Haemophagocytic syndrome in rheumatic patients. A systematic review - PDF Document

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  1. European Review for Medical and Pharmacological Sciences 2012; 16: 1414-1424 Haemophagocytic syndrome in rheumatic patients. A systematic review M. ATTERITANO1, A. DAVID2, G. BAGNATO1, C. BENINATI3, A. FRISINA4, C. IARIA5, G. BAGNATO1, A. CASCIO6 1Department of Internal Medicine, University of Messina, Policlinico G. Martino, Messina, Italy 2Department of Neurosciences, Psichiatric and Anesthesiological Sciences, University of Messina, Italy 3Elie Metchnikoff Department, University of Messina, Messina, Italy 4Dipartimento Materno Infantile, Policlinico G. Martino, Messina, Italy 5Infectious Diseases Unit, Azienda Ospedaliera Piemonte-Papardo, Messina, Italy 6Tropical and Parasitological Diseases Unit, Department of Human Pathology, Policlinico G. Martino, Messina, Italy Abstract. – BACKGROUND: Hemophagocyt- ic lymphohistiocytosis (HLH), is a potentially fa- tal hyperinflammatory syndrome characterized fever, hepatosplenomegaly, and cytopenias. HLH can be either primary, with a genetic aetiology, or secondary, associated with malignancies, au- toimmune diseases, or infections. Among rheumatic disorders, HLH occurs most frequent- ly in systemic juvenile idiopathic arthritis. AIM: To draw attention on this severe syn- drome that may often go undiagnosed in patient with rheumatic diseases. MATERIALS AND METHODS: PubMed search was performed by combining the terms (haemophagocytic, haemophagocytosis, hemo- phagocytosis, hemophagocytic, erythrophagocy- tosis, macrophage activation syndrome) and (rheumatic, rheumatologic, arthritis, lupus, Sjö- gren’s syndrome, scleroderma, polymyositis, der- matomyositis, polymyalgia rheumatic, mixed con- nective tissue disease, polychondritis, sarcoido- sis, polyarteritis nodosa, Henoch-Schönlein, serum sickness, wegener’s granulomatosis, giant cell arteritis, temporal arteritis, Takayasu’s arteri- tis, Behçet’s syndrome, Kawasaki, Buerger’s). RESULTS: 117 papers describing 421 patients were considered. HLH was described in systemic lupus erythematosus in 94 patients, in Still’s dis- ease in 37 patients, in rheumatoid arthritis in 13 patients, in systemic juvenile arthritis in 219 pa- tients, in dermatomyositis in 7 patients, in Kawasaki disease in 25 patients, in systemic scle- rosis in 5 patients, in Behcet disease in one pa- tient, in polyarteritis nodosa in 6 patients, in anky- losing spondylitis in 2 patients, in mixed connec- tive tissue disease in one patient, in sarcoidosis in 5 patients, in Sjögren’s syndrome in 3 patients, in Wegener's granulomatosis in one patient, and in unclassifiable disorders in two patients. CONCLUSIONS: HLH occurring in the course of rheumatic diseases is an important and often underdiagnosed clinical entity, which can affect prognosis. Key Words: Hemophagocytic lymphohistiocytosis (HLH), Zoonoses, Developing countries, Epidemiology, Review. Introduction Rheumatic diseases are frequent chronic con- ditions that impose a great burden to society in terms of losses in quality of life and cumbersome dependency1. Although they are considered be- nign diseases as a whole, some rheumatic dis- eases may nevertheless be mortal, especially those characterized by severe inflammation2. Hemophagocytic lymphohistiocytosis (HLH), is a potentially fatal hyperinflammatory syn- drome that is characterized by histiocyte prolifer- ation and hemophagocytosis. The most typical presenting signs and symptoms are fever, he- patosplenomegaly, and cytopenias. Less frequently observed clinical findings are neurological symp- toms, lymphadenopathy, edema, skin rash, and jaundice3,4. Common laboratory findings include hypertriglyceridemia, hyperferritinemia, a coagu- lopathy with hypofibrinogemia, and elevated aminotransferases3,4. However, HLH should be di- agnosed using clinical criteria developed by the Study Group of the Histiocyte Society (Table I)5,6. Two forms of the syndrome have been well charac- terized: a familial HLH and secondary HLH. The diagnosis of familial HLH requires either a positive family history of HLH or the presence of genetic mutations, such as perforin gene mutations7. The pathogenesis is poorly understood. How- ever, the strong link between systemic inflam- matory syndrome response and haemophagocy- tosis coupled with peripheral T-cell expansion 1414 Corresponding Author: Antonio Cascio, MD; e-mail: acascio@unime.it

