Successful treatment of PR3-ANCA-positive interstitial pneumonia with a moderate dose of glucocorticoid and rituximab.

Antineutrophil cytoplasmic antibody (ANCA)-positive interstitial pneumonia (IP) is reported as IP that is ANCA-positive and does not involve organ damage associated with vasculitis other than the lungs. While the combination of glucocorticoid and rituximab is effective in ANCA-associated vasculitis, the treatment strategy for ANCA-positive IP has not been established. Here, we report the first case of successful treatment of proteinase 3 (PR3)-ANCA-positive IP with a moderate dose of glucocorticoid and rituximab. The patient was an 80-year-old male who presented with subacute dry cough and dyspnoea. Blood tests revealed elevated levels of C-reactive protein, Krebs von den Lungen 6 (KL-6), and PR3-ANCA. Chest computed tomography (CT) showed interstitial shadows and infiltrates around honeycomb cysts. 18F-fluorodeoxyglucose (FDG) positron emission tomography CT revealed an uptake of FDG in the IP area. After starting treatment with a moderate dose of prednisolone and rituximab, the patient's clinical symptoms disappeared, C-reactive protein and KL-6 turned to be normal, and infiltrates around the cysts of honeycomb lungs disappeared. Prednisolone was gradually decreased to 2 mg, and no relapse or adverse events were observed during the course of treatment. Our case suggests that early treatment with a moderate dose of glucocorticoid and rituximab is effective for PR3-ANCA-positive IP.

Atypical Cogan's Syndrome with Large-vessel Vasculitis Successfully Treated with Tocilizumab.

A 61-year-old man presented with weight loss, bilateral ocular redness, blurred vision, and sensorineural hearing loss. Fluorodeoxyglucose-position emission tomography/computed tomography demonstrated an uptake in the ascending and descending aorta, abdominal aorta and femoral arteries. Atypical Cogan's syndrome complicated with large-vessel vasculitis (LVV) was diagnosed. He was treated with high-dose prednisolone and subcutaneous tocilizumab (162 mg/week), resulting in successful improvements in his ocular and vascular involvements. Although there is currently no established treatment strategy for LVV associated with Cogan's syndrome, our case and literature review suggest that tocilizumab is a viable treatment option for this rare but life-threatening complication.

Allergic disorders and their risk factors in primary Sjögren's syndrome.

Objective: This study aimed to evaluate the prevalence of allergic disorders in patients with primary Sjögren's syndrome (pSS), compare it with that of patients with rheumatoid arthritis (RA), and examine the risk factors in patients with pSS. Methods: We retrospectively examined the records of patients diagnosed with pSS and RA who regularly visited our department between 2010 and 2020. Allergic disorders included drug allergy, food allergy, allergic contact dermatitis (ACD), allergic rhinitis (AR)/allergic conjunctivitis (AC), and asthma. Results: Patients with pSS (292 patients) had a higher prevalence of food allergy, drug allergy, and AR/AC than those with RA (413 patients). The multivariate analysis revealed that patients with pSS who had drug allergy had a higher prevalence of food allergy, higher eosinophil levels, and higher positivity rates of anti-SS-related antigen A (SSA) antibodies than those without drug allergy; those with food allergy had a higher rate of ACD than those without food allergy and vice versa; those with AR/AC had a higher rate of ACD and asthma and higher eosinophil levels than those without AR/AC; those with asthma had a higher rate of AR/AC than those without asthma. Conclusions: Patients with pSS had a higher prevalence of allergic disorders than those with RA. Among patients with pSS, the risk factors for drug allergy were food allergy, higher eosinophil levels, and positivity for anti-SSA antibodies, the risk factor for food allergy was ACD and vice versa, the risk factors for AR/AC were ACD, asthma, and high eosinophil levels, and the risk factor for asthma was AR/AC.

