Hemophagocytic lymphohistiocytosis: a review inspired by the COVID-19 pandemic.

Hemophagocytic syndrome (HPS) or hemophagocytic lymphohistiocytosis (HLH) is an acute and rapidly progressive systemic inflammatory disorder characterized by cytopenia, excessive cytokine production, and hyperferritinemia. Common clinical manifestations of HLH are acute unremitting fever, lymphadenopathy, hepatosplenomegaly, and multiorgan failure. Due to a massive cytokine release, this clinical condition is considered as a cytokine storm syndrome. HPS has primary and acquired (secondary, reactive) forms. Its primary form is mostly seen in childhood and caused by various mutations with genetic inheritance and, therefore, is called familial HLH. Secondary HLH may be caused in the presence of an underlying disorder, that is, secondary to a malignant, infectious, or autoimmune/autoinflammatory stimulus. This paper aims to review the pathogenesis and the clinical picture of HLH, and its severe complication, the cytokine storm, with a special emphasis on the developed classification criteria sets for rheumatologists, since COVID-19 infection has clinical symptoms resembling those of the common rheumatologic conditions and possibly triggers HLH. MED-LINE/Pubmed was searched from inception to April 2020, and the following terms were used for data searching: "hemophagocytic syndrome" OR "macrophage activation syndrome" OR "hemophagocytic lymphohistiocytosis", OR "cytokine storm". Finally, AND "COVID-19" was included in this algorithm. The selection is restricted to the past 5 years and limited numbers of earlier key references were manually selected. Only full-text manuscripts, published in an English language peer-reviewed journal were included. Manuscript selection procedure and numbers are given in Fig. 2. Briefly, the database search with the following terms of "Hemophagocytic syndrome" OR "Macrophage activation syndrome" OR "Hemophagocytic lymphohistiocytosis" OR "Cytokine storm" yielded 6744 results from inception to April 2020. The selection is restricted to the past 5 years and only limited numbers of earlier key references were selected, and this algorithm resulted in 3080 manuscripts. The addition of (AND "COVID-19") resulted in 115 publications of which 47 studies, together with four sections of an online book were used in the final review. No statistical method was used. HLH is triggered by genetic conditions, infections, malignancies, autoimmune-autoinflammatory diseases, and some drugs. In COVID-19 patients, secondary HLH and cytokine storm may be responsible for unexplained progressive fever, cytopenia, ARDS, neurological and renal impairment. Differentiation between the primary and secondary forms of HLH is utterly important, since primary form of HLH requires complicated treatments such as hematopoietic stem cell transplantation. Further studies addressing the performance of HScore and other recommendations in the classification of these patients is necessary.

Response rate of initial conventional treatments, disease course, and related factors of patients with adult-onset Still's disease: Data from a large multicenter cohort.

BACKGROUND: Adult-onset Still's disease (AOSD) is a rare condition, and treatment choices are frequently dependent on expert opinions. The objectives of the present study were to assess treatment modalities, disease course, and the factors influencing the outcome of patients with AOSD. METHODS: A multicenter study was used to reach sufficient patient numbers. The diagnosis of AOSD was based on the Yamaguchi criteria. The data collected included patient age, gender, age at the time of diagnosis, delay time for the diagnosis, typical AOSD rash, arthralgia, arthritis, myalgia, sore throat, lymphadenopathy, hepatomegaly, splenomegaly, pleuritis, pericarditis, and other rare findings. The laboratory findings of the patients were also recorded. The drugs initiated after the establishment of a diagnosis and the induction of remission with the first treatment was recorded. Disease patterns and related factors were also investigated. A multivariate analysis was performed to assess the factors related to remission. RESULTS: The initial data of 356 patients (210 females; 59%) from 19 centers were evaluated. The median age at onset was 32 (16-88) years, and the median follow-up time was 22 months (0-180). Fever (95.8%), arthralgia (94.9%), typical AOSD rash (66.9%), arthritis (64.6%), sore throat (63.5%), and myalgia (52.8%) were the most frequent clinical features. It was found that 254 of the 306 patients (83.0%) displayed remission with the initial treatment, including corticosteroids plus methotrexate with or without other disease-modifying antirheumatic drugs. The multivariate analysis revealed that the male sex, delayed diagnosis of more than 6 months, failure to achieve remission with initial treatment, and arthritis involving wrist/elbow joints were related to the chronic disease course. CONCLUSION: Induction of remission with initial treatment was achieved in the majority of AOSD patients. Failure to achieve remission with initial treatment as well as a delayed diagnosis implicated a chronic disease course in AOSD.

