Qualitative evaluation of connective tissue disease with cytomegalovirus infection: A meta-analysis of case reports.

BACKGROUND: The primary therapies for connective tissue disease include glucocorticoids and immunosuppressants. However, their prolonged usage can precipitate opportunistic infections, such as cytomegalovirus infection. When managing connective tissue disease complicated by cytomegalovirus infection, judicious selection of treatment modalities is crucial. This involves assessing the necessity for antiviral therapy and contemplating the reduction or cessation of glucocorticoids and immunosuppressants. OBJECTIVE: This investigation sought to methodically review existing literature regarding treating connective tissue disease patients with cytomegalovirus infection. METHODS: On July 5, 2023, an exhaustive literature search was conducted. Data analysis utilized the Kruskal-Wallis test or one-way analysis of variance, supplemented by Bonferroni post hoc testing. RESULTS: Our meta-analysis incorporated 88 studies encompassing 146 connective tissue disease patients with CMV infections. The results indicated that patients with connective tissue disease and cytomegalovirus disease benefitted more from antiviral therapy than those not receiving such treatment (P = 0.003, P < 0.005). Furthermore, the strategic reduction of glucocorticoids and/or immunosuppressants was beneficial (P = 0.037, P < 0.05). Poor clinical outcomes with glucocorticoid-immunosuppressant combination therapy compared to other treatment modalities. The findings also suggested that CMV infection patients fare better without Cyclosporine A than using it (P = 0.041, P < 0.05). CONCLUSION: Antiviral therapy is a viable treatment option in cases of connective tissue disease co-occurring with cytomegalovirus disease. Additionally, when connective tissue disease is stable, there is potential merit in reducing glucocorticoids and/or immunosuppressants, especially avoiding the combination of these drugs. For all cytomegalovirus infection patients, Cyclosporine A may be avoided wherever possible for selecting immunosuppressive agents if its use is not deemed essential in the treatment regimen.

Vitamin D levels in idiopathic inflammatory myopathy patients: a meta-analysis.

PURPOSE: This meta-analysis aimed to explore correlations between vitamin D and idiopathic inflammatory myopathy (IIM). METHODS: A comprehensive database search was conducted on 13 October 2020. Mean differences (MDs) and aggregated risk ratios (RR) with 95% confidence intervals (CIs) were used to determine the correlation between vitamin D deficiency (VDD) and IIM. Statistical analysis was performed with RevMan 5.4 and Stata15, statistical significance was set at p < 0.05. RESULTS: Search revealed five studies with 286 IIM patients and 480 healthy controls. Results with random-effects modeling indicated that serum vitamin D levels were significantly lower in IIM patients than in healthy controls (MD = -13.10 ng/mL; 95% CI: -16.51 to -9.68; p < 0.00001). No differences were found between patients with IIM and other autoimmune diseases on vitamin D levels (MD =-2.65 ng/mL; 95% CI: -11.31-6.01; p = 0.55). In two studies with 185 IIM patients, those with low vitamin D levels exhibited higher creatine kinase levels (MD = 85.20 IU/L; 95% CI: 72.67-97.73; p < 0.00001) than those with normal vitamin D levels. VDD was correlated with an increased risk of IIM (RR = 3.24, 95% CI: 1.81-5.79; p < 0.0001). CONCLUSION: This meta-analysis showed correlations between vitamin D level and IIM. The results indicated, VDD may be a risk factor for IIM, a determinant of immune dysregulation in IIM, or a consequence of IIM. Also, it implied further research to determine whether vitamin D supplementation is beneficial for patients with IIM.

Combined glucocorticoids and cyclophosphamide in the treatment of Graves' ophthalmopathy: a systematic review and meta-analysis.

