnormalities, and the ILD did not progress. Anti-MDA5 antibody-positive dermatomyositis can be complicated by HPS.

Topics: Adrenal Cortex Hormones; Autoantibodies; Combined Modality Therapy; Cyclophosphamide; Dermatomyositis; Disease Progression; Female; Humans; Immunosuppressive Agents; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Lymphohistiocytosis, Hemophagocytic; Methylprednisolone; Middle Aged; Plasmapheresis; Pulse Therapy, Drug; Tacrolimus

Corticosteroids and immunosuppressive agents are considered mainstays of therapy for connective tissue disease-related interstitial lung disease (CTD-ILD); however, tacrolimus with corticosteroid therapy has not been fully investigated. Our objectives were to examine the multidimensional therapeutic benefit and tolerability of the combined therapy for the initial treatment of patients with CTD-ILD.. In this retrospective case series, we identified consecutive CTD-ILD patients treated with tacrolimus plus intravenous (i.v.) methylprednisolone (1000 mg i.v. 3 days a week for 2 weeks) followed by low-dose prednisolone (10 mg/day). We assessed the multidimensional therapeutic benefit and tolerability including lung physiology, exercise capacity, exercise oxygen desaturation, modified Medical Research Council (MMRC) and St George's Respiratory Questionnaire (SGRQ).. A total of 26 ILD patients with the underlying CTD diagnoses included 11 with rheumatoid arthritis, 9 with dermatomyositis, 4 with Sjögren's syndrome and 2 others. From baseline to 12 months, the combined therapy significantly improved forced vital capacity (FVC; 77.8% to 94.6%, P < 0.001), diffusing capacity of the lung for carbon monoxide (DL. In our cohort of CTD-ILD, two courses of pulse dose methylprednisolone therapy followed by prednisone and oral tacrolimus appeared to be well tolerated, and to have multidimensional efficacy.

Topics: Aged; Connective Tissue Diseases; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Japan; Lung; Lung Diseases, Interstitial; Male; Methylprednisolone; Middle Aged; Prednisone; Pulse Therapy, Drug; Respiratory Function Tests; Retrospective Studies; Tacrolimus; Treatment Outcome

Topics: Connective Tissue Diseases; Humans; Lung Diseases, Interstitial; Methylprednisolone; Prednisone; Tacrolimus

Topics: Anti-Bacterial Agents; Antibodies, Antinuclear; Autoantigens; Cyclophosphamide; Extracorporeal Membrane Oxygenation; Female; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Middle Aged; Myositis; Oxygen Inhalation Therapy; Respiratory Insufficiency; Ribonucleoproteins; Rituximab; SS-B Antigen; Tacrolimus

Autoantibodies to melanoma differentiation-associated protein 5 (MDA5) are associated with a subset of patients with dermatomyositis (DM) who have rapidly progressive interstitial lung disease (RP-ILD) with poor prognosis. Intensive immunosuppressive therapy is initiated before irreversible lung damage can occur; however, there are few lines of evidence for the treatment of RP-ILD. Here, we report three cases of anti-MDA5 antibody-associated DM with RP-ILD in which the patients were treated with combined-modality therapy, including high-dose prednisolone, tacrolimus, intravenous cyclophosphamide and intravenous immunoglobulin (IVIG). In all three cases, serum ferritin levels, which are known to represent the disease activity of RP-ILD, were decreased after IVIG administration. IVIG might contribute to the control of the disease activity of anti-MDA5 antibody-positive DM. Moreover, palmar violaceous macules/papules around the interphalangeal joints, which was observed in all three cases in the incipient stage, might be a useful sign in suggesting a diagnosis of anti-MDA5 antibody-associated DM.

