Biomarker combination predicting imminent relapse after discontinuation of biological drugs in patients with rheumatoid arthritis in remission.

OBJECTIVES: Compared to conventional disease-modifying antirheumatic drugs (DMARDs), biological DMARDs demonstrate superior efficacy but come with higher costs and increased infection risks. The ability to stop and resume biological DMARD treatment while maintaining remission would significantly alleviate these barriers and anxieties. The objective of this study was to identify biomarkers that can predict an imminent relapse, hopefully enabling the timely resumption of biological DMARDs before relapse occurs. METHODS: Forty patients with rheumatoid arthritis who had been in remission for more than 12 months were included in the study. The patients discontinued their biological DMARD treatment and were monitored monthly for the next 24 months. Out of the 40 patients, 14 (35%) remained in remission at the end of the 24-month period, while 26 (65%) experienced relapses at different time points. Among the relapse cases, 13 patients experienced early relapse within 6 months, and another 13 patients had late relapse between 6 months and 24 months. Seventy-three cytokines in the sera collected longitudinally from the 13 patients with late relapse were measured by multiplex immunoassay. Using cytokines at two time points, immediately after withdrawal and just before relapse, volcano plot and area under the receiver operating characteristic curves (AUC) were drawn to select cytokines that distinguished imminent relapse. Univariate and multivariate logistic regression analyses were used for the imminent relapse prediction model. RESULTS: IL-6, IL-29, MMP-3, and thymic stromal lymphopoietin (TSLP) were selected as potential biomarkers for imminent relapse prediction. All four cytokines were upregulated at imminent relapse time point. Univariate and multivariate logistic regression showed that a combination model with IL-6, MMP-3, and TSLP yielded an AUC of 0.828 as top predictors of imminent relapse. CONCLUSIONS: This methodology allows for the prediction of imminent relapse while patients are in remission, potentially enabling the implementation of on- and off-treatments while maintaining remission. It also helps alleviate patient anxiety regarding the high cost and infection risks associated with biological DMARDs, which are the main obstacles to benefiting from their superb efficacy.

Serum level of IFNß distinguishes early from late relapses after biologics withdrawal in rheumatoid arthritis.

Since the advent of biological disease modifying anti-rheumatic drugs (bDMARDs) in the treatment of rheumatoid arthritis (RA), most RA patients receiving such drugs have achieved remission at the expense of cost and infection risk. After bDMARDs are withdrawn, a substantial proportion of patients would have relapses even if they were in complete remission. In our previous report, relapse prediction could be made at the time of bDMARD withdrawal by measuring the serum levels of five cytokines. We report herein that, among 73 cytokines examined, serum levels of only interferon ß (IFNß) at the time of bDMARD withdrawal could predict early relapse (within 5 months) in patients who were categorized to relapse by the five cytokines in our previous report, with a cut-off value of 3.38 in log2 and AUC of 0.833. High serum levels of IFNß in the early-relapse group remained high until actual relapse occurred. Therefore, patients who relapse early might be biochemically different from those who relapse late or do not relapse at all. We recommend that patients who are predicted to relapse early continue bDMARDs even if they are in complete remission. This finding contributes to shared decision-making regarding how and when bDMARDs should be discontinued.

A novel multi-biomarker combination predicting relapse from long-term remission after discontinuation of biological drugs in rheumatoid arthritis.

Biological disease modifying anti-rheumatic drugs (bDMARDs) show dramatic treatment efficacy in rheumatoid arthritis (RA). Long-term use of bDMARDs, however, has disadvantages such as high costs and infection risk. Therefore, a methodology is needed to predict any future RA relapse. Herein, we report a novel multi-biomarker combination which predicts relapse after bDMARDs-withdrawal in patients in remission. Forty patients with RA in remission for more than 12 months were enrolled. bDMARDs were withdrawn and they were followed monthly for the next 24 months. Fourteen patients (35%) of 40 in the cohort remained in remission at 24 months, whereas 26 (65%) relapsed at various time-points. Serum samples obtained longitudinally from patients in remission were assessed for the relapse-prediction biomarkers and index from 73 cytokines by the exploratory multivariate ROC analysis. The relapse-prediction index calculated from the 5 cytokines, IL-34, CCL1, IL-1ß, IL-2 and IL-19, strongly discriminated between patients who relapsed and those who stayed in remission. These findings could contribute to clinical decision-making as to the timing of when to discontinue bDMARDs in RA treatment.