PURPOSE: To evaluate the efficacy and safety of combined glucocorticoids (GCs) and cyclophosphamide (CYC) treatment in Graves' ophthalmopathy (GO). METHODS: We searched PubMed, Embase, Cochrane Library, and four Chinese databases (Chinese National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), WanFang, and SinoMed) for any published randomized controlled trials (RCTs) produced from inception to December 1, 2023. Articles obtained using appropriate keywords were selected independently by two reviewers according to the established inclusion and exclusion criteria. FINDINGS: We retrieved 1120 records which were eventually reduced to 13 RCTs which were then included in this evaluation. Pooled results indicated that the experimental group (CYC/GCs) showed a higher response rate than control group (GCs or negative control) (RR 1.27; 95% confidence interval 1.19 to 1.37). The subgroup analysis showed that the difference in response rates among treatment protocols (CYC/P, CYC/MPS, CYC/DEX) was not statistically significant (p = 0.23). IMPLICATIONS: The combination of GCs and CYC could be recommended as a therapeutic option for GO, especially in patients who experience recurrence after a withdrawal GCs, have a poor response to GCs, or cannot obtain monoclonal antibody agents for various reasons.

Risk factors for invasive fungal infections in patients with connective tissue disease: Systematic review and meta-analysis.

OBJECTIVE: Invasive fungal infections (IFIs) are life-threatening opportunistic infections in patients with connective tissue disease CTD) that cause significant morbidity and mortality. We attempted to determine the potential risk factors associated with IFIs in CTD. METHODS: We systematically searched PubMed, Embase, and the Cochrane Library databases for relevant articles published from the database inception to February 1, 2023. RESULTS: Twenty-six studies were included in this systematic review and meta-analysis. Risk factors identified for IFIs were diabetes (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.00 to 2.64), pulmonary diseases (OR 3.43; 95% CI 2.49 to 4.73), interstitial lung disease (ILD; OR, 4.06; 95% CI, 2.22 to 7.41), renal disease (OR, 4.41; 95% CI, 1.84 to 10.59), glucocorticoid (GC) use (OR, 4.15; 95% CI, 2.74 to 6.28), especially moderate to high-dose GC, azathioprine (AZA) use (OR, 1.50; 95% CI, 1.12 to 2.01), calcineurin inhibitor (CNI) use (OR, 2.49; 95% CI, 1.59 to 3.91), mycophenolate mofetil (MMF) use (OR, 2.83; 95% CI, 1.59 to 5.03), cyclophosphamide (CYC) use (OR, 3.35; 95% CI, 2.47 to 4.54), biologics use (OR, 3.43; 95% CI, 2.36 to 4.98), and lymphopenia (OR, 4.26; 95% CI, 2.08 to 8.73). Hydroxychloroquine (HCQ) use reduced risk of IFIs (OR, 0.67; 95% CI, 0.54 to 0.84). Furthermore, 17 of the 26 studies only reported risk factors for Pneumocystis jiroveci pneumonia (PJP) in patients with CTD. Pulmonary disease; ILD; and the use of GC, CNIs, CYC, methotrexate (MTX), MMF and biologics, and lymphopenia increased the risk of PJP, whereas the use of HCQ reduced its risk. CONCLUSION: Diabetes, pulmonary disease, ILD, renal disease, use of GC (especially at moderate to high dose) and immunosuppressive drugs, and lymphopenia were found to be associated with significant risk for IFIs (especially PJP) in patients with CTD. Furthermore, the use of HCQ may reduce the risk of IFIs in patients with CTD.

Cyclophosphamide in the Treatment of Systemic Lupus Erythematosus-related Guillain-Barré Syndrome: A Systematic Review of Case Reports.

A small category of Guillain-Barré syndrome (GBS) occurs in the presence of systemic lupus erythematosus (SLE). However, specific treatments for this condition have not been established. Cyclophosphamide (CYC) has been reported to benefit patients with SLE-related GBS in some isolated case reports. Consequently, our objective was to investigate the effectiveness of CYC in SLE-related GBS by means of a systematic literature review. Three online databases, PubMed, Embase and Web of Science, were searched for English articles describing the effectiveness of CYC treatment for SLE-related GBS. We extracted data on patient characteristics, disease course, and CYC efficacy and tolerance. Of 995 studies identified, 26 were included in this systematic review. The data for 28 patients (9 men and 19 women) with SLE-related GBS were reviewed, and the patient age at diagnosis varied from 9 to 72 years (mean: 31.5 years [median: 30.5 years]). Sixteen patients (57.1%) had SLE-related GBS before SLE diagnosis. With regard to CYC response, 24 patients (85.7%) showed resolution (46.4%) or improvement (39.3%) of neurological symptoms. Relapse occurred in one patient (3.6%). Four patients (14.3%) showed no improvement in neurological symptoms following CYC administration. With regard to CYC safety, infections developed in two patients (7.1%), and one death (3.6%) due to posterior reversible encephalopathy syndrome was reported. Lymphopenia developed in one patient (3.6%). Our preliminary data suggest that CYC appears to be an effective treatment for SLE-related GBS. However, it is important to differentiate patients with pure GBS concurrent with SLE, because CYC is ineffective for pure GBS.