Topics: Aged; Anti-Inflammatory Agents; Autoantibodies; Combined Modality Therapy; Cyclophosphamide; Dermatomyositis; Female; Hand Dermatoses; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Male; Middle Aged; Prednisolone; Tacrolimus; Treatment Outcome

Topics: Autoantibodies; Dermatomyositis; Drug Monitoring; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Male; Middle Aged; Prognosis; Ribonucleosides; Severity of Illness Index; Tacrolimus; Tomography, X-Ray Computed; Treatment Outcome

Patients with myositis-associated interstitial lung disease (MA-ILD) are often refractory to conventional treatment, and predicting their response to therapy is challenging. Recent case reports and small series suggest that tacrolimus may be useful in refractory cases.. A retrospective cohort study of patients with MA-ILD comparing clinical characteristics between those who responded to or failed conventional treatment. In those who failed conventional treatment and received adjunctive tacrolimus, response to tacrolimus was measured by the improvement in myositis, ILD, and change in the dose of glucocorticoids.. Thirty-one of 54 patients (57%) responded to conventional treatment based on the predefined variables of improvement in myositis and/or ILD. Patients with polymyositis (PM)-ILD were more likely to respond to conventional treatment than those with dermatomyositis (DM)-ILD (67% vs 35%, p = 0.013). Twenty-three patients failed conventional treatment, 18 of whom subsequently received adjunctive tacrolimus. Ninety-four percent had improvements in ILD and 72% showed improvement in both myositis and ILD. The mean doses of prednisone decreased from baseline by 65% at 3-6 months (p = 0.002) and 81% at 1 year (p < 0.001).. Patients with PM-ILD were more likely to respond to conventional treatment than patients with DM-ILD, but clinical characteristics and serology did not otherwise predict response to therapy. A majority of patients with MA-ILD refractory to conventional therapy improved while receiving tacrolimus and were able to decrease their dose of both glucocorticoids and other disease-modifying antirheumatic drugs.

Topics: Adult; Anti-Inflammatory Agents; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Middle Aged; Myositis; Prednisone; Retrospective Studies; Tacrolimus; Treatment Failure; United States

Topics: Adrenal Cortex Hormones; Cyclophosphamide; Dermatomyositis; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Middle Aged; Rituximab; Tacrolimus; Treatment Outcome

Topics: Azathioprine; Drug Substitution; Drug Therapy, Combination; Gynecomastia; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Methylprednisolone; Middle Aged; Polymyositis; Prednisone; Tacrolimus

We evaluated the safety and effectiveness of adjunctive tacrolimus therapy with conventional immunosuppression in patients with severe connective tissue disease-related interstitial lung disease (CTD-ILD). We included patients from our interstitial lung disease (ILD) registry with CTD-ILD, in whom tacrolimus was added to corticosteroids and an additional immunosuppressive agent. Demographic data, clinical features, lung function, radiographic images, and pathologic findings were reviewed. Effectiveness was assessed by comparing pulmonary function tests (PFTs) closest to tacrolimus initiation to PFTs approximately 6-12 months later. Corticosteroid dose at these time points was also evaluated. We report adverse events attributed to tacrolimus. Seventeen patients with CTD-ILD were included in adverse event analysis; twelve were included in efficacy analysis. Length of tacrolimus therapy ranged from 6 to 110 months (mean 38.8 months ± 31.4). The mean improvement in percent predicted total lung capacity was 7.5% ± 11.7 (p = 0.02). Forced vital capacity mean improvement was 7.4% ± 12.5 (p = 0.06). The average decrease in corticosteroid dose at follow-up was 20.3 mg ± 25.2 (p = 0.02) with complete discontinuation in six patients. No patients experienced a life-threatening adverse event attributed to tacrolimus. Tacrolimus can be effective and is well tolerated as an adjunctive therapy and allows tapering of corticosteroids.