Fatal Thrombotic Microangiopathy and Posterior Reversible Encephalopathy Syndrome in a Patient with Anti-melanoma Differentiation-associated Gene 5 Antibody-positive Dermatomyositis.

A 56-year-old woman presented with dermatomyositis positive for anti-melanoma differentiation-associated gene 5 antibody. No interstitial lung disease was detected. Despite treatment with methylprednisolone pulse therapy and cyclosporine, dysphagia developed. Furthermore, the presence of thrombocytopenia, elevated lactate dehydrogenase levels, and an undetectable haptoglobin level suggested the possibility of thrombotic microangiopathy (TMA). Disturbed consciousness developed shortly after TMA onset, and brain magnetic resonance imaging revealed hyperintensity lesions in the bilateral basal ganglia, thalami, and brainstem. The patient was diagnosed with atypical posterior leukoencephalopathy syndrome before dying of heart failure later that day. In conclusion, early TMA recognition and prompt intensive treatment are critical in such cases.

Risk factors correlated with immunosuppressant discontinuation in antineutrophil cytoplasmic antibody-associated vasculitis patients.

AIM: The use of an immunosuppressant is recommended as a treatment for remission induction in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, the immunosuppressant is sometimes discontinued due to an adverse event. We sought to identify the cause and risk factors for immunosuppressant discontinuation in patients with AAV receiving remission induction treatment. METHODS: We retrospectively analyzed the cases of AAV patients treated in 2005-2016 with immunosuppressants to induce remission. We defined "discontinuation" as stopping, switching, or delaying immunosuppressant administration due to adverse events. We performed a multivariate analysis to identify risk factors for immunosuppressant discontinuation. RESULTS: We identified 50 patients treated with an immunosuppressant for remission induction: cyclophosphamide was used in 45 patients (90%), methotrexate in 4 (8%), and cyclosporine A in 1 patient (2%). Among them, 26 patients (52%) underwent discontinuation of the immunosuppressant. Infection and myelosuppression were the major causes of discontinuation. Multivariate Cox proportional hazards regression analysis revealed that a cumulative dose of prednisolone ≥ 2000 mg (hazard ratio [HR] =2.18, 95% confidence interval [CI] =1.37-3.70, P < .001), performance status of 3-4 (HR = 1.80, 95% CI = 1.07-3.03, P = .027), and oral cyclophosphamide (HR = 1.81, 95% CI = 1.11-2.97, P = .018) were independent risk factors correlated with immunosuppressant discontinuation. CONCLUSION: Physicians should be aware of risk factors predicting immunosuppressant discontinuation when treating AAV patients with an immunosuppressant.

Increase of a wide range of bioactive substances in an active phase of neuro-Sweet disease.

We present the case of a patient whose skin findings and human leucocyte antigen (HLA) typing were key findings for the diagnosis of his neuro-Sweet disease. A 55-year-old Japanese man with skin rashes and high fever suddenly developed consciousness disturbance, and brain MRI showed encephalitis and leptomeningitis. Neuro-Behçet disease or microbial infection was initially suspected, but he was eventually diagnosed with neuro-Sweet disease based on his skin rashes and pathology and the presence of HLA-B54 and Cw1. He responded to glucocorticoid and recovered without neurological sequelae. The involvement of cytokines has been implicated in the pathogenesis of Sweet disease, but the number of cytokines assayed in each case report is limited. In our patient's case, the result of a 27-cytokine assay showed increases in a wide range of bioactive substances including inflammatory cytokines, growth factors and chemoattractants in the active phase, indicating the involvement of multiple cytokines in the pathogenesis of Sweet disease.

Salmonella enterica Subspecies arizonae Detected from Bilateral Pleural Fluid in a Patient with Systemic Lupus Erythematosus and Malignant Lymphoma.