  2. Haemophagocytic syndrome in rheumatic patients. A systematic review Table I. HLH 2004 Diagnostic criteria (modified from ref.5,6). The diagnosis of HLH can be established if one of either 1 or 2 below is fulfilled: 1. A molecular diagnosis consistent with HLH 2. Diagnostic criteria for HLH are fulfilled (five out of the eight criteria below): • Fever • Splenomegaly • Cytopenias (affecting ≥ 2 lineages in the peripheral blood): – Hemoglobin < 90 g/l (in infants < 4 weeks: hemoglobin < 100 g/l – Platelets < 100.000/ml – Neutrophils < 1000/ml • Hypertriglyceridemia and/or hypofibrinogenemia: – Fasting triglycerides ≥ 265 mg/dl – Fibrinogen ≤ 1.5 g/L • Hemophagocytosis in bone marrow or spleen or lymphnodes • Low or absent NK-cell activity • Ferritin ≥ 500 µg/l • Soluble CD25 ≥ 2400 U/L Comments: 1. If hemophagocytic activity is not proven at the time of presentation, further search for hemophagocytic activity is en- couraged. If the bone marrow specimen is not conclusive, material may be obtained from other organs. Serial marrow aspirates over time may also be helpful 2. The following findings may provide strong supportive evidence for the diagnosis: (1) spinal fluid pleocytosis (mononu- clear cells) and/or elevated spinal fluid protein, (2) histological picture in the liver resembling chronic persistent hepati- tis (biopsy) 3. Other abnormal clinical and laboratory findings consistent with the diagnosis are: cerebromeningeal symptoms, lymph node enlargement, jaundice, edema, skin rash. Hepatic enzyme abnormalities, hypoproteinemia, hyponatremia, VLDL ↑, HDL ↓ and deficient natural killer (NK) activity often found in patients with HLH strongly supports the hypothesis of a defective regulation in the inflammatory and immune response8. Thus, as in infection-associated hyperinflammatory syn- dromes activation of receptors and cells of the innate immunity system is likely to play a major role in HLH9-12. Secondary HLH, called also macrophage acti- vation syndrome (MAS), may develop at any age and can occur during systemic infection, immun- odeficiency or malignancy3,14. Among rheumatic disorders, MAS occurs most frequently in sys- temic juvenile idiopathic arthritis (sJIA). In sJIA, MAS belongs to the clinical picture of disease being present in subclinical form in 30-40% of patients, whereas the overt form occurs in 10- 20%15. Moreover, in patients with sJIA, several mutations possibly related to HLH have been re- cently reported16,17. However, application of the HLH-2004 protocol to MAS/HLH secondary to sJIA may be imperfect. In fact, the clinical fea- tures of MAS/HLH secondary to sJIA, may dif- fer from those seen in other forms of HLH18. In addition, in recent years this syndrome has been increasingly reported in patients with juvenile systemic lupus erythematosus (SLE)19,20-22, Still’s disease21,23and other rheumatic disorders21,24-29. Because HLH is a serious condition that can follow a rapidly fatal course, its prompt recogni- tion is imperative30. The purpose of this system- atic review is to draw attention on this severe syndrome that may often go undiagnosed in pa- tient with rheumatic diseases. Literature Review PubMed search of human cases of HLH occurring during rheumatic diseases was performed by com- bining the terms (haemophagocytic, haemophagocy- tosis, hemophagocytosis, hemophagocytic, ery- throphagocytosis, macrophage activation syndrome) and (rheumatic, rheumatologic, arthritis, lupus, Sjö- gren’s syndrome, scleroderma, polymyositis, der- matomyositis, polymyalgia rheumatic, mixed con- nective tissue disease, polychondritis, sarcoidosis, polyarteritis nodosa, Henoch-Schönlein, serum sick- ness, Wegener’s granulomatosis, giant cell arteritis, temporal arteritis, Takayasu’s arteritis, Behçet’s syn- drome, Kawasaki, Buerger’s) for the period January 1990 to August 2012. References were also checked for relevant articles, including review papers. A study was considered eligible for inclusion in the systemat- ic review if it reported data on patients with rheumat- ic diseases who had microscopic signs of haemophagocytosis and/or fulfilled the diagnostic criteria of Study Group of the Histiocyte Society. 1415

