Titel: Thrombotische Mikroangiopathie Bei Kranken Mit Adultem M.Still: Fallbericht Und

Title: Thrombotic microangiopathy in adult onset Still's disease: case report and review of the literature

Titel: Thrombotische Mikroangiopathie bei Kranken mit adultem M.Still: Fallbericht und

Literaturübersicht

INTRODUCTION:

Adult onset Still's disease (AOSD) is a systemic disorder of unknown origin without any pathognomonic signs. Yamaguchi and the Adult Still's Disease Research Committee studied 90 patients with adult onset Still's disease and proposed eight criteria, which include: fever of ≥ 39ºC lasting ≥ 1 week, arthralgias lasting ≥ 2 weeks, typical rash, and leukocytosis (≥104/ml including

>80% granulocytes) as major signs, and sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction, and the absence of rheumatoid factor and antinuclear antibodies, as minor criteria. Five criteria, including at least two major ones, after a strict exclusion process, yielded the diagnosis with 96.2% sensitivity and 92.1% specificity (1).

Thrombotic microangiopathies (TMA) include several diseases characterized by a microangiopathic hemolytic anemia, profound thrombocytopenia and organ failure of variable severity. Together with hemolytic-uremic syndrome (HUS), thrombotic thrombocytopenic purpura

(TTP) belongs to the category of primary (idiopathic) thrombotic microangiopathies, which have to be distuinguished from secondary TMA forms with underlying or associated disorders, such as: neoplasia, eclampsia, preeclampsia, autoimmune diseases (antiphospholipid antibody syndrome, systemic lupus erythematosus, and others), HIV infection, drugs, and others. Thrombotic thrombocytopenic purpura is associated with a severe deficiency of a von Willebrand factor- cleaving protease (termed „ADAMTS13“ as an acronym for a disintegrin and metalloprotease with thrombospondin-1- like domains), a plasma enzyme specifically involved in the clevage of unusually large (UL) von Willebrand factor (vWF) multimers into smaller and less adhesive vWF forms. Failure to degrade these UL-vWL multimers leads to excessive platelet aggregation and microvascular occlusion. ADAMTS13 deficiency is related to mutation of the encoding gene in hereditary TTP, whereas in acquired forms it results from autoantibodies that may alter the 2

protein function. This latter finding suggests that acquired idiopathic thrombotic thrombocytopenic purpura is correspondent to an autoimmune disease. Severe deficiency of ADAMTS13 activity is present in many, but not all patients with idiopathic TTP, but patients with secondary thrombotic thrombocytopenic purpura associated with autoimmune disorders may also have a severe deficiency of ADAMTS13 activity.

Thrombotic thrombocytopenic purpura was originally described by Moschowitz in 1925 as a disease characterized by unique pathological findings of hyaline thrombi in many organs (2).

Amorosi and Ultmann defined the classic pentad of clinical features: thrombocytopenia, microangiopathic hemolytic anemia, acute renal impairment, neurologic abnormalities, and fever

(3). The availability of curative treatment has created an urgency for diagnosis and therefore the stringency of diagnostic criteria has decreased. At the present time, only the dyad of otherwise unexplained thrombocytopenia and microangiopathic hemolytic anemia (MAHA) are sufficient to establish the diagnosis of thrombotic microangiopathy and initiate treatment (4).

Both TTP and HUS share similar clinical and pathological findings of hyaline thrombi with microvascular occlusions in many organs, such as kidney, brain, or lung. Neurological manifestations are the predominant features in thrombotic thrombocytopenic purpura, whereas renal failure predominates in hemolytic uremic syndrome (5).

Based on information from the Oklahoma TTP-HUS Registry, the annual incidence of patients with a clinical diagnosis of TTP, standardized to United States population, is 11.29/10 6

(6). 3

CASE REPORT:

A 34-year-old caucasian man was admitted to the hospital with a 4-week history of fever, arthralgias, diffuse muscle pain, and skin rash. At presentation, he did not use any drugs, except those he had prevously received a day before admittance; glucocorticoids, antihistamins, gentamicyn and, calcium, for the skin rash.

Physical examination revealed a temperature of 39ºC, bilateral inflammation of the carpometacarpal joints, cervical, axillar, and inguinal lyphadenopathy, and a nonpruritic, macular, confluating rash, behind the ears, on forehead and on the extremities.

Initial laboratory findings: erythrocyte sedimentation rate (ESR) 89mm/h (normal 3-23 mm/h); C-reactive protein 148 mg/l (normal <5.0 mg/l); white blood cell count (WBC) 17.3x109/l

(normal 4-10) with a differential count of: 87.8 % neutrophils, 8 % lymphocytes, 2.7 % monocytes,

1.2 % eosinophils, and 0.3 % basophils; red blood cell count (RBC) 4.05x10 12/l (normal 4.4-5.8); normocytic anemia with a hemoglobin of 11.8 g/dl (normal 14-18 g/dl); platelets 561x10 9/l (normal

140-440). Serum ferritin level was higly elevated (7999 µg/l [normal 10-300 µg/l] or in SI units

17973 pmol/l), protein level was 80g/l (normal 65-85 g/l). The renal function tests were all normal.