A 72-year-old woman was admitted to our hospital with bilateral pleural effusions. She had a 31-year history of systemic lupus erythematosus and had been treated with prednisolone and azathioprine. Pleural fluid culture revealed Salmonella enterica subsp. arizonae infection. This pathogen rarely infects humans but is commonly found in the gut flora of reptiles, especially snakes. Our patient had not come in contact with reptiles. Despite antibiotic therapies and negative pleural cultures, the pleural effusion persisted. Colon cancer was detected concomitantly, and she finally died. The autopsy revealed that the pleuritis was due to underlying diffuse large B cell lymphoma.

A Non-smoking Woman with Anti-phospholipid Antibodies Proved to Have Thromboangiitis Obliterans.

A 48-year-old woman with severe pain and numbness of her right leg and foot was admitted to our hospital. She had never smoked and had little exposure to passive smoking. Initially, polyarteritis nodosa with anti-phospholipid antibodies was considered. Combination therapy with methylprednisolone pulse therapy, intravenous cyclophosphamide pulse therapy, vasodilators, antiplatelet agents, and anticoagulants was not effective. Vasculopathy was progressive, and she presented with gangrene of the toes. She required amputation of her right leg. The pathological findings of the amputated leg revealed thromboangiitis obliterans (TAO). TAO should be considered even in non-smoking women. Non-response to immunosuppressant and anticoagulant therapies may be a clue to the diagnosis of TAO.

Unilateral bamboo node of the vocal fold associated with anti-SS-A and anti-SS-B antibody.

Voice disorder is occasionally associated with systemic autoimmune diseases. Bamboo nodes of the vocal fold have a characteristic bamboo-shaped appearance and strongly indicate the presence of an underlying autoimmune disorder. Both mechanical and immunologic mechanisms are assumed to be involved in the pathogenesis of vocal disorder. We present a 27-year-old woman with hoarseness, sore throat, and a unilateral bamboo node of the vocal fold. Serum anti-SS-A and -SS-B antibodies were positive, but she had no systemic signs or symptoms suggestive of Sjögren's syndrome. Oral systemic glucocorticoid treatment was not effective, but surgical resection improved her hoarseness. Histopathologic findings of the resected vocal node revealed fibrosis with hyaline degeneration. Thereafter, she had no recurrence of hoarseness for 2 years. Bamboo nodes of the vocal fold may occur without definitive autoimmune diseases, although immunologic abnormalities such as autoantibody-positivity may occur.

Simultaneous Oculomotor and Facial Nerve Palsies in a Patient with Systemic Lupus Erythematosus and Sjögren's Syndrome.

A 70-year-old man with systemic lupus erythematosus (SLE) presented with simultaneous right oculomotor nerve palsy and right facial nerve palsy. Brain magnetic resonance imaging and cerebrospinal fluid analysis revealed no abnormality. Coexistent Sjögren's syndrome was diagnosed on the basis of anti-SS-A antibody positivity, salivary gland scintigraphy, and histological findings on minor salivary gland biopsy. As there was no obvious cause of multiple cranial neuropathies, we supposed that the palsies were induced by either of the underlying diseases. The patient was treated with a high-dose of prednisolone and intravenous cyclophosphamide, and both palsies recovered almost completely within two weeks.

Independent association of HLA-DPB1*02:01 with rheumatoid arthritis in Japanese populations.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized with joint destructions; environmental and genetic factors were thought to be involved in the etiology of RA. The production of anti-citrullinated peptide antibodies (ACPA) is specifically associated with RA. DRB1 is associated with the susceptibility of RA, especially ACPA-positive RA [ACPA(+)RA]. However, a few studies reported on the independent associations of DPB1 alleles with RA susceptibility. Thus, we investigated the independent association of DPB1 alleles with RA in Japanese populations. METHODS: Association analyses of DPB1 were conducted by logistic regression analysis in 1667 RA patients and 413 controls. RESULTS: In unconditioned analysis, DPB1*04:02 was nominally associated with the susceptibility of ACPA(+)RA (P = 0.0021, corrected P (Pc) = 0.0275, odds ratio [OR] 1.52, 95% confidence interval [CI] 1.16-1.99). A significant association of DPB1*02:01 with the susceptibility of ACPA(+)RA was observed, when conditioned on DRB1 (Padjusted = 0.0003, Pcadjusted = 0.0040, ORadjusted 1.47, 95%CI 1.19-1.81). DPB1*05:01 was tended to be associated with the protection against ACPA(+)RA, when conditioned on DRB1 (Padjusted = 0.0091, Pcadjusted = 0.1184, ORadjusted 0.78, 95%CI 0.65-0.94). When conditioned on DRB1, the association of DPB1*04:02 with ACPA(+)RA was disappeared. No association of DPB1 alleles with ACPA-negative RA was detected. CONCLUSION: The independent association of DPB1*02:01 with Japanese ACPA(+)RA was identified.