The therapeutic efficacy and safety of intravenous immunoglobulin in dermatomyositis and polymyositis: A systematic review and meta-analysis.

OBJECTIVES: To evaluate the efficacy and safety of intravenous immunoglobulin (IVIG) in the treatment of dermatomyositis (DM) and polymyositis (PM). METHODS: We searched PubMed, Embase, and the China National Knowledge Infrastructure for relevant studies from July 1919 to May 2021. RESULTS: Seventeen papers pertinent to our questions were found: In a meta-analysis, we found that IVIG significantly improved the level of CK (SMD (STD. Mean Difference) = -0.69; 95%CI -0.93, -0.46; P < 0.0001), Manual Muscle Test (SMD = 1.12; 95%CI 0.77, 1.47; P < 0.00001), Medical Research Council (SMD = 1.59; 95%CI 0.86, 2.33; P < 0.00001), Activities of Daily Living (SMD = 1.07; 95%CI 0.59, 1.56; P < 0.0001). The CK levels in DM and PM were also significantly improved after IVIG (SMD = -0.73; 95%CI -1.12, -0.34; P = 0.0002 and SMD = -3.29; 95%CI -5.82, -0.76; P < 0.0001, respectively). The meta-analysis of three RCTs showed that there was a statistically significant improvement after IVIG (SMD = 0.63; 95%CI 0.22, 1.03; P = 0.002). In a random effects model, pooled muscle power improvement rate was 77% (95% CI: 66.0-87.0%). Meta-analyses of IVIG as first-line therapy showed a significant improvement of the CK level (SMD = -0.71; 95%CI -1.12, -0.30; P = 0.0007). The polled improvement rate of oesophageal disorders was 88% (95% CI: 80.0-95.0%). There was no statistically significant difference in the rate of improvement between the number of courses <2 and ≥2 (0.80% vs. 0.80%, P = 0.9). The proportion of corticosteroid-sparing success reached 81.8%. Adverse reactions following IVIG administration are usually mild and transient. Seven patients developed serious adverse events. CONCLUSION: IVIG seems to be an effective drug for DM/PM, improving muscle strength, CK levels, and oesophageal involvement, and it is well tolerated by patients.

Cyclophosphamide for Treatment of Refractory Chronic Inflammatory Demyelinating Polyradiculoneuropathy: A Systematic Review and Meta-analysis.

PURPOSE: This study evaluates the tolerability and efficacy of cyclophosphamide (CYC) for the treatment of refractory chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: We searched PubMed, Embase, Cochrane Library, and 2 Chinese databases (Chinese National Knowledge Infrastructure and SinoMed) for studies published between database inception and September 30, 2021. Articles obtained using the appropriate keywords were independently selected by 2 reviewers on the basis of the established inclusion and exclusion criteria. FINDINGS: In total, 240 records that were eventually curtailed to 13 studies with 83 patients were retrieved and subsequently included in this evaluation. All 13 studies were included in the systematic review, 7 of which were included in the meta-analysis. The pooled estimate of the response rate was 68% (95% CI, 45%-90%). The pooled estimate of the adverse reaction rate was 8% (95% CI, 0%-15%). The disease duration before the first CYC treatment was negatively correlated with the reduction in the modified Rankin Scale score (r = -0.76, P < 0.001). However, the response rates did not differ significantly between patients of different sexes (P = 0.716) or between patients who received and those who did not receive concurrent glucocorticoids (P = 0.617). IMPLICATIONS: CYC might be a recommended therapeutic option for patients with refractory CIDP, especially those who are unable to accept rituximab treatment. Earlier CYC treatment yields better therapeutic outcomes in patients with refractory CIDP without CYC-related contraindications.

Increased risk of mortality in systemic sclerosis-associated pulmonary hypertension: a systemic review and meta-analysis.