  3. M. Atteritano, A. David, G. Bagnato, C. Beninati, A. Frisina, C. Iaria, G. Bagnato, A. Cascio Results and are listed in Table II together with a brief comment. HLH was described in systemic lupus erythematosus (SLE) (94 patients)19-23,31-57, Still’s disease (37 patients)21,23,58-73, rheumatoid arthritis (RA) (13 patients)21,23,74-83, systemic juvenile arthri- tis (S-JRA) (219 patients)15,22,30,31,48,84-102dermato- myositis (7 patients)24,103-108, Kawasaki disease (25 patients)25,48,109-123, systemic sclerosis (SSc) (5 pa- The PubMed search identified 580 papers. Duplicate publications or paper not reporting clinical cases were excluded. After scrupulous analysis, 117 papers describing 421 patients were further evaluated. These papers have been categorized on the basis of rheumatic diseases Table II. Papers describing cases of HLH in the course of rheumatic diseases. Systemic disease N° parer/ cases References and note SLE 19Retrospective study, 15 cases; 20Retrospective study, 15 patients; 21retrospecive study, 14 cases; 22retrospective study, 19 children; 31retrospective, 2 children; 233 cases; 3218-year old female, lupus mesenteric vasculitis, EBV reactivation; 3336 year-old woman; 34,35antiphospholipid antibodies; 36,3721-year-old man, HLH and SLE simultaneously; 38,39,4058-year-old female, interstitial pneumonia, CMV. Gancyclovir resolved the pancytopenia, pneumonia, and fever; 41 non-Hodgkin’s lymphoma; 42,43,4435-year-old woman, Graves’ disease, parvovirus B19; 4528-year-old woman; 4638-year-old woman; 47EBV lupus nephritis; 48,4944-year-old woman, corticosteroid and cyclophosphamide, lupus nephritis, CMV colitis; 50CMV-induced hemophagocytic syndrome and colitis; 51,52Successful use of etanercept; 53,54Successful use of infliximab; 55pregnant patient, preeclampsia cerebral hemorrhage; 562 cases, one after parturition, the other after abortion; 5733-year-old woman, 3 weeks after parturition 58Adult patient, interstitial pneumonia with pneumomediastinum/recurrent pneumothorax; 5949-year-old woman; 608-year-old child, acute respiratory failure, coagulopathy 61after initiation of sulfasalazine; 622 cases; 6346-year old woman, high-dose steroid treatment; 64CMV; 6550-year-old female, steroids and antimalarial drugs; 66six patients, one death due to pneumonia, one etanercept; 21retrospective study 4 cases; 23retrospective study 4 cases; 67,68,69after initiation of etanercep; 7016-year-old female successful use of etanercept; 718 patients, successful use of infliximab in 2 cases; 72adult, liver transplant recipient; 73after initiation of adalimumab, histoplasmosis. 74,75After initiation of infliximab; 76after initiation of etanercept; 7776-year-old man, oral prednisolone and methotrexate; 78leflunomide; 79,80,8163-year-old female; 21retrospecive study 2 cases; 23one case; 82visceral leishmaniasis; 8362-year-old Japanese woman successfully treated with etanercept 84Hypocomplementemia 3 cases; 22retrospective study, 102 children 854 patients; 86,48,87misdiagnosed as Kawasaki disease; 8812 year old female child, fatal; 89child after etanercept; 90,3038 children; 9113 children; 92,939 children, etanercept potentially useful for obtaining remission in children not responding to steroids and cyclosporin A; 9413-month-old boy; 95five children; 314 children; 15Occult MAS in patients who undergo BMA; 967 cases in retrospective study; 31retrospective, 18 children; 97hepatitis A- report of 2 cases; 98,99after initiation of etanercept; 100successfully treated with etanercept; 101,102successfully treated with anakinra. 103Central nervous system lesions and review eight literature cases of dermatomyositis and HLH; 2417-year-old woman, fatal dermatomyositis with anti-Mi2 antibodies; 104,1057 years old boy, plasmapheresis; 106platelet-specific hemophagocytosis; 107,10860 year old male. 109,253-year-old girl with incomplete Kawasaki disease; 1106-year-old boy; 111retrospective study 7 cases; 11218-month-old child, respiratory failure, fatal; 113-1152 cases; 116,48,117autoimmune hemolytic anemia; 11832-month-old Japanese boy; 1192 cases; 12014-year-old boy; 121,1225-year-old girl, response to gamma-globulin therapy, ischemic colitis; 123infant of 7 weeks after clinical response to treatment, suddenly died from a myocardial infarction at 11 weeks. 32 94 Still’s disease 18 37 RA 112 13 S-JRA 23 219 Dermatomyositis 7 7 Kawasaki disease 17 25 Table Continued 1416