Topics: Adrenal Cortex Hormones; Adult; Aged; Anti-Inflammatory Agents; Connective Tissue Diseases; Dermatomyositis; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Middle Aged; Monitoring, Physiologic; Radiography; Respiratory Function Tests; Retrospective Studies; Tacrolimus; Total Lung Capacity; Treatment Outcome; Vital Capacity

Topics: Antibodies; Dermatomyositis; Fingers; Humans; Immunosuppressive Agents; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Male; Middle Aged; Prednisone; Respiratory Function Tests; Skin Diseases, Papulosquamous; Skin Ulcer; Tacrolimus; Tomography, X-Ray Computed

Interstitial lung diseases (ILDs) complicated with PM or DM are frequently aggressive and refractory to treatment. Recently some reports have suggested the potential benefit of tacrolimus for severe ILD complicated with PM/DM. However, little evidence has yet shown the efficacy of tacrolimus in these settings. The aim of this study was to evaluate the efficacy of tacrolimus as a treatment for PM-/DM-related ILD.. This retrospective study comprised 49 previously untreated patients diagnosed as PM-/DM-related ILD admitted to Hokkaido University Hospital from January 2000 to July 2013. These patients were treated with tacrolimus plus conventional therapy or only with conventional therapy (prednisolone, i.v. CYC and/or ciclosporin). The primary endpoint was defined as the time to relapse or death of respiratory cause or a serious adverse event. The secondary endpoint was defined as the time from the initiation of immunosuppressive treatment to relapse or death of respiratory cause. Endpoints were compared by adjusted Cox regression model by using inverse probability of treatment weighting in order to reduce the impact of these selection biases and potential confounding factors.. After adjustment, the tacrolimus group (n = 25) had significantly longer event-free survival as compared with the conventional therapy group (n = 24). The weighted hazard ratio (HR) was 0.32 (95% CI 0.14, 0.75, P = 0.008). In addition, the tacrolimus group had significantly longer disease-free survival as compared with the conventional therapy group. The weighted HR was 0.25 (95% CI 0.10, 0.66, P = 0.005).. The addition of tacrolimus to conventional therapy significantly improved the prognosis of patients with PM-/DM-related ILD.

Topics: Adult; Aged; Dermatomyositis; Endpoint Determination; Female; Humans; Immunosuppressive Agents; Japan; Lung Diseases, Interstitial; Male; Middle Aged; Polymyositis; Prognosis; Proportional Hazards Models; Retrospective Studies; Survival Rate; Tacrolimus; Treatment Outcome

Topics: Dermatomyositis; Female; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Polymyositis; Tacrolimus

Topics: Dermatomyositis; Female; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Polymyositis; Tacrolimus

Topics: Dermatomyositis; Female; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Polymyositis; Tacrolimus

A 49-year-old man with dyspnea was found to have reticular opacities and ground-glass attenuation with traction bronchiectasis or bronchiolectasis on computed tomography. The patient met the criteria for lung-dominant connective tissue disease (LD-CTD) and histopathologically exhibited a chronic fibrotic interstitial pneumonia illustrating framework of a usual interstitial pneumonia-like pattern. Due to worsening of the disease, therapy was initiated with corticosteroids in combination with cyclosporine A. However, treatment with these drugs was ineffective. Pirfenidone and intravenous cyclophosphamide therapy also proved ineffective. The cyclosporine A was therefore switched to tacrolimus, and the patient's disease improved, allowing for a reduction in the dose of the corticosteroids. Our experience in this case suggests that treatment with tacrolimus might be useful for treating refractory LD-CTD even when histopathologically chronic fibrotic interstitial pneumonia is evident.

Topics: Connective Tissue Diseases; Fibrosis; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Middle Aged; Tacrolimus; Treatment Outcome