BACKGROUND: Pulmonary hypertension (PH) is a frequent complication of systemic sclerosis (SSc) and is currently one of the primary causes of death in patients with this disease. We conducted a systematic review and meta-analysis to assess the association between PH and mortality in patients with SSc to verify trends in mortality in patients with SSc-associated PH. METHODS: We searched the PubMed and Embase databases for published studies on SSc-associated PH from inception to May 2021. All cohort studies in which mortality and/or survival for SSc-associated PH were reported were included in the analysis. The outcome parameters were pooled and analyzed using a random-effects model via generic inverse-variance weighting in conventional and cumulative meta-analysis. RESULTS: The literature search identified 1161 citations, and the full texts of 54 studies were examined. Sixteen articles, with a total of 7857 patients with SSc and 1140 patients with SSc-associated PH, were included in the meta-analysis. Patients with SSc-associated PH had a higher pooled risk of mortality than patients with SSc without PH (risk ratio = 3.12; 95% confidence interval: [2.44, 3.98]). CONCLUSIONS: This meta-analysis revealed a higher mortality in patients with SSc-associated PH. PH was a significant predictor of death in patients with SSc. Thus, early diagnosis and treatment of PH are important in patients with SSc.

Angiotensin-converting enzyme inhibitors prior to scleroderma renal crisis in systemic sclerosis: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Angiotensin-converting enzyme inhibitors (ACEIs) are widely used in the treatment of scleroderma renal crisis (SRC), and their use prior to the onset of SRC in patients with systemic sclerosis (SSc) has received wide attention in recent years. We undertook an evidence-based approach to identify whether the use of ACEIs prior to the onset of SRC is beneficial for patients with SSc. METHODS: We searched PubMed and Embase for any published studies produced between database inception and 22 October 2021. Articles obtained after using appropriate keywords were selected independently by two reviewers according to the established inclusion and exclusion criteria. RESULTS: Nine studies were included. Pooled results indicated that using ACEIs prior to SRC was associated with a higher incidence of SRC than no ACEIs prior to SRC (RR 2.05, 95% confidence interval 1.08-3.91, p = 0.03). Compared with patients who did not use ACEIs prior to the onset of SRC, a higher proportion of patients with SRC who used ACEIs prior to its onset had a poorer prognosis (RR 1.46, 95% confidence interval 1.20-1.78, p < 0.01). The difference in mortality between patients who used ACEIs prior to SRC onset and those who did not was not statistically significant (RR 1.12, 95% confidence interval 0.76-1.65, p = 0.57). WHAT IS NEW AND CONCLUSIONS: We recommend against using ACEIs prior to SRC in SSc patients. The use of ACEIs prior to SRC is associated with a higher incidence of SRC and poorer prognosis, especially in patients with progressive SSc or SSc-related renal vasculopathy (SSc-related hypertension and proteinuria).

Cardiovascular events in adult polymyositis and dermatomyositis: a meta-analysis of observational studies.

OBJECTIVES: We aimed to review whether PM and DM patients have an increased cardiovascular (CV) risk, including ischaemic heart disease (IHD), cerebrovascular accidents (CVA) and venous thromboembolism. METHODS: We searched PubMed, Embase and the Cochrane database for relevant studies from inception to February 2021. RESULTS: Twenty-two studies comprising 25 433 patients were included. With PM/DM vs general populations, the risk was significantly increased for CV events [relative risk (RR) = 2.37, 95% CI: 1.86, 3.02]. The RR of CV events for males with PM/DM was higher than for females (RR = 1.43; 95% CI: 1.17, 1.74). PM/DM patients followed for one to five years had a significantly higher CV risk than those followed for five to ten years (RR = 3.51, 95% CI: 1.95, 6.32). The risk was increased for North Americans (RR = 4.28, 95% CI: 2.57, 7.11), Europeans (RR = 2.29, 95% CI: 1.58, 3.31) and Asians (RR = 2.03, 95% CI: 1.41, 2.90). Our meta-analysis found that the elevated CV event risk was related to PM (RR = 2.35, 95% CI: 1.51, 3.66) and DM (RR = 2.55, 95% CI: 1.66, 3.93). Subgroup analyses showed that the risk was significantly increased for IHD (RR = 1.76, 95% CI: 1.40, 2.21), CVA morbidity (RR = 1.31, 95% CI: 1.03, 1.67) and ischaemic stroke (IS) (RR = 1.47, 95% CI: 1.26, 1.73), with no statistically significant increased risk of haemorrhagic stroke mortality (RR = 1.43, 95% CI: 0.92, 2.21). The CV event risk was increased for venous thromboembolism (RR = 4.60, 95% CI: 3.17, 6.66), deep venous thrombosis (RR = 5.53, 95% CI: 3.25, 9.39) and pulmonary embolism (RR = 5.26, 95% CI: 2.62, 10.55). CONCLUSION: This meta-analysis found that PM/DM patients had a ∼2.37 times increased CV risk, particularly males diagnosed in the previous five years. PM/DM may be an independent risk factor for developing IHD, IS, deep venous thrombosis and pulmonary embolism.