Other biochemical values which were revealed to be elevated were: aspartate aminotransferase

(AST 56 U/l), alanine aminotransferase (ALT 79 U/l), lactic acid dehydrogenase (LDH 565 U/l), gamma-glutamyl transferase (GGT 312 U/l), alcal phosphatase (AP 187 U/l) and a normal total bilirubin level (normal AST 7-49 U/l, ALT 7-49 U/l, LDH 170-430 U/l, GGT 6-56 U/l, AP 43-120 U/l

). Laboratory evaluation for systemic or malignant diseases : Latex rheumatoid factor, Waaler-

Rose, antibodies to nuclear antigen, dsDNA, cardiolipine, cryoglobulins, complement levels, serum angiotensine-converting enzyme (ACE), and tumor markers, were negative or within a normal range.

Bone marrow aspiration, performed from the sternum, showed increased cellularity as well as increased granulocytopoesis, without other morphological abnormalities. Lymphoid node aspiration revealed reactive lymph nodes. Cervical lymph node biopsy revealed nonspecific hyperplasia. Blood and urine cultures were negative. Serological evaluation for hepatitis B and C, 4

HIV infection, and brucellosis was negative. Tuberculosis was ruled out by mycobacteria growth indicator tube and Amplified Mycobacterium Tuberculosis Direct Test. Serological evaluation for

A. fumigatus and C. neoformans was negative, and a positive small titre of C.albicans was revealed (indirect hemaglutination 1:320). MSCT of abdomen, echocardiogram, and muscle biopsy, were unremarkable. Skin biopsy and direct immunofluorescence revealed hypersensitive reaction. Extensive diagnostic workout excluded infectious, malignant, and hematological disease as causes of the symptoms.

The patient was diagnosed with adult onset Still's disease, which was affirmed by

Yamaguchi criteria (6) in the presence of 4 major criteria (fever spike, arthralgia, typical rash and leukocytosis), and 3 minor criteria (lymphadenopathy, liver dysfunction, absence of rheumatoid factor and antinuclear antibodies). The patient was treated with intravenous glucocorticoids

(methylprednisolonum), and a few days later general status was significantly improved. The fever had resolved and laboratory findings were in regression. Five months after presentation, the patient was doing well on low-dose oral glucocorticoids and we initiated chloroquine phosphate

(250 mg/day). After three more months the glucocorticoid therapy was excluded.

Nine months after the initial symptoms of adult Still’s disease, and after four months of continuous therapy with chloroquine phosphate, the patient was admitted to the hospital for asymptomatic thrombocytopenia. Physical status was unremarkable except for the pallor of skin and mucosa. Neurological abnormalities were not observed.

Laboratory evaluation revealed: platelets 27 x109/l, RBC 2.89x1012/l, Hct 0.279 L/L

(normal 0.41-0.55 L/L), Hb 94 g/l (9.4 g/dL), Rtc 133 x109/l (normal 22-97) or in SI units 0.042,

WBC 6.5 x109/l, ESR 23 mm/h, C-reactive protein 4.1 mg/l. LDH, total bilirubin and indirect bilirubin levels were elevated (LDH 690 U/l [normal 170-430 U/l], total bilirubin 33,2 µmol/l [normal

3.4-20.5 µmol/l], indirect bilirubin 28.3 µmol/l [normal 3.4-15.4 µmol/l]). Haptoglobin level was decreased to 0.1 g/l (normal 0.3-2 g/l) or in SI units 1 µmol/l. AST, ALT, GGT, AP and serum uric acid levels were normal. Serum ferritin level was markedly elevated to 1185 µg/L. Blood urea nitrogen and creatinine levels were within normal range (Cr 90 µmol/l [normal 53-106 µmol/l] and 5

BUN 3.9 mmol/l [normal 3.3-7.8 mmol/l]). The patient’s potassium level was decreased 3.8 mmol/l

(normal 4.1-5.5 mmol/l) but other electrolytes were within normal range. Urine analysis revealed

4-5 red blood cells, and 2-3 leukocytes per high power field, and proteinuria was absent. Urine culture was negative. Coagulation profile was within normal limits. The serum anticardiolipin antibodies, Coombs’ tests (direct and indirect), antinuclear and anti dsDNA antibodies, were all negative.