Monoclonal anti-TNF antibodies can elevate hemoglobin level in patients with ankylosing spondylitis.

UNLABELLED: Anemia is one of the extra-articular findings of ankylosing spondylitis (AS), and anti-TNF therapy has been shown benefit in patients with anemia associated AS. In this study, we aimed to evaluate and compare the effects of biological and non-biological agents on hemoglobin levels in AS patients. One hundred consecutive patients who fulfilled ASAS criteria for AS were included in the study. Fifty-four of the patients treated with anti-TNF agents (20 patients treated with infliximab, 20 patients with adalimumab, and 14 patients with etanercept), and 46 patients treated with non-steroidal anti-inflammatory drugs and/or other disease modifying anti-rheumatic drugs. The C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), hemoglobin (HGB), hematocrit (HCT) counts, and BASDAI scores were compared before starting therapy and at 52 weeks. There was no statistically significant difference between patients about demographical data (age, sex) and disease age (p > 0.05 for all). Significant difference was determined between HGB, HCT, CRP, ESR, and BASDAI values before and after therapy (for infliximab p: 0.001; 0.000; 0.000; 0.000; 0.000, respectively, and for adalimumab p: 0.017; 0.03; 0.001; 0.002; 0.000, respectively). In etanercept group, there was no significant difference in HGB values, when compared with before starting therapy and at 52 weeks (p > 0.05). In the group of treated with non-biological agents, ESR values and BASDAI scores showed distinctive improvement after 52 weeks of therapy, but was not a significant difference in hemoglobin and hematocrit values. CONCLUSION: Anti-TNF-alpha therapy with monoclonal antibodies (adalimumab and infliximab) did not only suppress disease activity but also provided a significant improvement in HGB levels. In the groups of treated with a TNF-alpha receptor antagonist (ETA) and non-biological agents, disease activity was suppressed, but there was not founded significant improvement in HGB levels after 52 weeks. Different outcomes of anti-TNF agents may be associated with their different effect mechanisms.

The effect of TNF-alpha blockers on psychometric measures in ankylosing spondylitis patients: a preliminary observation.

There is a high co-morbidity between chronic inflammatory disorders and depression. Proinflammatory cytokines like TNF-α seem to play a central role in the pathogenesis of these disorders, and its neutralization provides a potent treatment for inflammatory disorders. Few studies showed that TNF-α blockers also caused an improvement in depressive symptoms associated with these chronic inflammatory disorders. To evaluate the effectiveness of TNF-α blockers on symptoms of ankylosing spondylitis (AS), depression, anxiety and quality of life, 9 AS patients resistant to classical therapy were enrolled and followed-up at 2nd and 6th weeks after a TNF-α blocker was started. Hamilton Depression and Anxiety Scales (HAM-D, HAM-A), Hospital Depression and Anxiety Questionnaire (HAD), Quality of Life Scale (SF36) and AS severity index (BASDAI) were applied to the patients at weeks 0, 2 and 6. ESR and CRP were evaluated to monitor biological disease activity. There was a significant reduction in HAM-D (p = 0.00), HAM-A (p = 0.00), HAD anxiety scores (p = 0.02) and a significant improvement in SF36 physical function (p = 0.00), physical role limitations (p = 0.00), bodily pain (p = 0.05), general health (p = 0.01), vitality (p = 0.03) and emotional role limitations (p = 0.00) subscales, BASDAI scores (p = 0.00), ESR (p = 0.00) and CRP (p = 0.00). Change in clinical disease activity (BASDAI) was not correlated with change in depression-anxiety scores, while change in biological disease activity (CRP) was correlated with change in depression-anxiety scores. TNFα blockers may have a potential antidepressant effect besides its anti-inflammatory effect that seems to be independent of its clinical effect.