Successful treatment with tofacitinib for relapse of rapidly progressive interstitial lung disease in anti-melanoma differentiation-associated gene 5 antibody-positive clinically amyopathic dermatomyositis.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody is associated with clinically amyopathic dermatomyositis (CADM) with rapidly progressive interstitial lung disease (RP-ILD). Recently, several studies have reported that tofacitinib (TOF), a Janus kinase inhibitor, might be effective for cases of new or refractory RP-ILD in anti-MDA5 antibody-positive CADM; however, it is unknown whether TOF can also be effective for relapsed cases. We herein report a relapsed case of RP-ILD in anti-MDA5 antibody-positive CADM, which was successfully treated by combination therapy with TOF (5 mg twice daily). Our case suggests that TOF may also be a potential treatment option for relapsed cases of this disease.

Aseptic meningitis as an initial manifestation of primary Sjögren's syndrome.

Aseptic meningitis is a rare life-threatening complication of primary Sjögren's syndrome (pSS), and its characteristics and prognosis remain unknown. We present our case of aseptic meningitis associated with pSS and reviewed the published literature to elucidate their characteristics and prognosis. An 84-year-old man was admitted to our hospital for fever and disturbance of consciousness. Acute aseptic meningitis was diagnosed based on the results for cerebrospinal fluid and head imaging tests. As an aetiological investigation for his aseptic meningitis, serum anti-Sjögren's-syndrome-related antigen A and anti-Sjögren's-syndrome-related antigen B antibodies were found to be positive, and the biopsy specimen of his labial salivary gland revealed lymphocytic sialadenitis, confirming a diagnosis of pSS. Treatment with moderate-dose glucocorticoid completely improved his aseptic meningitis. Relapse of the disease was not observed during his clinical course over 12 months. Our present case and literature review suggest that aseptic meningitis can be an initial manifestation of pSS and be treatable by immunosuppressive therapy. Thus, early recognition and treatment initiation are critical to prevent the irreversible damage of central nervous system in pSS-associated aseptic meningitis. In aseptic meningitis of unknown origin, pSS should be included in differential diagnoses, and testing for serum anti-Sjögren's-syndrome-related antigen A and anti-Sjögren's-syndrome-related antigen A antibodies may be useful as an initial screening.

Giant cell arteritis successfully treated with subcutaneous tocilizumab monotherapy.

Glucocorticoid remains the mainstay for treatment of large vessel vasculitis (LVV) including giant cell arteritis (GCA); however, the disease affects the elderly for whom the adverse effects of glucocorticoid are problematic. Recently, some reports have suggested that intravenous tocilizumab (TCZ) monotherapy is effective for this disease. To date, it remains unknown whether subcutaneous TCZ monotherapy is also effective. Here, we present a first case of GCA successfully treated with subcutaneous TCZ monotherapy. A 75-year-old woman presented with shoulder and hip pain. She was diagnosed with polymyalgia rheumatica (PMR) and treated with low-dose prednisolone (15 mg daily); however, she discontinued glucocorticoid therapy at her discretion due to the psychiatric adverse effect (cognitive dysfunction). Seven months later, her shoulder and hip pain relapsed. Furthermore, 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) revealed uptake in the descending thoracic aorta, indicating a complication of LVV. She refused to take glucocorticoid for fear of psychiatric adverse effects and chose subcutaneous TCZ monotherapy (162 mg weekly) for treating this life-threatening urgent condition. Nine months later, her shoulder and hip pain resolved and FDG-PET/CT demonstrated no uptake in the descending thoracic aorta, indicating a successful treatment with subcutaneous TCZ monotherapy for the disease. No adverse events and disease relapse were found during observation period. Our case and the literature review suggest that not only intravenous injection but also subcutaneous injection of TCZ monotherapy can serve as an alternative treatment for patients with GCA who have comorbidities or refuse to take glucocorticoid.

Reduced versus maximum tolerated methotrexate dose concomitant with adalimumab in patients with rheumatoid arthritis (MIRACLE): a randomised, open-label, non-inferiority trial.