Peripheral blood smear showed polychromasia, aniso/poikylocytosis, frequent schistocytes, and a few thrombocytes. A bone marrow aspirate showed hypercellularity of two series, erythrocytopoesis (normoblastic, partially macroblastic) and an increase in megakaryocytes. Electrocardiogram revealed a right bundle branch block. Thoracic radiography and abdominal ultrasonography were unremarkable. All the above findings indicated that microangiopathic hemolytic anemia was not caused by disseminated intravascular coagulation

(DIC) or antiphospholipid syndrome (APS).

The association of unexplained microangiopathic hemolytic anemia and thrombocytopenia led to the clinical diagnosis of thrombotic microangiopathy, which is sufficient to initiate treatment. The patient was promptly treated with daily exchange plasmapheresis (5 sessions), fresh frozen plasma infusions (each approximately 3000 ml), intravenous glucocorticoids (methylprednisolonum up to 125 mg/day) and acetylsalicylic acid (50 mg/day).

After five plasmapheresis sessions, the platelet count reached 270 x10 9/l and his ferritin and LDH levels both decreased. The patient was discharged in good condition, on methylprednosolonum and acetylsalicylic acid. Two years after presentation there was no relapse of thrombotic microangiopathy. 6

DISCUSSION:

Medline/Pubmed was searched for the years 1966-2008 for an association of adult onset

Still's disease and thrombotic microangiopathies using the keywords: thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, chloroquine, and adult onset Still's disease.

This case is the fifteenth report in the literature on thrombotic microangiopathies associated with adult onset Still's disease (Table 1) (7-19). In Table 1, the main characteristics of patients with TMA and adult onset Still's disease are summarized. The mean age of adult Still's disease onset in these cases is 31.60 (15-46) years. The interval between onset of thrombotic microangiopathy and the diagnosis of adult onset Still's disease ranged from 3 days to17 years and the female/male ratio was 2/1. The mean age of thrombotic microangiopathy onset is 34.70

(15-62) years. Furthermore, in more than half of these patients (8/15) TMA occured within the first

6 months of establishing adult onset Still's disease. In five cases the diagnosis of renal thrombotic microangiopathy was proven histologically. Eleven of fifteen patients (73%) were treated with plasmapheresis in addition to glucocorticoid therapy, and among them 8 (73%) had complete remission, whereas the other 3 had permanent visual impairment and/or digital ischemia. Of the four patients who were not treated with plasmapheresis, two died, one developed end-stage renal disease, and one had complete remission. Anticardiolipine antibodies were negative in

90% (9/10) of cases with available data. As far as we know, testing for ADAMTS13 deficiency was reported in two of these cases. ADAMTS13 activity in one of these reported patients was decreased to <10 percent of that in the normal control plasma (with a presence of antibodies against ADAMTS13), and normal in the second patient. In our case, ADAMTS13 activity was not measured due to technical inability.

To the best of our knowledge, thrombotic microangioapthy has not been described in literature as a complication of chloroquine treatment. None of the patients reviewed in these 14 cases were treated with chloroquine before or at the time of TMA onset. There is one reported case of TMA in a patient with rheumatoid arthritis, that occurred after 18 months of therapy with 7

glucocorticoids and chloroquine phosphate, with no known precipitating factor (20). It is possible that in our case chloroquine phosphate may have been a co-factor for thrombocytopenia but it is not likely to have induced thrombotic microangiopathy.

Thrombotic microangiopathy as a clinical diagnosis must be made in a timely manner in order to initiate urgent intervention. Assays for ADAMTS13, and antibodies against ADAMTS13 are not always available, and, even if available, results may not be known for some time. Thus, while testing for ADAMTS13 deficiency is important for understanding the pathogenesis of the congenital and acquired causes of this disorder, it should not be used for making the diagnosis, since delays in initiating treatment may be fatal.

In the era before effective treatment with plasma exchange, 90 percent of patients with

TTP died from systemic microvascular thrombosis that caused cerebral and myocardial infarctions and renal failure (3). Initial treatment of TMA includes plasma exchange and glucocorticoids. For adults, plasma exchange is the only treatment for which there are firm data on its effectiveness (21). If the patient has idiopathic TTP, adjunctive immunosuppressive treatment with glucocorticoids is appropriate, even without measurements of ADAMTS13 activity

(22). Similarly, in patients whose platelet counts do not increase within several days of plasma exchange, or those in whom thrombocytopenia recurs when plasma exchange treatments are diminished or discontinued, addition of glucocorticoids is appropriate (4). Antiplatelet agents, such as aspirin and dipyridamole, are not effective when given alone for TMA (23). It is possible, however, that they may be of some benefit when added to plasma exchange (21).