The Efficacy and Safety of Infliximab in Refractory Noninfectious Uveitis: A Meta-Analysis of Observational Studies.

Background: Although infliximab has been recommended for the second-line treatment of seronegative spondyloarthropathy- or juvenile idiopathic arthritis-related uveitis, the issue of its systemic efficacy and safety in a broader diversity of refractory noninfectious uveitis is debatable. To assess the short-term and relatively long-term efficacy of infliximab in refractory noninfectious uveitis, we performed a systematic review and meta-analysis of observational studies. Methods: PubMed, Cochrane Library, EMBASE, and Wanfang Med Online were systematically searched from January 2005 to March 2020. Two investigators independently assessed eligibility. Data were independently collected by two investigators. The pooled proportions were estimated with patients for intraocular inflammation control and improvement of visual acuity. Pooled proportions with 95% credible intervals were computed. Study homogeneity was investigated using I 2 statistics to quantify the percentage of variation across studies. To pool the results, the Mantel-Haenszel fixed-effects or random-effects models were used. Results: Of 2316 studies identified, 16 unique studies with 509 unique participants were included in the meta-analysis. The pooled proportions of intraocular inflammation control reached 92% (95% CI: 87%-98%; I 2: 1%; p=0.42) and 95% (95% CI: 93%-97%; I 2: 0%; p=0.91) in groups of ≤6- and ≥12-month follow-up durations. During the relatively long follow-up period, the pooled proportions of maintaining visual acuity stable or increasing at least one line reached 99% (95% CI: 96%-100%; I 2: 0%; p=0.54) in the involved eyes. The corticosteroid-sparing effect of infliximab was also well demonstrated, with the proportion of corticosteroid-sparing success reaching 85.5% (112/131). Besides, about serious adverse events, 2.6% (13/500) of patients experienced hypersensitivity reactions, 2.4% (12/500) of patients experienced serious infections, 1.8% (9/500) of patients experienced autoimmune diseases, and 0.6% (3/500) of patients experienced neoplasia. Conclusions: This meta-analysis provided evidence that infliximab might be a promising choice in controlling inflammatory activity, gaining visual acuity, and sparing corticosteroid use with relatively few side effects when applied in treating refractory noninfectious uveitis. Systematic Review Registration: [website], identifier [registration number].

Rituximab in the treatment of immune-mediated necrotizing myopathy: a review of case reports and case series.

Immune-mediated necrotizing myopathy (IMNM) is a group of immune-related myopathies characterized by progressive proximal muscle weakness, extremely high serum creatine kinase (CK) levels, and necrotic muscle fibers with a relative lack of inflammation. Treatment of IMNM is challenging, with most cases refractory to high-dose steroids in combination with multiple immunotherapies. The role of rituximab (RTX) for IMNM has been explored in isolated case reports and small series. The aim of this article was to perform a literature review of patients with IMNM treated with RTX and to evaluate RTX efficacy and safety. A total of 34 patients with IMNM were reviewed: 52.9% (18/34) with anti-signal recognition particle (SRP) antibodies and 47.1% (16/34) with anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies. Patient age at onset varied from 11 years to 81 years (mean 41 years). The majority of patients presented as a severe proximal muscle weakness and the peak level of CK varied from 3900 IU/L to 56,000 IU/L (mean 18,440 IU/L). Prior to RTX administration, all patients were treated with high-dose steroids and most were treated with multiple immunotherapies. The reason for initiating RTX was that 64.7% (22/34) of patients showed no improvement after previous treatments, and 35.3% (12/34) of patients relapsed when attempting to wean steroids or other immunosuppressive agents. With regard to RTX efficacy, 61.8% (21/34) of patients presented a response to RTX. Our data may support the use of RTX as an effective treatment strategy against IMNM resistant to steroids and multiple immunotherapies. Meanwhile, RTX as a first-line therapy could be a choice in IMNM, particularly in African Americans with anti-SRP antibody-positive subsets. ANA, antinuclear antibody; CK, creatine kinase; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; IMNM, immune-mediated necrotizing myopathy; MAC, membrane attack complex; MHC-I, major histocompatibility complex-I; RTX, rituximab; SRP, signal recognition particle.