The cost of care of rheumatoid arthritis and ankylosing spondylitis patients in tertiary care rheumatology units in Turkey.

OBJECTIVES: To determine the direct and indirect costs due to rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients in Turkey. METHODS: An expert panel was convened to estimate the direct and indirect costs of care of patients with RA and AS in Turkey. The panel was composed of 22 experts chosen from all national tertiary care rheumatology units (n=53). To calculate direct costs, the medical management of RA and AS patients was estimated using 'cost-of-illness' methodology. To measure indirect costs, the number of days of sick leave, the extent of disability, and the levels of early retirement and early death were also evaluated. Lost productivity costs were calculated using the 'human capital approach', based on the minimum wage. RESULTS: The total annual direct costs were 2,917.03 Euros per RA patient and 3,565.9 Euros for each AS patient. The direct costs were thus substantial, but the indirect costs were much higher because of extensive morbidity and mortality rates. The total annual indirect costs were 7,058.99 Euros per RA patient and 6,989.81 for each AS patient. Thus, the total cost for each RA patient was 9,976.01 Euros and that for an AS patient 10,555.72 Euros, in Turkey. CONCLUSIONS: From the societal perspective, both RA and AS have become burden in Turkey. The cost of lost productivity is higher than the medical cost. Another important conclusion is that indirect costs constitute 70% and 66% of total costs in patients with RA and AS, respectively.

Serious menstrual bleeding associated with use of TNF alpha blocker: two cases.

Menstrual disorders associated with the use of TNF alpha blocker have been rarely reported. Herein, we reported two cases aged 31 and 41, presenting with excessive menstrual bleeding occured after adalimumab administration which was subsequently discontinued.

Bronchocentric granulomatosis in a patient with rheumatoid arthritis.

Bronchocentric granulomatosis is an uncommon entity which has no specific clinical, radiological and immunological features. It is usually diagnosed at morphological examination of biopsy or resected lung material. Aetiology of bronchocentric granulomatosis is unclear. A 49-year-old female patient, who was followed up with diagnosis rheumatoid arthritis in our outpatient clinic, presented with right lobe nodular lesion in chest radiography. Right thoracotomy and wedge resection was performed. Pathological examination revealed bronchocentric granulomatosis. Bronchocentric granulomatosis has been rarely reported in rheumatoid arthritis. This case might be a proof that bronchocentric granulomatosis may be one of the respiratory manifestations of rheumatoid arthritis.

Recent advances in the diagnosis and therapy of large vessel vasculitis.

Large vessel vasculitis (LVV), including Takayasu arteritis (TAK) and giant cell arteritis (GCA), causes granulomatous vascular inflammation mainly in large vessels, and is the most common primary vasculitis in adults. Vascular inflammation may evoke many clinical features including vision impairment, stroke, limb ischemia, and aortic aneurysms. The best way to diagnose LVV is to combine medical history, physical examination, various laboratory tests, and imaging modalities. Progress in imaging modalities facilitated early diagnosis and follow­up of the disease activity. Conventional angiography is no longer the gold standard for the diagnosis of TAK. Similarly, temporal artery biopsy is no longer the only tool for diagnosing cranial GCA. In selected cases, color Doppler ultrasound may be used for this purpose. Despite some similarities, TAK and GCA differ in many aspects and they are different diseases. They also have different clinical subtypes. The presence of aortitis does not always implicate the diagnosis of TAK or GCA; infectious aortitis, as well as noninfectious aortitis associated with other autoimmune rheumatic diseases should be excluded. Treatment of LVV includes glucocorticoids (GCs), conventional immunosuppressive agents, and biological drugs. Tumor necrosis factor inhibitors are ineffective in GCA but effective in TAK. On the other hand, tocilizumab may be used to treat both diseases. Promising targeted therapies evaluated in ongoing clinical trials include, for example, anti­IL­12/23 (ustekinumab), anti­IL­17 (secukinumab), anti­IL­1 (anakinra), anti­IL­23 (guselkumab), anti­cytotoxic T­lymphocyte antigen 4 (abatacept), Janus kinase inhibitors (tofacitinib and upadacitinib), anti­granulocyte / macrophage colony­stimulating factor (mavrilimumab), and endothelin receptor (bosentan) therapies.

