Fatal haemophagocytic syndrome in the course of dermatomyositis with anti-Mi2 antibodies

S. Madaule, L. Porte, B. Couret and E. Arlet-Suau

Service de Médecine Interne, Clinique Dieulafoy, CHU Toulouse-Purpan, 31059 Toulouse cedex, France

SIR, In the December 1998 issue of Rheumatology, Yasuda et al. [1] described a haemophagocytic syndrome (HS) in a patient with dermatomyositis (DM). We report a second case.

An 83-yr-old man was admitted to hospital with muscle weakness, in particular of the pelvic girdle and associated myalgia of about 1 month's duration. He also presented cutaneous signs: heliotrope rash with oedema of the eyelids, the Gottron sign, nail-fold lesions and ragged cuticles (manicure sign) and periungual haemorrhage.

DM was diagnosed on the basis of the physical examination and the following criteria: biochemical [creatine phosphokinase (CPK) 3.208 IU/l, normal value <195; aldolase 100 IU/l, normal value <7.6 IU/l; lactate dehydrogenase 1355 IU/l, normal value <480 IU/l]; electromyographic (myogenic syndrome); immunological [antinuclear antibodies (ANA), 1/2500 on mouse liver extracts with spotted fluorescence, presence of anti-Mi2 antibodies, absence of anti-JO1 and anti-PM-Scl antibodies]; and anatomopathological (myocyte necrosis and degeneration, expression of HLA class I molecules). There was also evidence of an inflammatory syndrome [erythrocyte sedimentation rate 70 mm/h, C-reactive protein 25 mg/l (normal value <15 mg/l), fibrinogen 6.8 g/l].

Blood tests showed moderate inflammatory anaemia (Hg 11.5 g/dl), with normal numbers of white blood cells (WBC) and platelets. There was no evidence of neoplasia [clinical examination, chest radiography, abdominal echography, CT scan of the abdomen and thorax, barium swallow and tumour markers (prostate-specific antigen and carcinoembryonic antigen)].

Ten days after admission, corticotherapy was initiated with prednisolone (1.5 mg/kg per day). Two weeks later, clinical worsening was evident, with general functional disability, difficulty in swallowing and persistently elevated CPK. Methotrexate (i.m., 15 mg/week) was therefore started, together with folic acid. One week later, the patient showed signs of respiratory distress due to muscle weakness, and was given immunoglobulins (1 g/kg i.v. over 48 h); the prednisolone treatment was maintained.

The course was marked by febrile pancytopenia and decreasing CPK. Blood and urine cultures and bronchial aspiration gave no evidence of infectious disease. Bone marrow aspiration showed decreased numbers of megakaryocytes, erythroblasts, white cell lines and macrophages with cytophagocytosis. There was no malignant infiltration.

Fever continued despite broad-spectrum antibiotic treatment, and the patient died in a context of severe haemorrhagic syndrome with worsening of the cytopenia (white blood cells 0.2 x 109/l, Hb 5.8 g/dl, platelets 10 x 109/l).

HS is defined by benign macrophagic proliferation developing into febrile pancytopenia. The aetiological circumstances are various: infections (viral or bacterial), malignancies (lymphoma), but also autoimmune diseases [2, 3]. Systemic lupus erythematosus is the most frequent in this group but chronic juvenile arthritis, scleroderma and adult-onset Still's disease have also been reported. Except for the case reported by Yasuda, as far as we aware HS has never been described in the course of DM. In our patient there was no evidence of an infectious or malignant disease, so DM seems to have been the cause of the HS.

The pathophysiology of HS implies the involvement of CD4+ T lymphocytes, which, through overproduction of lymphokines (interferon {gamma} in particular), would boost the macrophage response, leading to haemophagocytosis per se, and to the release of the cytokines [interleukin 1 and tumour necrosis factor {alpha} (TNF-{alpha})] responsible for the clinical signs. In the context of HS associated with autoimmune diseases, multiple mechanisms may operate, involving autoantibodies, immune complexes or cytokines.

It is interesting to note that DM is characterized immunohistologically by muscle infiltration of mononuclear cells, CD4+ lymphocytes being predominant. Furthermore, there is evidence that TNF and interferon {gamma} play an important role in both HS and DM [4, 5].

Wherever possible, treatment of HS is aetiological, implementing conventional haematological reanimation procedures (antibiotherapy, transfusion). Corticotherapy and i.v. immunoglobulins may be used, especially in cases of associated autoimmune pathology. In our patient, HS developed while these treatments were being given. Steroid pulse therapy or immunosuppressives drugs may also be effective in severe HS.

The patient described by Yasuda et al. showed no signs of muscular involvement. Our patient presented authentic DM. The presence of anti-Mi2 antibodies seems to be specific for DM [6] and is classically associated with a good prognosis [7]. In our patient, HS was responsible for the fatal outcome (gastrointestinal bleeding) while muscular marker enzymes were showing improvement.

The HS associated with autoimmune diseases is a recognized entity whose mechanisms remain, to a large extent, obscure. Here, we have reported a fatal case of HS associated with DM, without evidence of an infectious or tumoral origin. DM should therefore be added to the list of disorders which may promote HS.

Notes

Correspondence to: S. Madaule, 28 avenue Lascardos, 31320 Castanet-Tolosan, France. Back

References

  1. Yasuda S, Tsutsumi A, Nakabayashi T et al. Haemophagocytic syndrome in a patient with dermatomyositis. Br J Rheumatol1998;37:1357–8.[ISI][Medline]
  2. Wong KF, Hui PK, Chan JK, Chan YW, Ha SY. The acute lupus hemophagocytic syndrome. Ann Intern Med1991;114:387–90.[ISI][Medline]
  3. Kukamura S, Ishikura H, Yamagata S, Kobayashi S. Autoimmune associated hemophagocytic syndrome. Am J Med1997;102:113–5.[ISI][Medline]
  4. Kalovidouris AE. Mechanisms of inflammation and histopathology in inflammatory myopathy. Rheum Dis Clin North Am1994;20:881–97.[ISI][Medline]
  5. Fujiwara F, Hibi S, Imashuku S. Hypercytokinemia in hemophagocytic syndrome. Am J Pediatr Hematol Oncol1993;15:92–8.[ISI][Medline]
  6. Targoff I, Reichlin M. The association between Mi-2 antibodies and dermatomyositis. Arthritis Rheum1985;28:796–803.[ISI][Medline]
  7. Miller FW. Myositis-specific autoantibodies. J Am Med Assoc1993;270:1846–9.[ISI][Medline]
Accepted 30 March 2000





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