Methotrexate (MTX) is a standard agent used in combination with calcineurin inhibitors for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic hematopoietic cell (HCT) transplantation. We retrospectively compared the incidence of acute GVHD (aGVHD), transplant-related morbidity, and mortality in patients given sirolimus/tacrolimus ± antithymocyte globulin (ATG) versus MTX/tacrolimus or cyclosporine and allogeneic transplantation for hematologic malignancies. Between January 1, 2005, and April 30, 2009, 106 consecutive patients received peripheral blood HCT or bone marrow grafts after 1 of 6 myeloablative conditioning regimens. The incidence of grade II-IV aGVHD was 18.6% in patients who received sirolimus/tacrolimus compared to 48.9% who received MTX (P = .001). The incidence of grade III-IV aGVHD was 5% and 17% (P = .045), respectively. There was no difference in overall survival (OS) between the groups (P = .160). Chronic GVHD (cGVHD) occurred in 40.4% who received sirolimus and 41.9% receiving MTX (P = .89). The incidence of thrombotic microangiopathy or interstitial pneumonitis was not significantly different between groups. The reduction in the risk of severe aGVHD was offset by an increased (20% versus 4%, P = .015) incidence of and mortality from sinusoidal obstructive syndrome (SOS). Sirolimus/tacrolimus appears to reduce the incidence of aGVHD after conventional allotransplantion compared to MTX-calcineurin inhibitor prophylaxis; however, this did not improve survival.

Topics: Adult; Antilymphocyte Serum; Calcineurin Inhibitors; Cyclosporine; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Methotrexate; Middle Aged; Retrospective Studies; Risk Factors; Sirolimus; Survival Analysis; Tacrolimus; Thrombotic Microangiopathies; Transplantation Conditioning; Transplantation, Homologous; Young Adult

A 58-year-old male was admitted to our hospital because of periungual nailfold an erythema and erythematous rash on the dorsal joints of his hands and feet, but no muscle weakness. He was thus diagnosed to have amyopathic dermatomyositis. He had moderate hypoxemia and his chest computed tomography scans demonstrated bilateral ground-glass opacities, implicating complication with interstitial pneumonia. Therapy was initiated with pulsed methylprednisolone followed by high-dose corticosteroids, pulsed cyclophosphamide, and cyclosporine. The skin manifestations improved; however, the pulmonary infiltrates and hypoxemia deteriorated during the 2-month period of the treatment. The treatment was switched from cyclosporine to tacrolimus because of an inadequate clinical response to the therapy, and this resulted in the resolution of interstitial pneumonia. This case indicates that tacrolimus administration should be considered for patients with this life-threatening disorder when it is judged to be refractory to cyclosporine.

Topics: Adrenal Cortex Hormones; Cyclophosphamide; Cyclosporine; Dermatomyositis; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Middle Aged; Tacrolimus; Treatment Failure

A 30-year-old pregnant woman experienced mild dyspnea in April 2009. She complained of mild myalgia and was subsequently admitted to our hospital in June 2009 because of worsening dyspnea. Physical examination revealed fine crackles in the lower lung field, but no eruptions externally. Laboratory findings revealed elevated serum levels of myogenic enzymes (aldolase, 17.6 IU/l and myoglobin, 247.2 ng/ml) and positive titers for the anti-Jo-1 antibody and hypoxia (PaO(2), 79.4 Torr). The chest radiograph revealed a ground-glass opacity. The patient was diagnosed as interstitial pneumonia (IP) associated with polymyositis (PM) at 20 weeks of gestation. On July 9, we commenced the initial treatment-steroid pulse therapy with 60 mg/day of prednisolone and 3 mg/day of tacrolimus. We also induced abortion. The treatment of corticosteroids and tacrolimus was, however, ineffective even after increasing the tacrolimus dose to 6 mg/day. On July 30, she suddenly experienced chest pain along with severe dyspnea. Computed tomography revealed the presence of pneumomediastinum and deterioration of the IP. We added cyclophosphamide pulse therapy to the existing regimen ; this improved the disease course, reduced hypoxia, and improved radiographic findings. We believe that this is a rare case of IP with PM during pregnancy.