Pseudo-pseudo Meigs syndrome developed under the leflunomide therapy.

Pseudo-pseudo Meigs syndrome or Tjalma syndrome is characterized by increased CA-125 level, pleural effusion and ascites in systemic lupus erythematosus (SLE) patients without over tumor. The disorder is relatively rare and it has been reported usually in SLE patients with impaired renal functions. Herein, we present a case of a 47-year-old female patient who developed Tjalma syndrome after administration of leflunomide for rheumatoid arthritis. Surprisingly renal functions of our patient were found in normal limits. This is the first case of Tjalma syndrome that is developed in normal renal functions and the probable role of leflunomide therapy is discussed.

Anaplastic large cell lymphoma in a patient with rheumatoid arthritis.

It is known that patients with rheumatoid arthritis (RA) have an increased risk for non-Hodgkin's lymphomas in comparison with the general population. Although increased risk of lymphoma is attributed to the disease activity, the drugs used in the therapy of RA may also cause increased risk of malignancy. Herein, we report on an RA patient who developed non-Hodgkin's lymphoma after methotrexate therapy and review the literature about it. A 74-year-old man with RA had been treated with low-dose methotrexate and subsequently developed anaplastic large cell lymphoma of the T-cell phenotype. Anaplastic large cell lymphoma has been reported rarely in rheumatoid arthritis.

Interleukin-1 Inhibitors and Vaccination Including COVID-19 in Inflammatory Rheumatic Diseases: A Nonsystematic Review.

Newly emerging variants of coronavirus 2 (SARS-CoV-2) raise concerns about the spread of the disease, and with the rising case numbers, the Coronavirus disease 2019 (COVID-19) remains a challenging medical emergency towards the end of the year 2021. Swiftly developed novel vaccines aid in the prevention of the spread, and it seems that a specific cure will not be at hand soon. The prognosis of COVID-19 in patients with autoimmune/autoinflammatory rheumatic diseases (AIIRD) is more severe when compared to the otherwise healthy population, and vaccination is essential. Evidence for both the efficacy and safety of COVID-19 vaccination in AIIRD under immunosuppression is accumulating, but the effect of Interleukin-1 on vaccination in general and in AIIRD patients is rarely addressed in the current literature. In light of the current literature, it seems that the level of agreement on the timing of COVID-19 vaccination is moderate in patients using IL-1 blockers, and expert opinions may vary. Generally, it may be recommended that patients under IL-1 blockade can be vaccinated without interrupting the anti-cytokine therapy, especially in patients with ongoing high disease activity to avoid disease relapses. However, in selected cases, after balancing for disease activity and risk of relapses, vaccination may be given seven days after the drug levels have returned to baseline, especially for IL-1 blocking agents with long half-lives such as canakinumab and rilonacept. This may help to ensure an ideal vaccine response in the face of the possibility that AIIRD patients may develop a more pronounced and severe COVID-19 disease course.

Pathogenesis and treatment of cytokine storm in COVID-19.