BACKGROUND: Efficacy of combination therapy with methotrexate and biological disease-modifying antirheumatic drugs is well established in the management of patients with rheumatoid arthritis; however, the optimal dose of methotrexate to administer with a tumour necrosis factor inhibitor remains unclear. We aimed to clarify the efficacy and safety of adalimumab combined with reduced methotrexate dose compared with the maximum tolerated methotrexate dose in patients with rheumatoid arthritis and an inadequate response to methotrexate monotherapy. METHODS: In this open-label, randomised controlled trial, we recruited methotrexate-naive patients with rheumatoid arthritis and a disease duration of less than 2 years across 24 secondary or tertiary care hospitals across Japan, South Korea, and Taiwan. At initiation, methotrexate was given orally and increased to the maximum tolerated dose by week 12. Patients who did not achieve remission on the basis of the Simplified Disease Activity Index (SDAI) at week 24 were randomly assigned (1:1) to receive adalimumab (40 mg biweekly) combined with a continued maximum tolerated dose of methotrexate or adalimumab combined with a reduced dose of methotrexate. The primary endpoint was non-inferiority of adalimumab plus reduced-dose methotrexate to adalimumab plus maximal-dose methotrexate based on SDAI remission at week 48, assessed in the modified full-analysis set with a pre-specified non-inferiority margin of -15%, based on a two-sided 90% CI. Adverse events were assessed in the safety analysis set. This trial is registered with ClinicalTrials.gov, NCT03505008 and has been completed. FINDINGS: From April 18, 2018, to June 2, 2020, from 323 patients screened, 300 were enrolled, and 291 patients were included in the full analysis set. The mean age was 57·7 years (SD 15·2), 217 (75%) were female, 74 (25%) were male, and all patients were of Asian ethnicity. The mean SDAI at study enrolment was 26·5 (SD 12·4). 52 patients discontinued the study before week 24 or at week 24 before randomisation. At week 24, 105 (36%) of 291 patients achieved remission and continued methotrexate monotherapy through week 48. 134 (46%) did not achieve remission at week 24 and were randomly assigned to receive adalimumab plus the maximum tolerated dose of methotrexate (n=68) or adalimumab plus reduced-dose methotrexate (n=66). Remission at week 48 was achieved in 25 (38%) of 66 and 27 (44%) of 61 patients, respectively, with an adjusted risk difference of 6·4% (90% CI -7·0 to 19·8), which met the non-inferiority margin of -15%. Adverse events after week 24 tended to be more frequent in the maximum tolerated dose group than in the reduced-dose group (24 [35%] vs 13 [20%], p=0·054). Between week 24 and 48, there were 14 serious adverse events (6 in the methotrexate monotherapy group, 5 in the adalimumab plus maximal-dose methotrexate, and 3 in the adalimumab plus reduced-dose methotrexate group), and no deaths. INTERPRETATION: The MIRACLE study showed that the efficacy of adalimumab combined with reduced methotrexate dose was not inferior to that with the maximum tolerated methotrexate dose, with a tendency to a better safety profile. FUNDING: Eisai.

Risk factors associated with cytomegalovirus reactivation in patients receiving immunosuppressive therapy for rheumatic diseases: a retrospective study.

Immunosuppressive treatment is a common cause of cytomegalovirus (CMV) reactivation. However, there is no consensus regarding the risk factors for CMV reactivation in rheumatic diseases. Therefore, this study aimed to elucidate the risk factors associated with CMV reactivation. We retrospectively collected the data of 472 patients with rheumatic diseases whose CMV pp65 antigen (C7-HRP) titer was measured. We divided the patients into those with and those without C7-HRP. We retrospectively collected data on age, sex, primary condition and organ involvement, and blood test results. We also investigated the use of immunosuppressants and the maximum and cumulative doses of prednisolone (PSL). We performed univariate and multivariate analyses to identify risk factors for CMV reactivation. Multivariate analysis showed that higher age (71.2 vs. 64.4 years, p = 0.0022), hypoalbuminemia (2.9 vs. 3.4 g/dL, p = 0.0104), higher creatinine level (1.2 vs. 0.9 mg/dL, p = 0.0026), cyclosporine use (8.2 vs. 3.6%, p = 0.0101), and higher maximum (552.4 vs. 243.3 mg, p < 0.0001) and cumulative (2785.9 vs. 1330.5 mg, p < 0.0001) doses of PSL were associated with CMV reactivation. Older age, hypoalbuminemia, higher creatinine level, cyclosporine use, and higher maximum and cumulative doses of PSL were significant risk factors for CMV reactivation in rheumatic diseases.