Topics: Adult; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Mediastinal Emphysema; Polymyositis; Pregnancy; Pregnancy Complications; Pulse Therapy, Drug; Tacrolimus

A 67-year-old woman was admitted to our hospital because of erythema in the eyelids and fingers of both hands. Slight muscle weakness in the proximal limbs, a heliotrope rash, Gottron's sign, and mechanic's hand were observed. Creatine kinase serum levels were slightly elevated (376U/l), and the patient tested negative for all autoantibodies except for the antinuclear antibody. Chest computed tomography showed interstitial pneumonia (IP). Based on these findings, the patient was given a diagnosis of dermatomyositis (DM) associated with IP. Combined prednisolone (1 mg/kg/day) and cyclosporin-A (Cy-A 4 mg/kg/day) therapy was initiated; the patient showed marked improvement, but the Cy-A caused liver damage. Therefore, Cy-A was tapered off, and tacrolimus was simultaneously started, initially at a dose of 1 mg/day, building up to a sustained dose of 4 mg/day. The patient's IP and liver condition improved. Tacrolimus is a useful drug for the treatment of DM-IP in cases where Cy-A causes intolerable adverse reactions.

Topics: Cyclosporine; Dermatomyositis; Female; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Middle Aged; Tacrolimus

This report presents the case of a patient demonstrating multicentric Castleman's disease (MCD) with a lung lesion that was successfully treated with an anti-interleukin-6 receptor antibody, tocilizumab in combination with corticosteroid and tacrolimus. A 43-yr-old female with abnormal shadows on a chest X-ray was referred to the hospital for further examination. She was diagnosed as having MCD based on the characteristic pathology of inguinal lymph node, lung lesions, laboratory data, and undifferentiated arthritis. Corticosteroid and rituximab therapy did not fully ameliorate the symptoms; thus, the therapeutic regimen was changed to include tocilizumab, oral corticosteroid and tacrolimus. This regimen resulted in clinical remission and the dose of tocilizumab and corticosteroid could be tapered. Tocilizumab in combination with corticosteroid and tacrolimus may therefore be a beneficial treatment regimen for lung lesions associated with MCD.

Topics: Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Castleman Disease; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Lymph Nodes; Receptors, Interleukin-6; Tacrolimus; Tomography, X-Ray Computed

Pulmonary fibrosis associated with amyopathic dermatomyositis is known to have a generally aggressive course and is ultimately fatal. We report the case of a 50-year-old patient with amyopathic dermatomyositis, who developed progressive interstitial pneumonia that was unresponsive to corticosteroids and multiple immunosuppressive agents, including cyclosporine and tacrolimus hydrate. Five courses of lecithinized superoxide dismutase were administered without adverse effects. Improvements in physiological parameters, such as pulmonary function and exercise tolerance, as well as the serum Krebs von den Lungen 6 level, were observed. This is the first report of a case of steroid-refractory interstitial pneumonia treated with lecithinized superoxide dismutase.

Topics: Adrenal Cortex Hormones; Cyclosporine; Dermatomyositis; Exercise Tolerance; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Methylprednisolone; Middle Aged; Mucin-1; Phosphatidylcholines; Prednisolone; Pulmonary Fibrosis; Radiography; Respiratory Function Tests; Superoxide Dismutase; Tacrolimus; Treatment Outcome

Cutaneous plasmacytosis is a rare condition affecting middle-aged individuals, characterized by multiple red-brown papules and plaques over the trunk. It has been reported mainly in Japan. The condition is accompanied by polyclonal hypergammaglobulinemia and superficial lymphadenopathy. Lung or retroperitoneal involvement occurs rarely. In the present study, 3 consecutive cases of cutaneous plasmacytosis were observed histologically to have abundant infiltration of IgG4-bearing plasma cells. All 3 were associated with superficial lymphadenopathy, one with interstitial lung involvement showing ground-glass opacity on computed tomography and the others with bone marrow plasmacytosis, showing histologic evidence of more IgG4-positive plasma cells. All 3 had polyclonal hypergammaglobulinemia, one had high serum concentration of IgG4, and all had elevated serum IL-6. The ratios of IgG4+ to IgG+ plasma cells were assessed using skin biopsy specimens with pemphigus (n = 7), discoid lupus erythematosus (n = 5), and morphea (n = 2) (mean ratios, 19%, 0%, and 0%, respectively); we noted the proportion of IgG4-positive plasma cells in cutaneous plasmacytosis (mean, 48%). IgG4-related sclerosing disease is a newly recognized systemic disorder characterized by lymphoplasmacytic infiltration and fibrosis and by a high serum IgG4 level and increased IgG4-positive plasma cells in the tissues. Skin manifestations of this disorder have not been described. Although cutaneous plasmacytosis could be a chronic allergic hypersensitivity reaction, our findings raise the possibility of a relationship in pathogenesis between cutaneous plasmacytosis and IgG4-related sclerosing disease.

