Successful treatment of severe cytophagic histiocyticpanniculitis with cyclosporine A

Successful Treatment of Severe Cytophagic Histiocytic Panniculitis With Cyclosporine A Barbara E. Ostrov, Balu H. Athreya, Andrew H. Eichenfield, and Donald P. Goldsmith Cytophagic histiocytic panniculitis (CHP) can be a severe variant of WeberChristian disease characterized by the histopathologic appearance of Iobular panniculitis infiltrated by histiocytes containing blood cell fragments and by a clinical course with marked systemic features including multiorgan failure, hypertriglyceridemia, and coagulopathy, which may lead to death. Therapy of CHP includes standard treatment for panniculitis, such as antimalarials, plus immunosuppressives for more severe cases. The response to treatment, however, is unpredictable. In several recent reports, cyclosporine A has been successfully used to treat panniculitis. We report a patient and review the literature on CHP and the use of cyclosporine A as therapy. Published reports reveal that in instances of severe CHP when cyclosporine A was not given, 19 of 27 patients died (70% mortality). When severe CHP was treated with cyclosporine A, rapid remission was achieved in our patient and all five previously published cases (0% mortality). We believe cyclosporine A is the drug of choice in severe CHP and should be considered in all such patients. Semin Arthritis Rheum 25:404-413. Copyright © 1996 by W.B. Saunders Company INDEX WORDS: Cytophagic histiocytic panniculitis; Weber-Christian disease; cyclosporine A; panniculitis YTOPHAGIC

histiocytic

panniculitis

C (CHP) is one of the more severe variants of Weber-Christian disease. CHP is characterized by lobular panniculitis with histiocytes

From the Milton S. Hershey Medical Center, Penn State University School of Medicine, Hershey, PA; the Children's Seashore House, Philadelphia, PA; the Mount Sinai School of Medicine, New York, NY; and the St. Christopher's Hospital for Children, Philadelphia, PA. Barbara E. Ostrov, MD: Associate Professor of Pediatrics and Medicine, Pediatric and Adult Rheumatology, Milton S. Hershey Medical Center, Penn State University School of Medicine, Hershey, PA; Balu H. Athreya, MD: Professor of Pediatrics and Chief, Pediatric Rheumatology, Children's Seashore House, Philadelphia, PA; Andrew H. Eichenfield, MD: Associate Professor of Pediatrics and Chief, Pediatric Rheumatolog, Mount Sinai School of Medicine, New York, NY; Donald P. Goldsmith: Professor of Pediatrics, Temple University School of Medicine, and Chief Rheumatology, St. Christopher's Hospital for Children, Philadelphia, PA. Address reprint requests to Barbara E. Ostrov, MD, Associate Professor of Pediatrics and Medicine, Pediatric and Adult Rheumatology, Milton S. Hershey Medical Center Penn State University School of Medicine, Hershey, PA 17033. Copyright © 1996 by W..B. Saunders Company 0049-0172/96/2506-000555. O0/0 404

containing blood cell fragments often associated with marked systemic features including bone marrow and liver failure, hypertriglyceridemia, and coagulopathy. Multiorgan failure, hemorrhagic diathesis, and overwhelming infections may lead to death. 1-3Therapy has included standard treatment for panniculitis, such as hydroxychloroquine and dapsone. When more severe systemic disease has been present, high dose corticosteroids, and/or immunosuppressive drugs such as azathioprine and cyclophosphamide have been tried with variable success. 3,4 In several recent case reports, cyclosporine A has been successfully used to treat this illness. 5-8 We report an additional patient and review the literature on the use of cyclosporine A in treating CHP. This review suggests that cyclosporine A significantly reduces the mortality from this severe form of CHP. CASE REPORT

DZ first presented at age 16 years in 1987 with fever, weight loss, and malaise. Initial evaluation revealed autoimmune thyroiditis with