Dermatomyositis Which Was Double Positive for Anti-MDA5 and Anti-ARS Antibodies That Was Successfully Treated by Intensive Immunosuppressive Therapy.

Myositis-specific autoantibody is associated with the clinical phenotype and prognosis of dermatomyositis. Anti-melanoma differentiation-associated gene 5 (MDA5) and anti-aminoacyl-tRNA synthetase (ARS) antibodies are generally mutually exclusive. We herein present an extremely rare case of dermatomyositis which showed double positivity for anti-MDA5 and anti-ARS antibodies. There have been very few reported cases of double positive anti-MDA5, anti-ARS antibodies. In such cases, the clinical characteristics of each autoantibody can coexist. Thus, we should pay attention to the rapidly progressing features of anti-MDA5 as well as the chronic relapsing features of anti-ARS for the better management of this rare condition.

Immune-mediated necrotizing myopathy which showed deposition of C5b-9 in the necrotic muscle fibers and was successfully treated with intensive combined therapy with high-dose glucocorticoids, tacrolimus, and intravenous immunoglobulins.

Currently, no standard treatment strategy has been established for immune-mediated necrotizing myopathy (IMNM). Here we present a case of IMNM which was successfully treated with intensive combined therapy with high-dose glucocorticoids, tacrolimus, and intravenous immunoglobulins. Her muscle weakness was rapidly progressive and severe so that she became bedridden one week after admission. She was complicated with dysphagia and had serum myogenic enzymes elevation, ventricular diastolic dysfunction, and interstitial lung disease. Serum anti-SRP antibody was positive and her muscle biopsy revealed many necrotic fibers with minimal inflammation. Further histological analysis demonstrated infiltration of phagocytic macrophages with deposition of membrane attack complex (C5b-9) in the necrotic muscle fibers, suggesting activation of complement pathway and macrophages as a pathomechanism of this disease. She was diagnosed as IMNM and was immediately initiated a combination therapy described above, which led to dramatic clinical improvements. Recent studies suggest that intravenous immunoglobulins and tacrolimus can inhibit the activation of complement pathway and macrophages. Our present case suggests that early initiation of intensive combined therapy including intravenous immunoglobulins and tacrolimus might be effective for preventing irreversible muscle damages by disrupting a pathogenic activation of complement and macrophages in IMNM.

Acute encephalitis in primary Sjögren's syndrome: A case report and literature review.

Acute encephalitis is an extremely rare condition in primary Sjogren's syndrome (pSS), and its characteristics and prognosis remain unclear. Here, we report the case of pSS presented with acute encephalitis. She was admitted to our hospital for acute disturbance of consciousness. Acute encephalitis was diagnosed based on the results of the cerebrospinal fluid test (the increase of leucocyte counts, proteins, and interleukin-6 levels), magnetic resonance imaging, and single-photon emission computed tomography with 99mTc. The infectious aetiologies and underlying malignancies were excluded. Serum anti-Sjogren's syndrome-related antigen A autoantibody was positive with extremely high titre. The biopsy specimen of her labial salivary gland revealed a focal lymphocytic sialadenitis with a score of grade 4 in the Greenspan grade. She also developed diffuse alveolar haemorrhage during the clinical course. She was diagnosed with pSS complicated with acute encephalitis followed by diffuse alveolar haemorrhage and successfully treated with pulse steroids, high dose of prednisolone and intravenous cyclophosphamide. Our present case and literature review suggest that acute encephalitis associated with pSS can be treatable with the immunosuppressive therapy, and thus early recognition and treatment initiation are important for this life-threatening condition. Thus, pSS should be included in the differential diagnosis of unexplained encephalitis. Notably, our case characteristically showed diffuse alveolar haemorrhage, adding new insights into the pathogenesis of acute encephalitis associated with pSS that capillaritis might be the underlying cause of this condition.

Dropped head in systemic sclerosis: a case based review.