Topics: Anti-Inflammatory Agents; Biopsy; Case-Control Studies; Cell Count; Dermatologic Surgical Procedures; Diagnosis, Differential; Fibrosis; Follow-Up Studies; Humans; Hypergammaglobulinemia; Immunoglobulin G; Immunohistochemistry; Immunosuppressive Agents; Inflammation; Interleukin-6; Japan; Lung; Lung Diseases, Interstitial; Lymphatic Diseases; Male; Middle Aged; Ointment Bases; Pemphigus; Plasma Cells; Prednisolone; Radiography; Sclerosis; Skin; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adrenal Cortex Hormones; Antibodies, Antinuclear; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Myography; Polymyositis; Respiration, Artificial; Respiratory Distress Syndrome; Syndrome; Tacrolimus

Polymyositis and interstitial lung diseases, predominantly nonspecific interstitial pneumonia (NSIP), are known to be frequent in antisynthetase syndrome, where anti-aminoacyl-tRNA synthetase antibodies are often identified. An unusual case of acute respiratory distress syndrome, secondary to such proven NSIP of cellular type with predominant CD8 lymphocytes, is described herein. The patient described in the present case study initially had a poor recovery with high dose of steroids, but this was followed by a good improvement after the prescription of tacrolimus and a low dose of prednisone. A precise diagnosis in similar circumstances may be life-saving, allowing the successful application of new immunosuppressants.

Topics: Antibodies, Antinuclear; Autoantibodies; CD8-Positive T-Lymphocytes; Cyclosporine; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Middle Aged; Polymyositis; Respiratory Distress Syndrome; Syndrome; Tacrolimus; Tomography, X-Ray Computed; Treatment Outcome

A 74-year-old woman was experiencing rheumatoid arthritis complicated with interstitial pneumonitis (IP), and tacrolimus treatment was started. She presented with dyspnea. Chest X-ray and computed tomography (CT) showed ground-glass opacity and IP. Although tacrolimus was stopped, she died of respiratory failure. At autopsy, both the upper and lower lung fields showed usual IP and the organizing stage of diffuse alveolar damage. The former is common, but the latter is uncommon, suggesting tacrolimus may cause severe alveolar damage.

Topics: Aged; Arthritis, Rheumatoid; Fatal Outcome; Female; Humans; Immunosuppressive Agents; Lung; Lung Diseases, Interstitial; Respiratory Insufficiency; Tacrolimus

A 64-year-old woman had been treated with prednisolone (PSL) for interstitial pneumonia (IP) of unknown origin since 1988. The IP progressed gradually, however, and home oxygen therapy was instituted in 1993. In 2002, persistent arthritis of the hands appeared and diagnosis of rheumatoid arthritis (RA) was finally established based on radiological and pathological findings. Salazosulfapyridine was given with only partial effect. On October 2002, she was hospitalized because of back pain followed by dyspnea. Chest X-ray revealed multiple giant bullae on bilateral upper lung fields, accompanied by deterioration of IP. Methyl-prednisolone pulse therapy followed by 30 mg/day of PSL was instituted and the bullae were diminished with gradual improvement of IP and synovitis. On the 55th hospital day, she complained of chest oppression, and chest X-ray revealed a complication of pneumomediastinum. Since IP was still active and serum KL-6 remained high, 3 mg/day of tacrolimus was added to control IP further and to reduce the dosage of PSL which was recognized as one of the aggravation factors of pneumomediastinum. As a result, pneumomediastinum disappeared gradually along with amelioration of IP. PSL was successfully tapered to 15 mg/day by the 87th hospital day and the patient was discharged. Although the efficacy of tacrolimus on IP complicated with polymyositis / dermatomyositis and other autoimmune diseases has been reported, this case first suggests its efficacy on IP associated with RA.