Relapses are rare in patients with thrombotic microangiopathy, except in those with a severe deficiency of ADAMTS13 activity. Half of such patients may have a relapse, most within a year (24). In refractory patients, firstly plasma exchange should be intensified (26), and corticosteroids should be initiated in patients not yet receiving immunosuppressive drugs. Also, if not previously employed, addition of other modalities may be helpful: prednisone, rituximab, cyclosporine, cyclophosphamide, azathioprine and intravenous immune globulin (22, 26-28).

Small case series have suggested lower rates of relapse after splenectomy (29). 8

The etiology of adult onset Still’s disease is unknown. Different viral and bacterial agents have been implicated in the disease pathogenesis. It has also been suggested that AOSD may be a form of vasculitis mediated by non-necrotizing immune complexes.

The thrombotic microangiopathies are characterized pathologically by the development of platelet microthrombi that occlude small arterioles and capillaries, and result from a disruption of the normal platelet–endothelial interface. This can occur either through direct vascular endothelial wall damage by Shiga toxin (Shiga toxin HUS) or Thomsen–Friedenreich antigen activation

(pneumococcal HUS), or from a defect in normal plasma regulatory systems, such as factor H deficiency or ADAMTS13 deficiency (constitutional or acquired). However, the pathophysiology of many of the secondary causes of TMA remains unknown.

The exact pathogenesis of adult onset Still’s disease associated thrombotic microangiopathy is unclear and may differ between patients. Unfortunately, only two of the fifteen patients reviewed here were tested for ADAMTS13 activity, and one of them for antibodies against ADAMTS13. Because of the relatively small number of reported cases, and insufficient data on functional studies of ADAMTS13 activity, we may only speculate that the development of thrombotic microangiopathy in patients with adult onset Still’s disease is not coincidental but may be the result of a more generalized (auto)immune process. Further studies are needed, especially to characterize antibodies against ADAMTS13.

CONCLUSION:

Whether the association between adult onset Still's disease and thrombotic microangiopathy is coincidental, or whether they share a similar pathogenic mechanism, remains unclear. In summary, the purpose of this case report and literature review is to emphasize the importance of inquiring about clinical and laboratory signs of TMA in patients with adult onset

Still's disease, especially within the first six months of establishing the diagnosis of adult onset

Still’s disease. 9

There is no potential conflict of interest. 10

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Table 1:Main characteristics of patients with thrombotic microangiopathy and adult onset Still's disease

Masson Boki et Boki Diamond Kuo et Domingues Perez Quéméneur Hirata Robert Wang et Okwuosa et Sayarlioglu This Portoles et et al. al. et al. (10) al. et al. and et al. (14) et al. et al. al. al. et al. case al. (9) (7) (8) (8) (11) (12) Rodwig (15) (16) (17) (18) (19) (13)

Gender F F F M M M F F M F F F M F F

Age (years) 45 33 28 31 22 23 15 45 42 23 17 42 27 46 34

Fever + + + + + + + + + + + + + + + Arthralgia + + + + + + + + + + + + + + + and/or arthritis Sore throat + NA NA + NA + NA + + NA NA - + + - Adenopathies - NA - - NA - - NA - NA NA - - + + Rash + + + + + + + + + NA + + + + + Hypertrans- - NA NA + NA + - - + - + NA + + + aminasemia

Time from 17 3 8 19 4 3 2 3 2 4 3 7 4 5 9 AOSD to years years years days months months months days weeks years months years weeks years Months TMA

Anticardiolipin NA - - - NA - NA - + NA NA - - - - antibodies

Serum 660 123 187 565 942 707 502 HD 865 97 396 442 132 220 90 creatinine (µmol/l)

Diminished ND NA NA ND ND ND ND ND ND + - ND ND ND ND ADAMTS-13 activity

Kidney biopsy Renal ND ND Arteriolar Arteriolar ND Arteriolar ND Arteriolar ND ND ND ND ND ND TMA and and and and (post glomerular glomerular glomerular glomerular mortem) TMA TMA TMA TMA

Treatment CS PP, PI, PI, PP, PI, CS, PP, PI, CS, PP, CS, CS, aspirin CS, CS, IV Ig CS, PP, PP, CS PP, CS, Cy, PP, PP, CS, CS HD IVIg, HD HD PP, ASA, CS, HD vincristine CS CS Aspirin HD, PP splenectomy, AZA, Outcome Death CR CR PR visual CR CR Death CR ESRD CR CR PR PR visual CR CR impairment creatinin- diffuse impairment emia digital 88µmol/l gangrene

NA not available, ND not done, TMA thrombotic microangiopathy, AOSD adult onset Still's disease, HD hemodyalisis, CS corticosteroids, PP plasmapheresis, PI plasmainfusion, IV Ig intravenous immunoglobulins, AZA azathioprine,

Cy cyclophosphamide, CR complete remission, PR partial remission, ESRD end stage renal disease