Seminars in Arthritis and Rheurnatism, Vol 25, No 6 (June), 1996: pp 404-413

CYCLOSPORINEA IN CHP

405

phils or plasma cells. No vasculitis was visible (Fig 2). The patient was placed on indomethacin with diminution of fever and symptomatic improvement. By late February 1988, 5 months after the onset of the illness, a large mass of coalesced nodules rapidly developed around the lower trunk. Numerous 5- to 10-mm-diameter nodules were palpable on the trunk and extremities. Daily fevers to 40°C and hepatosplenomegaly were noted, but her examination was otherwise normal. Laboratory evaluation revealed the following: WBC count, 3,100 cell/l~L with a normal differential; hemoglobin level, 6.8 g/dL with a positive direct Coombs' test; prothrombin time (PT) 16.0 seconds; partial thromboplastin time (PTT) 45 seconds (normal up to 12.0 and 30 seconds, respectively); fibrinogen level was 55 mg/dL; and fibrin split products (FSP), 1:80. Platelet count was 64,000 cells/ram~. Bone marrow biopsy revealed mildly increased red cell precursors. Repeat skin biopsy revealed

hypothyroidism; thyroid replacement resulted in slight improvement in the fatigue. She denied alopecia, photosensitivity, musculoskeletal complaints, or rash. Four months into her first admission, in January 1988, (Fig 1), she continued to experience daily fevers to 39°C, and three asymptomatic subcutaneous nodules were detected. Laboratory evaluation revealed a white blood cell (WBC) count of 6000 cells/mm3 with a normal differential, a hematocrit level of 33 %, a mean corpuscular volume of 78 fL, normal urinalysis results, an erythrocyte sedimentation rate of 50 mm/h, normal complement levels, negative rheumatoid factor, normal liver function tests, and antinuclear antibody (ANA) 1:640 in a homogeneous pattern. Anti-double stranded DNA, anti-Smith, anti-ribonucleoprotein, anti-SS-A and anti-SS-B antibodies were not detected. All cultures were negative. Biopsy of one of the nodules revealed lobular panniculitis characterized predominantly by a lymphocytic and histiocytic infiltrate with few neutro-

cycle A

1000• loo-1 50-1

I

40~

cycle A

]

'-"

~r splenic abscesses discovered l e n e / ~ ~

36

30000~ 250004 5°°°-b 1250 4

1oooq ~- 750 -4

s ooo-I 0

I O0

/

/ I

I

i

I

'~

L_^

I

I

I

/ I CO

I 00

i ¢0

I CO

I" O0

I CO

I

I

I

I 0,.3

x CO

~ (30

CO

03

CO

o0

CO

O~

DATE Fig 1 :

Fever pattern, laboratory changes, and treatment course in patient DZ. Pred, prednisone; WBC, white blood cell count; SGOT, serum glutanic pyruvic transaminase.

406

Fig 2: Skin biopsy revealing Iobular panniculitis (original magnification 400 x).

lobular panniculitis without malignant cells or vasculitis. Indomethacin was withheld and corticosteroids instituted at 2 mg/kg/day, with regression of panniculitis. The laboratory abnormalities improved with a WBC count of 3,800 cells/ixL, a hemoglobin level of 9.4 g/dL, and a platelet count of 400,000 cells/mm3. Repeat ANA titer was 1:640, with both homogeneous and peripheral patterns. All other serologies were again negative and complements were normal. Liver function abnormalities were noted for the first time: serum glutamic pyruvic transaminase (SGPT), 250 U/L; serum glutamic oxaloacetic transaminase (SGOT) 250 U/L; total bilirubin level, 1.6 mg/dL; alkaline phophatase, 400 U/L; cholesterol level, 250 mg/dL; and triglyceride level, 500 mg/dL. Hepatitis A and B serology, cytomegalovirus, and EpsteinBarr virus titers were negative, and ceruloplasmin and oL-1antitrypsin levels were normal. At the time of liver biopsy 6 weeks later, scleral and cutaneous icterus, mild alopeeia, and scattered, small nontender subcutaneous nodules were noted. Fevers to 39°C, one to three times per day, had reappeared. Abdominal ultrasound revealed splenomegaly and an enlarged, fatty liver without biliary tract dilatation. Laboratory study results were as follows: SGOT, 1100 U/L; alkaline phosphatase concentration, 800 U/L; total bilirubin level, 8.1 mg/dL (indirect 0.8 mg/dL); cholesterol level, 350 mg/dL; triglyceride level, 1400 mg/dL; WBC count, 2,000 cells/mm3; hemoglobin level, 8.4 g/dL; platelet count, 220,000 cells/mm3; urinalysis results, negative; PT, 11.1 seconds; PTT, 30