COVID-19 is a viral infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that killed a large number of patients around the world. A hyperinflammatory state resulting in a cytokine storm and adult respiratory distress syndrome seems to be the major cause of the death. Many mechanisms have been suggested in the pathogenesis of COVID-19 associated cytokine storm (COVID-CS). Insufficient viral clearance and persistence of a strong cytokine response despite inadequate antiviral immunity seem to be the main mechanisms underlying the pathogenesis. The diagnosis of COVID-19 is based on relatively constant clinical symptoms, clinical findings, laboratory tests, and imaging techniques, while the diagnosis of COVID-CS is a rather dynamic process, based on evolving or newly emerging findings during the clinical course. Management of COVID-19 consists of using antiviral agents to inhibit SARS-CoV-2 replication and treating potential complications including the cytokine storm together with general supportive measures. COVID-CS may be treated using appropriate immunosuppressive and immunomodulatory drugs that reduce the level of inappropriate systemic inflammation, which has the potential to cause organ damage. Currently corticosteroids, IL-6 blockers, or IL-1 blockers are most widely used for treating COVID-CS.

A practical approach for vaccinations including COVID-19 in autoimmune/autoinflammatory rheumatic diseases: a non-systematic review.

The COVID-19 pandemic has occupied the world agenda since December 2019. With no effective treatment yet, vaccination seems to be the most effective method of prevention. Recently developed vaccines have been approved for emergency use only and are currently applied to large populations. Considering both the underlying pathogenic mechanisms of autoimmune/autoinflammatory rheumatological diseases (AIIRDs) and the immunosuppressive drugs used in treatment, vaccination for COVID-19 deserves special attention in such patients. In this article, we aimed to give simple messages to the clinicians for COVID-19 vaccination in patients with AIIRDs based upon the current evidence regarding the use of other vaccines in this patient group. For this purpose, we conducted a "Pubmed search" using the following keywords: Influenza, Hepatitis B, Pneumococcal, and Shingles vaccines and the frequently used conventional and biologic disease-modifying antirheumatic drugs (DMARDs). Likewise, an additional search was performed for the COVID-19 immunization in patients with AIIRDs and considering such drugs. In summary, patients with AIIRDs should also be vaccinated against COVID-19, preferably when disease activity is under control and when there is no concurrent infection. Low-degree immunosuppression does not appear to decrease antibody responses to vaccines. Ideally, vaccinations should be done before the initiation of any biological DMARDs. Patients receiving rituximab should be vaccinated at least 4 weeks before or 6 months after treatment. Since tofacitinib may also reduce antibody responses, especially in combination with methotrexate, it may be appropriate to discontinue this drug before vaccination and to restart after 14 days of immunization. Key points • COVID-19 vaccinations should preferably be made during remission in patients with autoimmune/autoinflammatory rheumatological diseases. • Low-degree immunosuppression may not interfere with antibody response to vaccines. • Ideally, vaccinations should be made before the initiation of any biological DMARDs. • Timing of vaccination is especially important in the case of rituximab.

Werner's syndrome: a quite rare disease for differential diagnosis of scleroderma.

Werner's syndrome (WS) is an autosomal recessive disorder characterized by premature aging. The main features of the disease are scleroderma-like skin appearance, premature atherosclerosis, short stature, diabetes mellitus, early osteoporosis and early aging. Herein, we describe a patient with WS, who has scleroderma-like skin changes and discuss the literature about WS as a disease in the differential diagnosis of systemic sclerosis.

Erythema nodosum associated with granulomatous mastitis: report of two cases.

Granulomatous mastitis is a rare breast disease characterized by chronic inflammation. Clinical presentation of granulomatous mastitis usually mimics malignancy or infection. Coincidence of granulomatous mastitis and erythema nodosum is a quite rare feature. In this paper, we aimed to present two young women with granulomatous mastitis accompanied by erythema nodosum and successfully treated with corticosteroids. Granulomatous mastitis should be kept in the mind for differential diagnosis of erythema nodosum.

Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment.