Raoultella planticola Bacteremia in a Patient with Early Gastric Cancer.

The patient was an 81-year-old man who was found to have bacteremia due to Raoultella planticola, which might have entered the circulation through the bile duct during the passing of a gallbladder stone. In the present case, we screened for malignancies because most cases of R. planticola bacteremia occur after trauma, invasive procedures, or in patients with malignancy (70.6%). Early gastric cancer was detected. Although the association between R. planticola bacteremia and malignancy remains speculative in the present case, it may be useful to scrutinize similar cases involving low-virulence bacteremia for possible malignancies or immune conditions.

Unaffected reaction level in tuberculin skin test by long-term therapy with tumor necrosis factor inhibitors for rheumatoid arthritis.

AIM: The tuberculin skin test (TST) is used to diagnose tuberculosis; however, the influence of tumor necrosis factor (TNF) inhibitors on the test is unclear. This study investigated whether therapy with TNF inhibitors suppresses the TST reaction due to immunosuppression or whether the TST reaction increases due to reactivation of latent Mycobacterium tuberculosis infection. METHOD: Ninety-one patients with rheumatoid arthritis receiving TNF inhibitors (40 using infliximab and 51 using etanercept) were studied. The TST was performed before starting TNF inhibitors (T1) and more than 1 year after starting them (T2). RESULTS: At T1, the reaction was negative in 45 patients, weakly positive in 21 patients, moderately positive in 18 patients and strongly positive in seven patients, while the numbers at T2 were 44, 20, 16 and 11, respectively. There were no significant differences of the TST reaction between T1 and T2 in all patients (P = 0.657), patients using infliximab (P = 0.462) or patients using etanercept (P = 1.00). No patients with a strongly positive TST reaction at T1 became negative at T2. However, two patients who were negative at T1 became strongly positive at T2. Although they had no signs of M. tuberculosis infection, isoniazid prophylaxis was given. CONCLUSION: The TST reaction was not suppressed after more than 1 year of therapy with TNF inhibitors. Patients in whom the TST reaction changes from negative to strongly positive may need appropriate prophylaxis.

Difference in relapse-rate and clinical phenotype by autoantibody-subtype in Japanese patients with anti-neutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: To correlate the serotype specificity to myeloperoxidase (MPO) and proteinase-3 (PR3) with clinical characteristics in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Clinical characteristics and outcomes of patients with AAV in our division from 2005 to 2014 were retrospectively compared on the basis of ANCA subtype. RESULTS: We collected the data from 88 patients with MPO-ANCA vasculitis, and 17 with PR3-ANCA vasculitis. Patients with PR3-ANCA vasculitis were younger, and had higher involvement-rates in the eye, nose, and ear. In both MPO- and PR3-ANCA vasculitis, the most frequently involved organ was the respiratory system. Interstitial pneumonia was more frequent in MPO-ANCA vasculitis (52.3% versus 5.9%, p < 0.01), whereas nodular shadow was more frequent in PR3-ANCA vasculitis (9.1% versus 58.8%, p < 0.01). Multivariable Cox proportional hazard regression analysis showed that the hazard ratio of PR3-ANCA for relapse was 2.48 (95% confidence interval 1.14-5.42, p = 0.02). There was no difference in the survival and the progression to end-stage kidney disease and respiratory failure between the two vasculitides. CONCLUSION: MPO-ANCA vasculitis was a predominant form of AAV in Japan. Classification based on ANCA subtype would be clinically relevant in the prediction of organ involvement and relapse.