OSTROV ET AL

seconds; FSP, 1:80, fibrinogen level, 55 mg/dL. Blood and urine cultures were negative. Liver biopsy revealed macrovesicular fatty infiltrate and a mild chronic hepatitis with lymphocytic and histiocytic infiltrate expanding periportal tracts. Mild bile duct proliferation and portal fibrosis were noted. Over the next 10 days, the WBC count decreased to 700 cells/IxL with 5% neutrophils (absolute neutrophil count 35), hemoglobin level decreased to 9.0 g/dL and platelet counts decreased to 100,000 cells/ram3. Repeat bone marrow biopsy revealed decreased cellularity with a marked diminution in myeloid precursors. A large number of erythrophagocytic and neutrophilphagocytic histiocytes were visible (Fig 3). Pulse methylprednisolone was administered for 3 consecutive days, and she developed sepsis with Staphylococcus aureus and Klebsiella pneumonia. Broad spectrum antibiotic and amphotericin B therapy were begun. Ascites and asterixis developed. Plasmapheresis was performed on 5 consecutive days with transient lowering of the SGOT and SGPT and triglyceride levels. The absolute neutrophil count remained below 100 cells/txL. Intravenous gammaglobulin therapy was administered for 3 days without any improvement. On May 1, 1988, 8 months after the onset of her illness, the WBC count was 800 cells/ram, 3 with 10% neutrophils; hemoglobin level was 8.0 g/dL, platelet count was 50,000 cells/mm3; total bilirubin level was

Fig 3: Bone marrow biopsy revealing the classic "bean bag" cell or cytophagic histiocyte. The large histiocyte (arrow) contains a degenerating cell nucleus inside a vacuole (original magnification 1,000x).

CYCLOSPORINE A IN CHP

15.0 mg/dL (indirect 2.0 mg/dL), albumin level was 2.1 g/dL, SGOT level was 150 U/L, SGPT level was 350 U/L, cholesterol level 100 mg/dL, and triglyceride level was 1000 mg/dL. Repeat bone marrow revealed hypoplasia of all cell lines suggestive of an evolving aplastic anemia. Cytophagic histiocytes were again noted. Daily corticosteroids at 2 mg/kg/d were continued. Four days later intravenous cyclosporine A at 4 mg/kg/d was begun, and after 24 hours the patient became afebrile. Over the next 3 days the WBC count increased, reaching 2,500 cells/ IxL. Over the next month, all liver function tests and coagulation studies normalized and asterixis resolved. Serum lipid abnormalities improved and triglyceride levels decreased to 350 mg/dL. Serum cyclosporine A trough levels were maintained between 100 and 150 ng/mL. Amphotericin B was continued. Four weeks after cyclosporine A was begun, low-grade fevers developed and the WBC increased to 20,000 cells/mm 3 . Left upper quadrant abdominal pain occurred, and ultrasonography revealed multiple splenic abscesses. After 1 further month of amphotericin treatment, a splenectomy was performed. Although the splenic cultures were negative, microscopic analysis revealed micro-organisms consistent with Candida albicans. One day after splenectomy the patient became afebrile; over the next 3 months, she remained afebrile and the WBC count gradually returned to normal. Amphotericin B, 5-FU and cyclosporine A were continued and corticosteroids were gradually tapered. Fifteen months after the onset of the illness, in November 1988, the patient again experienced daily fevers up to 39°C. Three small asymptomatic nodules typical of panniculitis were noted in the right inguinal region. Cyclosporine A trough levels were <50 ng/mL and the patient admitted to poor compliance with her medications. Within 1 day of restarting the cyclosporine A, the fevers and panniculitis improved. Except for hirsutism and mild renal dysfunction, no cyclosporine A toxicity was noted. Six months later, disseminated varicella infection developed and cyclosporine A was discontinued. Corticosteroids were discontinued in the fall of 1989, 2 years after the onset of CHP. Except for persistent hypothyroidism requiring thyroid replacement therapy, she has

407

been well for more than 6 years without further recurrences of panniculitis or fever. Mild hypertriglyceridemia and hypercholesterolemia persist. LITERATURE! REVIEW AND DISCUSSION

Methods

A Medline review was performed through October 1994 to find all published cases of CHP and reports in which any type of panniculitis was treated with cyclosporine A. Cases were excluded if inadequate clinical information was provided, when CHP was limited to the skin, or if the systemic illness was mild consisting only of fever with or without leukopenia. Cases associated with malignancies, a-l-antitrypsin deficiency, systemic lupus erythematosus (SLE) or other known causes of panniculitis also were excluded. Thirty-two cases were found, v3,s'22 of which 5 were treated with cyclosporine A. 5-8 One patient with lobular panniculitis treated with cyclosporine A was reported. 23 Comparisons were made from published reports between the cases of CHP treated with cyclosporine A, plus our patient, and CHP patients not given this treatment. Clinical features and response to cyclosporine A therapy were assessed. Fisher's exact test was used in these analyses. Literature Review