Topics: Arthritis, Rheumatoid; Blister; Female; Humans; Immunosuppressive Agents; Lung Diseases; Lung Diseases, Interstitial; Mediastinal Emphysema; Middle Aged; Tacrolimus

A 67-year-old woman, suffering from continuous hemoptysis, was admitted to our hospital where she was managed with mechanical ventilation. Computed tomography of the chest demonstrated bilateral massive alveolar hemorrhage without evidence of infectious disease. She was diagnosed with anti-myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated diffuse alveolar hemorrhage because a high titer of MPO-ANCA was found in the serum. Plasmapheresis as well as methylprednisolone pulse therapy were initiated, followed by intravenous administration of cyclophosphamide. Tacrolimus was employed for the maintenance therapy, and the oral prednisolone dosage could successfully be tapered without recurrence, along with the decrement of the titer of MPO-ANCA.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Combined Modality Therapy; Cyclophosphamide; Drug Therapy, Combination; Female; Glucocorticoids; Hemorrhage; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Peroxidase; Plasmapheresis; Prednisolone; Pulmonary Alveoli; Radiography, Thoracic; Tacrolimus; Treatment Outcome

To assess the efficacy of tacrolimus in patients with anti-aminoacyl-transfer RNA synthetase (anti-aaRS)-associated interstitial lung disease (ILD) and idiopathic inflammatory myopathy (IIM).. Ninety-eight patients with anti-aaRS autoantibodies were identified in our IIM cohort of 536 patients. The medical records of 15 patients with anti-aaRS-associated ILD treated with tacrolimus between 1992 and 2003 were retrospectively reviewed. Pulmonary parameters of response included forced vital capacity, forced expiratory volume in 1 second, and diffusing capacity for carbon monoxide. Manual muscle testing results, serum creatine kinase (CK) levels, and the daily corticosteroid dosage were used to assess improvement in myositis. Random coefficient modeling considering polynomials of time was used to assess the clinical response to tacrolimus.. All patients, except for 1, who had pure ILD, had definite or probable IIM. Two patients received tacrolimus for fewer than 3 months, and their data were not analyzed. For the remaining 13 patients, the mean age at onset of ILD was 46.9 years, and the mean duration of pulmonary disease was 14.7 months. Twelve patients had anti-histidyl-transfer RNA synthetase autoantibody (anti-Jo-1) and 1 had anti-alanyl-transfer RNA synthetase autoantibody (anti-PL-12). Patients received tacrolimus for an average of 51.2 months. A significant improvement was observed in all pulmonary parameters measured. The serum CK level declined significantly, and 10 patients had either an improvement in muscle strength or maintained normal muscle strength. A statistically significant reduction in the corticosteroid dosage was also observed.. Tacrolimus is a well-tolerated and effective therapy for managing refractory ILD and myositis in anti-aaRS-positive patients.