The Role of Mycophenolate Mofetil for the Induction of Remission in ANCA-Associated Vasculitis: A Meta-Analysis.

Objectives: The successful introduction of mycophenolate mofetil (MMF) as a treatment for renal allograft reduced the incidence of acute rejection. The inspiring effects obtained by the MMF have led to an evaluation of its therapeutic potency on ANCA-associated vasculitis (AAV). However, there is little evidence of the MMF's efficacy on the AAV. The meta-analysis is carried out to evaluate the efficacy of MMF as a remission induction therapy in AAV. Methods: Up to June 30th, 2020, PubMed, Cochrane Library, and Embase have been searched comprehensively. According to heterogeneity, the pooled remission rates are synthesized by either fixed-effect or random-effect models. Results: The eight included studies comprising 230 patients who were treated with MMF as induction therapy are included in our analysis. The pooled overall remission rate is 74% (95% CI: 0.68-0.80). The remission rate, the infection rate and the rate of leukopenia of four randomized controlled trials aimed at comparing the effects of MMF with cyclophosphamide (CYC) during induction therapy for AAV have no statistical significance (P > 0.05). Conclusion: MMF may be an alternative to CYC for remission induction therapy in AAV with MPO-ANCA, mild to moderate renal involvement and non-life-threatening state. Whether to observe the effect of MMF in AAV or to compare the difference between MMF and CYC in the future studies, risk stratification and subgrouping of AAV patients should be first carried out to correctly identify the AAV subgroup suitable for MMF.

Lung nodules and IgG4 related disease: a single-center based experience.

BACKGROUND: This study was undertaken in an attempt to characterize the frequency and clinical features of lung nodules in IgG4 related disease (IgG4-RD) patients as an insight for help with the diagnosis of lung nodules. METHODS: A retrospective study was carried out in West China Hospital, Sichuan University from January 2012 to December 2018, 89 patients with definite IgG4-RD were enrolled. RESULTS: Fifty of 89 patients with definite IgG4-RD had radiologically confirmed lung nodules, 6 of whom were diagnosed with definite IgG4 related lung disease. Lung nodules detected in more than 40 patients were small and solid, always with regular margins. Multiple (41/50) and bilateral (34/50) distributions was also a major characteristic of these lung nodules. Lobulation and speculation were simultaneously detected in 3 patients, including 2 patients combined with pleural indentation. Calcification of nodules was detected in only one patient. Thirty-seven patients also had additional radiological abnormalities of lungs, including ground-glass opacity (21/50), thickening of pleura (9/50), thickening of interlobular septa (4/50), thickening of bronchial wall (3/50), pleural effusion (4/50), mass (3/50), interstitial changes (5/50), and mediastinal or hilar lymphadenopathy (32/50). Most patients (44/50) were treated with glucocorticoids alone or combined with immunosuppressive agents. Sixteen patients received a re-examination by chest computed tomography (CT) scan after treatment, 10 of whom showed a decrease in the size and/or the number of nodules. CONCLUSIONS: The incidence of lung nodules in IgG4-RD patients can be high. For an IgG4-RD patient with lung nodules, the possibility that the lung nodules related to IgG4-RLD is high. It is hard to differentiate IgG4 related lung nodules from other lung diseases, in particular, lung cancer. Radiological characteristics and positive responses to glucocorticoids and immunosuppressive agents can help with the differential diagnosis. For these patients, regular follow-up is also important.