Dropped head syndrome is a rare disease entity characterized by severe weakness of the cervical para-spinal muscles, resulting in a chin-on-chest deformity. Systemic sclerosis is one of the causes of dropped head syndrome, but its characteristics and prognosis remain unclear due to the extreme rarity of this condition. We present a case of dropped head which occurred in systemic sclerosis. He presented with severe dropped head and relatively mild weakness of the proximal limb muscles. Serum level of creatine kinase was elevated, myopathic change was observed in electromyography, and gadolinium enhancement was found in magnetic resonance imaging of his posterior neck muscles. Anti-topoisomerase I antibody was positive, while other autoantibodies such as anti-PM/Scl and anti-Ku antibodies were negative. Since his dropped head acutely progressed, high dose of glucocorticoid therapy was initiated, which successfully improved dropped head, serum level of creatine kinase, and gadolinium enhancement in magnetic resonance imaging. Our present case and literature review suggest that dropped head occurring in systemic sclerosis can be treatable with immunosuppressive therapy. It is important to recognize this rare but treatable involvement of systemic sclerosis because early diagnosis and treatment initiation are crucial to prevent the irreversible organ damage and the significant decrease of daily activities.

[ALLERGIC DISEASES IN ADULT-ONSET STILL'S DISEASE AND RHEUMATOID ARTHRITIS].

BACKGROUND: A high prevalence of allergic diseases was found in patients with adult-onset Still's disease (AOSD). However, the relative prevalence is unknown compared with other diseases. OBJECTIVES: We sought to compare the prevalence of allergic diseases in the control group of patients with rheumatoid arthritis (RA). METHODS: We retrospectively examined consecutive patients diagnosed with AOSD or RA in our hospital from 2010 to 2020. The patients with AOSD met the preliminary criteria for classification of AOSD. The patients with RA met the EULAR/ACR 2010 criteria. We included patients with RA without other rheumatic diseases. The analysis was performed on six types of allergic reactions: food allergy, drug allergy, allergic contact dermatitis, allergic rhinitis and/or allergic conjunctivitis, and asthma. RESULTS: Twenty-four patients with AOSD and 409 patients with RA were enrolled. The median ages (AOSD, RA) were 46.6, 68.2 years old. Females were 83.3%, 78.0%. Fifty% of AOSD patients and 34.5% of RA patients presented at least one type of allergic diseases (p = 0.12). These included food allergy (4.2%, 6.4%: p = 1.0), drug allergy (37.5%, 16.6%: p = 0.02), allergic rhinitis/allergic conjunctivitis (25.0%, 8.6%: p = 0.02), contact dermatitis (4.2%, 4.4%: p = 1.0), and asthma (4.2%, 5.9%: p = 1.0). CONCLUSION: Patients with AOSD had a higher prevalence of drug allergy, and allergic rhinitis/allergic conjunctivitis than patients with RA.

Risk Prediction Modeling Based on a Combination of Initial Serum Biomarker Levels in Polymyositis/Dermatomyositis-Associated Interstitial Lung Disease.

OBJECTIVE: To establish predictive models for mortality in patients with polymyositis/dermatomyositis-associated interstitial lung disease (PM/DM-ILD) using a combination of initial serum biomarker levels. METHODS: The Multicenter Retrospective Cohort of Japanese Patients with Myositis-Associated ILD (JAMI) database of 497 incident cases of PM/DM-ILD was used as a derivation cohort, and 111 cases were additionally collected as a validation cohort. Risk factors predictive of all-cause mortality were identified by univariate and multivariable Cox regression analyses using candidate serum biomarkers as explanatory variables. The predictive models for mortality were generated in patients with and those without anti-melanoma differentiation-associated gene 5 (MDA-5) antibody, using a combination of risk factors. Cumulative survival rates were assessed using Kaplan-Meier analysis, and were compared between subgroups using the Breslow test. RESULTS: In the derivation cohort, C-reactive protein (CRP) and Krebs von den Lungen 6 (KL-6) levels were identified as independent risk factors for mortality in both anti-MDA-5-positive and anti-MDA-5-negative patients. We then developed a prediction model based on anti-MDA-5 antibody status, CRP level, and KL-6 level, termed the "MCK model," to identify patients at low (<15%), moderate (15-50%), or high (≥50%) risk of mortality, based on the number of risk factors. The MCK model successfully differentiated cumulative survival rates in anti-MDA-5-positive patients (P < 0.01 for low versus moderate risk and P = 0.03 for moderate versus high risk) and in anti-MDA-5-negative patients (P < 0.001 for low versus moderate risk). The utility of the MCK model was replicated in the validation cohort. CONCLUSION: Our findings indicate that an evidence-based risk prediction model using CRP and KL-6 levels combined with anti-MDA-5 antibody status might be useful for predicting prognosis in patients with PM/DM-ILD.