Topics: Adult; Aged; Alanine-tRNA Ligase; Amino Acyl-tRNA Synthetases; Autoantibodies; Cohort Studies; Female; Histidine-tRNA Ligase; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Middle Aged; Myositis; Retrospective Studies; Tacrolimus; Treatment Outcome

Topics: Amino Acyl-tRNA Synthetases; Autoantibodies; Follow-Up Studies; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Pulmonary Diffusing Capacity; Retrospective Studies; Tacrolimus; Treatment Outcome

Survival after living-donor lobar lung transplantation has been reported to be similar to that after cadaveric lung transplantation. The purpose of this study was to summarize our 5-year experience of living-donor lobar lung transplantation for critically ill patients.. Between October 1998 and April 2004, we performed living-donor lobar lung transplantation in 30 critically ill patients with various lung diseases, including 5 (17%) patients on a ventilator. Mean age was 30.4 years (range, 8-55 years). Postoperative management included slow weaning from a ventilator, relatively low-dose immunosuppressants, and careful rejection monitoring on the basis of radiographic and clinical findings without transbronchial lung biopsy.. The average duration of mechanical ventilation was 15.4 days, intensive care unit stay was 23.5 days, and hospital stay was 64.6 days. Clinically judged acute rejection occurred at an average rate of 1.5 episodes per patient, but infection occurred in only one patient during the first month. In spite of the complicated postoperative course, all patients were discharged without oxygen inhalation. Four patients had unilateral bronchiolitis obliterans syndrome, but the decrease in their forced expiratory volume in 1 second values stopped within 9 months. All 30 recipients are currently alive, with a follow-up period of 1 to 66 months. All donors have returned to their previous lifestyles.. Living-donor lobar lung transplantation can be applied to both pediatric and adult patients with very limited life expectancies. It might provide better survival than conventional cadaveric lung transplantation.

Topics: Adolescent; Adult; Child; Cyclosporine; Female; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Living Donors; Lung Diseases; Lung Diseases, Interstitial; Lung Transplantation; Male; Middle Aged; Patient Selection; Retrospective Studies; Tacrolimus

Topics: Adult; Aged; Autoantibodies; Creatine Kinase; Female; Hand Strength; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Middle Aged; Polymyositis; Tacrolimus; Treatment Outcome

To study the mechanisms underlying the development of interstitial pneumonia in autoimmune disease, we analyzed bronchoalveolar lavage fluid (BALF) in an animal model of interstitial pneumonia in which an intratracheal instillation of staphylococcal enterotoxin B (SEB) induced interstitial pneumonia in autoimmune-prone mice. Increases in the numbers of total cells, macrophages, lymphocytes, and neutrophils were observed in BALF from SEB-treated MRL +/+ mice, and peaked at 3 d after SEB administration (Day 3). Flow cytometric analyses revealed increases in SEB-reactive Vbeta8(+) T cells, indicating that SEB-reactive cells play an important role in bronchoalveolar space. The expressions of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, JE/monocyte chemoattractant protein-1, regulated on activation, normal T cells expressed and secreted, and KC/gro messenger RNA (mRNA) in BALF cells from SEB-treated mice peaked at Day 3. Increased expression of TNF-alpha mRNA was observed mainly in macrophages and CD8(+) T cells, and the increase in IFN-gamma mRNA was observed mainly in CD8(+) T cells in BALF at Day 3. The expression of platelet-derived growth factor mRNA was very weak at Day 3 but strongly expressed at Day 14. An immunosuppressant, FK506, but not corticosteroid, suppressed SEB-induced T-cell expansion in BALF as well as increased cytokine and chemokine production in the bronchoalveolar space of SEB-treated mice. Histologically, FK506 but not corticosteroid significantly reduced both the cell infiltration to alveolar septal walls and the synthesis of pulmonary collagen fibers. Further, transfer of T cells of MRL +/+ mice with SEB into SCID mice gave rise to interstitial pneumonia. These results suggest that superantigen-reactive T cells in the bronchoalveolar space may trigger the development of interstitial pneumonia in this model.

Topics: Animals; Autoimmunity; Bronchoalveolar Lavage Fluid; Chemokines; Disease Models, Animal; Enterotoxins; Female; Gene Expression Regulation; Immunosuppressive Agents; Lung; Lung Diseases, Interstitial; Lymphocytes; Macrophages; Mice; Mice, SCID; Neutrophils; Prednisolone; Pulmonary Alveoli; RNA, Messenger; Spleen; T-Lymphocytes; Tacrolimus