Prediction of the therapeutic response to methotrexate at 24 weeks by methotrexate-polyglutamates concentration in erythrocytes at 8 weeks in patients with rheumatoid arthritis.

OBJECTIVES: The objective of this study is to evaluate the pharmacokinetics and pharmacodynamics of methotrexate-polyglutamates (MTX-PGs) in erythrocytes in patients with rheumatoid arthritis and correlate them with the efficacy. METHODS: MTX-PG concentrations in erythrocytes were measured in 42 MTX-naïve patients repeatedly for 24 weeks by high-performance liquid chromatography. In 56 patients receiving stable MTX doses for at least 12 weeks, the correlation between MTX doses and MTX-PG concentrations was examined. The efficacy was measured by the change of DAS28CRP (ΔDAS28CRP). RESULTS: There were moderate correlations between MTX dose and MTX-PG 3, 4, and 5. At 24 weeks, MTX-PG2, 3, 4, and 1-5 were higher in patients with ΔDAS28CRP >1.2 than in those with ≤1.2. The cutoff value of MTX-PG1-5 to discriminate ΔDAS28CRP >1.2 from ≤1.2 at 24 weeks was 68.7 nM. Among 20 patients with MTX-PG1-5 > 50.6 nM at 8 weeks, seven already improved at 8 weeks and additional 11 improved at 24 weeks (p < 0.001). On the contrary, among the nine patients with MTX-PG1-5 ≤ 50.6 nM at 8 weeks, none improved at 8 weeks and only one improved at 24 weeks (p = 0.500). CONCLUSIONS: Erythrocyte MTX-PGs might be a potential indicator and predictor of MTX efficacy.

Reactivation of hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs.

OBJECTIVE: To examine the incidence of hepatitis B virus (HBV) reactivation in patients with rheumatoid arthritis (RA) receiving biological disease-modifying antirheumatic drugs (DMARDs). METHODS: We retrospectively reviewed RA patients treated with biological DMARDs at our institution from July 2010 to December 2012. Patients with antibodies for hepatitis B core antigen and/or hepatitis B surface antigen were regarded as having prior HBV infection. Clinical data on these patients, including HBV-DNA levels, were retrieved from the medical records. RESULTS: During the study period, 251 patients were administered various biological DMARDs. Six patients with a history of HBV vaccination and one patient with positive HBV surface antigen were excluded from the study. Fifty-seven of the remaining 244 patients (23.4%) had prior HBV infection. These patients were followed for a median of 18 months (range: 2-27 months) and HBV-DNA was examined a median of seven times (range: 2-27). HBV-DNA was detected in three patients (5.3%), comprising two receiving tocilizumab and one receiving etanercept. However, HBV-DNA levels were below the quantitation limit (<2.1 log copies mL(-1) ) in all three patients. HBV-DNA became negative again within several months in all three patients, while biological DMARDs were continued and liver function tests remained normal throughout. CONCLUSION: HBV-DNA reactivation occurred in 5.3% of RA patients with prior HBV infection during treatment with biological DMARDs, but there were no associated clinical manifestations. Accordingly, it seems that biological DMARDs can be used safely in patients with RA.

[DRUG-INDUCED LUPUS CAUSED BY LONG TERM MINOCYCLINE TREATMENT FOR ACNE VULGARIS].

An 18-year-old Japanese girl had received oral minocycline 200mg daily for treatment of acne vulgaris since 16 years old. She had a fever three months before admission, followed by joint pains in her knees, elbows and several proximal interphalangeal joints one month before admission. She was referred to our hospital because of a high serum level of anti-DNA antibody. She had already discontinued oral minocycline five weeks before admission, because she missed her medication refilled. On admission, the arthralgia and fever spontaneously resolved, and there were no laboratory evidence of hypocomplementemia and cytopenia. She had neither erythema nor internal organ involvements. Because her symptoms subsided spontaneously after the cessation of minocycline, she was considered to have drug-induced lupus. Both the arthralgia and fever did not relapse, and anti-ds DNA antibody returned to normal during a follow-up period without treatment. There are few reports of drug-induced lupus caused by minocycline in Japan. This case highlights the importance of considering minocycline-induced lupus.