Correction to: Anti-cyclic citrullinated peptide antibody in the cerebrospinal fluid in patients with rheumatoid arthritis who have central nervous system involvement.

The authors regret that the original published version of the above article contained errors. The authors requested that these be noted.

Anti-cyclic citrullinated peptide antibody in the cerebrospinal fluid in patients with rheumatoid arthritis who have central nervous system involvement.

Central nervous system (CNS) involvement, including encephalopathy, encephalitis, leptomeningitis, and pachymeningitis, in rheumatoid arthritis (RA) is rather rare. We report the case of a 61-year-old female with a history of RA in remission for 7 years, who presented with numbness, weakness of the left upper limb, dysarthria, and headache. Magnetic resonance imaging (MRI) of the brain showed meningeal enhancement in the frontal, parietal, and temporal lobes. Cerebrospinal fluid (CSF) examination detected high levels of both rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA), with a high ACPA-immunoglobulin G index (> 2.0). She was diagnosed with rheumatoid meningitis. Following combined therapy with oral prednisolone and intravenous infusion of cyclophosphamide, her symptoms promptly improved. After treatment, RF and ACPA levels in the CSF were reduced, and MRI showed improvement of the meningeal structures. This case, along with existing literature, suggests that the ACPA level in the CSF may serve as a useful marker for diagnosing of CNS involvement in RA, as well as an index of effectiveness of the associated treatment.

Acute generalized pustular bacterid concomitant with erythema nodosum, polyarthritis, and Achilles tendinitis.

We report a case of acute generalized pustular bacterid (AGPB) concomitant with erythema nodosum (EN), polyarthritis, and Achilles tendinitis. The patient was admitted with a complaint of fever, widespread plural pustules, erythema, and polyarthralgia. Histopathological examination of the skin lesions demonstrated features of AGBP and EN. Although arthralgia and AGPB can be recognized together, EN and Achilles tendinitis are rare manifestations seen in patients with AGPB. In this case report, we suggest arthralgia, EN, and Achilles tendinitis could coexist with AGPB.

Pneumocystis jirovecii pneumonia developed in a patient with rheumatoid arthritis after 14 weeks of iguratimod add-on to treatment with methotrexate and etanercept.

A 66-year-old woman who had rheumatoid arthritis and underwent a long-term treatment with methotrexate and etanercept developed Pneumocystis jirovecii pneumonia (PCP) 3 months after iguratimod add-on. Although most rheumatologists might have the impression that iguratimod has less toxicity and immunosuppressive effect compared with methotrexate and biologic disease-modifying antirheumatic drugs, this case suggests that iguratimod may increase the risk of PCP, especially in combination with other drugs.

Long-term Eculizumab Treatment Contributes to Recovery from End-stage Renal Disease Caused by Atypical Hemolytic Uremic Syndrome.

We experienced a favorable outcome in an adult case of atypical hemolytic uremic syndrome (aHUS) after long-term eculizumab treatment. A 38-year-old Japanese man with a history of central retinal vein occlusion was admitted to our hospital with progressive dyspnea. He was found to have non-immune hemolytic anemia, thrombocytopenia, and acute renal failure two weeks after an episode of the common cold. Plasma exchange was ineffective; therefore, we initiated eculizumab after we excluded other thrombotic microangiopathies. Although long-term peritoneal dialysis was required, we successfully discontinued dialysis 18 months after the onset of aHUS with eculizumab.