  4. Haemophagocytic syndrome in rheumatic patients. A systematic review Table II (Continued). Papers describing cases of HLH in the course of rheumatic diseases. Systemic disease N° parer/ cases References and note SSc 26After initiation of etanercept; 124MPO-ANCA positive vasculitis; 21retrospecive study 1 case; 12533-year-old woman, etoposide; 12632-year-old woman 2743-year-old man, EBV 2873-year-old woman, EBV reactivation; 21retrospecive study 2 cases; 31retrospective, 2 children127 128Ankylosing spondylitis, infliximab; 12942-year-old woman 5 5 Behcet disease Polyarteritis nodosa Ankylosing spondylitis Mixed connective tissue disease Sarcoidosis 1 4 1 6 2 2 21Retrospecive study 1 case; 1 1 21Retrospecive study 1 case; 130,13142-year-old Indian patient with a 7-year-history, of sarcoidosis miliary tuberculosis, steroid, fatal; 132,133chronic steroid treatment, Histoplasma capsulatum 21Retrospecive study 1 case; 134one case; 23one case 5 5 Sjögren’s syndrome Wegener’s granulomatosis Unclassifiable disorders 3 3 29Azathioprine, prednisone, disseminated infection with herpes simplex virus-1. 1 1 31Retrospective, 2 children 1 2 RA = Rheumatoid arthritis; SLE = Systemic lupus erythematosus; S-JRA = Systemic juvenile arthritis; SSc = Systemic sclerosis. tients)21,26, 124-126, Behcet disease (one patient)27, pol- yarteritis nodosa (6 patients)21,28,31,127, ankylosing spondylitis (2 patients)128,129, mixed connective tis- sue disease (one patient)21, sarcoidosis (5 pa- pers)21,130-133, Sjögren’s syndrome (3 patients)21,23,134, Wegener’s granulomatosis (one patient)29, and un- classifiable disorders (two patients)31. Active infection was clearly reported in 16 cases of HLH: (4 CMV40,49,50,64, 4 EBV27,28,32,47, one HSV-129, one parvovirus B194, two hepatitis A8, one miliary tubercolosis12, 2 histoplasmo- sis73,133, one visceral leishmaniasis82. An active infection triggered or was a concause of HLH in 5/94 cases of SLE, 2/37 cases of Still’s disease, 1/13 cases of RA, 1/1 case of Behcet disease, 1/2 cases of polyarteritis nodosa, 2/5 of sarcoidosis, and 1/1 case of Wegener’s granulomatosis. In 20 cases HLH might have been triggered by immunosuppressive treatment of the rheumatic condition, including adalimumab73, inflix- imab74,75,128, etanercept26,66,68,69,76,83,89,98,99, lefluno- mide78, sulfasalazine61, azathioprine29, methotrex- ate77. Other possible triggers/cofactors were non- Hodgkin’s lymphoma41, and antimalarial drugs65. Of note, in 18 cases biologicals were used for HLH treatment including infliximab in three cas- es53,54etanercept in 13 cases51,52,70,93,100and anakinra in two cases101,102. Among SLE patients, HLH occurred in 2 cas- es after parturition, in 1 case after abortion and in 1 pregnant patient causing preeclampsia and cerebral hemorrhage55-57. Discussion Secondary HLH is a rare but potentially fatal condition associated with infections, transplanta- tion, cancers, and treatment of a variety of condi- tions including cancer and HIV/AIDS. Infections are the most common. Our Medline search iden- tified 421 well-documented cases of HLH occur- ring in the course of rheumatic diseases. Our review suggests that secondary HLH is more common than previously recognized, and demon- strates how HLH can complicate the course of not only S-JRA, with which it may be constitutively as- sociated, but also of virtually any rheumatic dis- ease. Parodi et al. proposed new diagnostic guide- lines for juvenile SLE indicating that bone marrow aspiration for evidence of macrophage hemophago- cytosis may be required in doubtful cases30. HLH should be recognized as a severe, poten- tially life-threatening complication of rheumatic diseases. Since HLH has a mortality rate of 8% to 22%31, early diagnosis and immediate treatment 1417

  5. M. Atteritano, A. David, G. Bagnato, C. Beninati, A. Frisina, C. Iaria, G. Bagnato, A. Cascio are crucial. In patients with systemic-onset JRA or SLE, HLH needs to be differentiated from an acute exacerbation of the underlying disease through clinical and laboratory findings. Diagnosis of HLH in systemic-onset JRA and SLE is compounded by the fact that some of the typical features, such as fever, splenomegaly, and anemia, are also seen in active systemic-onset JRA and during acute exac- erbation of SLE. Other important conditions to consider in differential diagnosis include infections and adverse effects of medications. A number of triggers have been