Panniculitis is, by definition, inflammation of fat and may be secondary to a variety of physical, infectious, rheumatic, or miscellaneous disorders, or it may be idiopathic (Table 1). 24,25 Panniculitis typically presents with subcutaneous nodules and/or plaques, which can be either asymptomatic or tender with overlying erythema and/or purplish discoloration. The lesions may lead to subcutaneous atrophy or may ulcerate and drain. The histological appearance consists of septal or lobular leukocytic and/or lymphocytic infiltrates with or without vasculitis. Septal panniculitis, clinically identified as erythema nodosum, is relatively common and is associated with a variety of conditions, particularly inflammatory bowel disease, sarcoidosis, tuberculosis, and following streptococcal infections. Lobular panniculitis is less common and is associated with underlying conditions such as SLE, a-1 antitrypsin deficiency, and

OSTROV ET AL

408

Table 1: Classification of Panniculitis Primary Weber-Christian disease Rothman-Makai Cytophagic histiocytic panniculitis Secondary Physically induced Cold

Factitious Infection: especially septal panniculitis Tuberculosis Streptococcal Other (viral, bacterial) Connective tissue diseases SLE Sarcoidosis Other Pancreatic disease a-1 antitrypsin deficiency Malignancy

infections. ;4-27Lobular panniculitis may be acute or chronic, and isolated to the skin or occur as part of a systemic illness. Historically, lobular panniculitis associated with fever and variable degrees of systemic illness has been known as Weber-Christian disease. Today, however, this term is known to encompass a variety of diseases, among them CHP. 1,~° CHP is lobular panniculitis with both a characteristic histiocytic infiltrate and lymphocytes which are primarily T helper cells. 16 These histiocytes contain phagocytosed red blood cells, leukocytes and/or platelets giving the classic "bean bag" appearance. 1,1°,24 Most lesions are seen in skin, liver, spleen, marrow (Fig 3), and/or lymph nodes. Malignancies have been diagnosed in some patients. 3,28 In certain individuals CHP is primarily a cutaneous disease with few systemic features? In others, a severe overwhelming illness develops characterized by multiorgan failure (including marrow and liver), infections, coagulopathy and hemorrhage. In many of these patients, response to treatment is poor with a progressive downhill course leading to death. 1,3,912,14,15,17,1s,2° Depending on the severity of the systemic illness in CHP, treatment usually consists of corticosteroids plus other therapy for panniculitis, such as antimalarials and dapsone. 2,5 Response to this treatment is often unsatisfactory,

so trials of immunosuppressives (eg, azathioprine, cyclophosphamide), alone or in combination, are given with unpredictable success. 1-4 Cyclosporine A has been successfully used to treat not only transplant patients, 29 but also individuals with a variety of autoimmune diseases, 3° including myasthenia gravis, 31 dermatomyositis, 32 psoriasis, 33 autoimmune hepatitis, 34 SLE, 35 juvenile rheumatoid arthritis (RA), 32 and RA. 36Cyclosporine A is a lipophilic peptide derived from the fungus Tolypocladium inflaturn gains. 29 Immunosuppressive effects are due primarily to inhibition of T cell mediated immune reactivity, particularly decreased helperinducer and cytotoxic T cell functions. Cyclosporine A appears to have limited direct effects on B cell and macrophage function. The primary action of cyclosporine A on these latter cells is disruption of lymphokine-dependent T cellmacrophage interactions with subsequent alteration of macrophage function. It also has been used successfully to treat early aplastic anemia 37 and autoimmune neutropenia 38 and was initially selected for our patient primarily because of pancytopenia and the development of an aplastic-appearing bone marrow. The various side effects of cyclosporine A often limit its usefulness. 39,4° Renal toxicity including hypertension, decreased glomerular filtration rate, and hyperkalemia are frequent, particularly at higher doses. Hypertrichosis, tremor, and gastrointestinal intolerance are also common. Late neoplasms have not been reported in the nontransplant population, although long-term experience is limited in this group. 41 The rate of nosocomial infections in transplant patients is actually less with cyclospofine A than with azathioprine, probably because of decreased corticosteroid requirements. 29 To minimize toxicity, recommended dosing is usually from 2 to 5 mg/kg/day in RA 36 and SLE. 35 Variable doses of cyclosporine A have been used in CHP patients, from 4 mg/kg/day initially up to 10 mg/kg/day. Trough levels were usually maintained at 100 to 200 ng/mL, which is generally felt to be adequate for immunosuppression required in chronic autoimmune disorders, 3° when compared with the trough levels of up to 300 ng/mL desired for organ transplantation. z9 It is noteworthy that when our patient's