COVID-19 infection has a heterogenous disease course; it may be asymptomatic or causes only mild symptoms in the majority of the cases, while immunologic complications such as macrophage activation syndrome also known as secondary hemophagocytic lymphohistiocytosis, resulting in cytokine storm syndrome and acute respiratory distress syndrome, may also occur in some patients. According to current literature, impairment of SARS-CoV-2 clearance due to genetic and viral features, lower levels of interferons, increased neutrophil extracellular traps, and increased pyroptosis and probable other unknown mechanisms create a background for severe disease course complicated by macrophage activation syndrome and cytokine storm. Various genetic mutations may also constitute a risk factor for severe disease course and occurrence of cytokine storm in COVID-19. Once, immunologic complications like cytokine storm occur, anti-viral treatment alone is not enough and should be combined with appropriate anti-inflammatory treatment. Anti-rheumatic drugs, which are tried for managing immunologic complications of COVID-19 infection, will also be discussed including chloroquine, hydroxychloroquine, JAK inhibitors, IL-6 inhibitors, IL-1 inhibitors, anti-TNF-α agents, corticosteroids, intravenous immunoglobulin (IVIG), and colchicine. Early recognition and appropriate treatment of immunologic complications will decrease the morbidity and mortality in COVID-19 infection, which requires the collaboration of infectious disease, lung, and intensive care unit specialists with other experts such as immunologists, rheumatologists, and hematologists.

Impairment of arterial distensibility in premenopausal women with systemic lupus erythematosus.

BACKGROUND AND AIM: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease affecting young women and is associated with increased frequency of atherosclerotic vascular diseases. Pulse wave velocity (PWV) is an index of arterial stiffness and a marker of cardiovascular events. This study aimed to investigate arterial distensibility using carotid-femoral (aortic) PWV measurements in premenopausal women with SLE. METHODS: We recruited 24 premenopausal women with SLE (SLE duration: 5.3+/-4.6 years) and 24 age- and sex-matched controls. Aortic PWV was determined by using an automatic device, the Complior Colson (France), which allowed on-line pulse wave recording and automatic calculation of PWV. RESULTS: The carotid-femoral PWV (8.98+/-2.05 vs. 8.05+/-0.94 m/s), systolic blood pressure (117.08+/-17.12 vs. 106.87+/-11.96 mmHg), pulse pressure (45.62+/-11.91 vs. 38.33+/-9.04 mmHg), heart rate (81.41+/-9.20 vs. 71.12+/-10.32 beat/min) and serum glucose levels (89.68+/-8.12 vs. 73.80+/-10.72 mg/dl) were significantly higher in premenopausal women with SLE, as compared with control subjects (p=0.04, p=0.02, p=0.02, p=0.001, p <0.001, respectively). We found a significant correlation between PWV and age, body mass index, waist--to-hip ratio, heart rate and blood pressure. CONCLUSION: Arterial distensibility is decreased in premenopausal women with SLE.

[Churg-Strauss syndrome associated with montelukast]. / Montelukast ile iliskili Churg Strauss sendromu.

A 47 year old woman who had a history of asthma for 15 years referred to our hospital because of infiltrates on her chest radiograph that not responded to antibiotic treatment. We found that she had eosinophilia in peripheral blood (38%) and bronchoalveolar lavage (54%), nasal polyposis, and transient pulmonary infiltrates, and in the base of these findings we diagnosed as Churg-Strauss Syndrome (CSS). She has been using montelukast for 2 years. By examining her previous medical records, we observed that while eosinophil rates in peripheral blood were normal before montelukast usage, after this therapy eosinophil rates were greater 10 percent. Therefore, we thought that CSS was to be associated with montelukast usage. After just montelukast therapy was discontinued, clinical and radiographic parameters and the eosinophil counts (20%) improved. We present this case of CSS associated with montelukast in whom spontaneous remission was observed without using corticosteroids and cytotoxic agents.