related to the development of HLH, including viral infectious agents, in particular EBV and CMV, bacteria, parasites (leishmaniasis), fungi, and also medica- tions, such as methotrexate, sulfasalazine, and anti-TNF-α (etanercept, infliximab)135-142. How- ever, HLH may occur without any identifiable precipitating factor. Although the cause of the HLH is unknown, dysregulation of macrophage- lymphocyte interactions with subsequent increas- es in the levels of both T-cell-derived and macrophage- derived cytokines, particularly TNF-α, interleukin (IL)-1, IL-6, interferon gam- ma (IFN-γ), soluble IL-2 receptor (sIL-2R), and soluble TNF receptors (sTNFRs), could be in- volved in this syndrome143. Such dysregulation leads to an intense systemic inflammatory reac- tion. Our data shown that S-JRA and SLE pre- dominated among the rheumatic disease compli- cated by HLH. In patients with S-JRA it was pro- posed that severely reduced expression of per- forin on CD8 T cells and natural killer (NK) cells, abnormal granzyme B expression, and low NK cell activity are linked with increased inci- dence of HLH144. SLE is an immunologically mediated disease; therefore either an immune complex-mediated or an autoantibody-mediated mechanism could participate in the pathogenesis of MAS. Other evidence suggests that cytokines, including IL-1b, IL-2, IFN-γ, IL-6, M-CSF (macrophage colony-stimulating factor), and TNF-α, play important roles in the pathogenesis of MAS associated with SLE, systemic sclerosis with vasculitis, and Kawasaki disease39,118,124,145. Although an abnormal immunoregulation of T cells resulting in hypercytokinemia has been pro- posed to contribute to the pathogenesis of HLH, the type of cytokine involved could depend on the underlying disease. Recently, other abnormalities have been demonstrated, including extensive ex- pression of the hemoglobin scavenger receptor (CD163) in an SLE patient with HLH and a severe IL-18/ IL-18BP imbalance in HLH secondary to other conditions. Expression of CD163 and deter- mination of serum levels of soluble CD163 have been found to be useful clinical markers of HLH and other disorders associated with overwhelming macrophage activity48,146while IL-18/IL-18BP im- balance may result in Th-1 lymphocyte and macrophage activation, which escapes control by NK-cell cytotoxicity and may allow for secondary HLH in patients with underlying diseases147,148. Our data showed 20 cases in which HLH ap- peared triggered by anti-TNF-α treatment, it is a paradox, in fact as TNF-α seems to have a piv- otal role in HLH and the use of inhibitors of TNF-α to treat this syndrome has been pro- posed100,93(notably, we found 18 cases in which biological were used in the treatment of HLH). It is possible that immunosuppression induced by anti-TNF-α treatment may favor the occurrence of serious infections leading, in turn, to HLH. Furthermore, it should stressed that the identi- fication of hemophagocytosis in bone marrow as- pirate (BMA) represents only one of 5/8 criteria needed for the diagnosis of HLH. Gupta et al149 pointed out that the number of hemophagocytosis at initial BMA is often low and variable, con- firming that a BMA lacking hemophagocytosis does not rule out the diagnosis of HLH. Further- more, a diagnosis of primary HLH should always be excluded. In fact, with improved molecular di- agnostics it is recognized that cases of adult on- set HLH that had previously been considered secondary may represent a primary HLH with underlying mutation in the PFR1 gene150,151. Treatment of HLH in patients with rheumatic diseases has not been standardized yet, but it commonly includes a variety of agents such as corticosteroids, cyclosporine A, intravenous im- munoglobulins, etoposide, cyclophosphamide, anti-TNF-α, methotrexate, G-CSF (granulocyte colony-stimulating factor), and in some cases plasmaphereis. Infectious causes should be treat- ed promptly along with administering supportive care. Treatment should be started without delay, yet it should be kept in mind that the use of im- munosuppression may further delay the diagno- sis and definitive treatment Conclusions HLH occurring in the course of rheumatic dis- eases is an important and often underdiagnosed clinical entity, which can affect prognosis. Physi- cians must keep the symptoms of HLH in mind, 1418

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