CYCLOSPORINEA IN CHP

409

cyclosporine A trough level decreased below 50 ng/mL, active panniculitis and fever recurred. Literature review revealed five previously reported patients with biopsy-proven CHP 5-8 and another patient with lobular panniculitis 23 treated with cyclosporine A (Table 2). These patients all had persistent or relapsing panniculitis along with a systemic illness, which was at best partially responsive to corticosteroids, antimalarials, immunosuppressive agents and/or intravenous immunoglobulin. The severe systemic illness improved rather promptly after cyclosporine A was begun in our patient and the other five cases with CHP. In all 7 cases panniculitis completely disappeared, and the patients remained well after cyclosporine A treatment. Literature review also revealed 27 cases of severe CHP not treated with cyclosporine A. 13,9-22The clinical and laboratory characteristics, treatment, and course of the illness were corn-

pared in the six patients with CHP treated with cyclosporine A (references 5 to 8, plus the current case) (Table 3). These two groups were comparable, although the six CHP patients given cyclosporine A were younger (mean 15.8 years, range 5 to 33 years versus mean 37.2 years, range 12 to 80 years). In the face of a similar overwhelming illness, the mortality in the cyclosporine A-treated group was zero (0/6) compared with 70% (19/27) in the cyclosporine A-untreated group (P < .01, Fisher's exact test). DISCUSSION

CHP is an uncommon but potentially lifethreatening illness, with 70% mortality in the most severe cases. Cyclosporine A was beneficial in our patient and was 100% effective in other patients reported in the literature. Our patient showed the characteristic lea-

Table 2: Clinical Features of Panniculitis Patients Treated With Cyclosporine A Schuval, 1993s Current Case

Case 1

Case 2

Diagnosis Age onset/gender Fever Skin

CHP 15y/F Yes Diffuse painless nodules

Biopsy Liver Biopsy Hematology WBC Anemia Platelet Coags Marrow Lipids ANA Treatment Initial

LP Hepatitis ~ liver failure Hepatitis histiocytes

CHP 7 y/M Yes Multiple nodules; ruptured bullae Septal and LP Hepatitis NR

Leukopenia --> neutropenia Coombs+ Markedly $ Coagulopathy CH chof & TG 1' 1:640 homo; others-

Leukopenia "anemia. . $ NR CH chol & TG 1' NR

indomethacin; steroids --> pulse; IVIG; plasmapheresis Progressive multisystem failure IV: 4 mg/kg/d ~ PO trough levels: 100-150 ng/mL Afebrile in 1 day better in 1 mo, remission off CyA Hirsutism, mild 1' creatinine

Antibiotics; steroids --> pulse; HCQ; IVIG Progressive panniculitis and pancytopenia IV: 10 mg/kg/d --> PO: 3 mg/kg/d Improved in 1 week; remission on CyA NR

Response Cyclosporine Response Toxicity

.

CHP 5y/M Yes Diffuse purple ulcerated nodules CHP Hepatitis Mild hepatitis

.

Leukopenia -> neutropenia anemia" $ NR "reactive" TG 1' ; chol normal 1:50 homo; othersDapsone; steroids --~ pulse; IVIG Progressive panniculitis and liver failure IV: 10 mg/kg/d -~ PO: 15 mg/kg/d Remission on CyA NR

410

OSTROV ET AL

Table 2.: Clinical Features of Panniculitis Patients Treated With Cyclosporine A (Cont'd)

Royle, 1992 ~

Oyama, 19897

Usuki, 19888

Entzian, 198723

CHP 33 y/M Yes Nodules

CHP 19y/M Yes Multiple nodules

CHP 16y/F Yes Recurrent tender nodules

LP 31 y/M Yes Liquefying nodules

CHP Hepatitis --> liver failure NR

LP Hepatitis NR

LP Hepatitis NR

LP Fatty liver NR

Lymphopenia Coombs+ NR Coagulopathy NR "Lipemic" NR

Leukopenia None Coagulopathy CH NR NR

Leukopenia ~ neutropenia Leukocytosis Coombs+ NR Markedly $ NR Coagulopathy NR CH NR chol & TG 1' NR NR "slightly + "

NSAID; steroids

Steroids

Partial response

Progressive liver failure and pancytopenia 6.5 mg/kg/d; trough IV: 100 mg/d ~ PO; trough levels: 70-350 ng/mL levels: 50-200 ng/mL Remission off CyA Better in 2 weeks, well in 2 mo; remission on CyA NR Hirsutism

Steroids --> pulse; IVIG; azathioprine

Steroids; HCQ; CTX

Progressive multiorgan failure IV --> PO: 100 mg/d trough levels: 125 ng/mL Afebrile in 1 wk, well in 2 wk; remission on CyA NR

Good for 2 years ~ poor 200 mg BID; trough levels: 300 ng/mL Remission on CyA "none significant"

Abbreviations: CHP, cytophagic histiocytic panniculitis; LP, Iobular panniculitis; NR, not reported; WBC, white blood cell; CH, cytophagic histiocytes; chol, cholesterol; TG, triglycerides; homo, homogenous pattern; IVIG, intravenous immunoglobulin; HCQ, hydroxychloroquine; NSAID, nonsteroidal anti-inflammatory drug; CyA, cyclosporine A.

tures of severe CHP: lobular panniculitis with fever, bone marrow and liver failure, marked hypertriglyceridemia, coagulopathy, and hemophagocytosis noted on biopsies. Although she had a positive ANA, thrombocytopenia, autoimmune hemolytic anemia, and lobular panniculitis, features often seen in SLE, the disease course and other clinical, histological, and serological features were atypical for lupus. In addition, a positive ANA may occur in CHP. 5,22 Infections frequently occur in patients with severe CHP. Although the fungal infection complicated the course of our patient, the CHP clearly remitted. The fungal infection was likely the result of prolonged neutropenia plus high dose corticosteroids and was unrelated to the

use of cyclosporine A. The brief recurrence of panniculitis and fever after 5 months of clinical remission and the resolution of the skin lesions and systemic illness immediately after achieving increased cyclosporine A levels strengthen our conviction that cyclosporine A was beneficial in our patient. Studies show that the lymphocytic infiltrates in the skin of patients with CHP are primarily proliferating T helper cells. 16In the hemophagocytic syndrome, an illness that is similar except for the lack of panniculitis, lymphocytes appear to be actively secreting excessive amounts of macrophage-activating lymphokines. 42 These stimulated macrophages then become cytophagic histiocytes. Additionally, in CHP, in-

CYCLOSPORINE A IN CliP

411

Table 3: Comparison of Patients With Biopsy Proven Cytophagic Histiocytic Panniculitis Treated With Cyclosporine A and Those Who Never Were Given Cyclosporine A Feature No. of patients Mean age Range in years Gender Male Female Skin Multiple lesions Single lesion Systemic features Fever Hepatomegaly Splenomegaly Laboratory changes Anemia Leukopenia Thrombocytopenia Hepatitis Coagulopathy Lipid abnormalities Histology: number with cytophagic histiocytes Skin Marrow Liver/spleen/lymph nodes Treatment§ Corticosteroids Cyclophosphamide or azathioprine Combination chemotherapy Otherll Outcome¶ Remission Death

Never CyA*

Plus CyAt

27 37.2 12-80

6 15.8 5-33

10 (37) 17 (63)

4 (67) 2 (33)

20 (74) 7 (26)

5 (83) 1 (17)

27 (100) 14 (52) 16 (59)

6 (100) 5 (83) 6 (100)

21 (78) 26 (96) 13 (48) 22 (81) 17/23 (74) 3/4 (75)

5 (83) 6 (100) 5 (83) 6 (100) 4/4 (100) 5/5 (100)

26 (96) 9 (33) 12 (44)

2 (33) 4 (67) 0

20/22 (91) 7/22 (32) 7/22 (32) 6/22 (27)

6 (100) 0 0 5 (83)

8 (30) 19 (70)

6 (100) 0

NOTE, All denominators equal total number of patients reported except where noted. Values in parentheses represent percentages. *References 1-3, 9-22. 1"References5-8, plus current case. §Reference number 10 did not report any treatments used in their 5 patients. Illntravenous immunoglobulin, antimalarials, plasmapheresis, dapsone. ¶Statistical analysis of outcome: remission versus death; with and without CyA use. Fisher's exact test: P < ,01, All other comparisons: P > .05, NS. Abbreviations:CHP, cytophagic histiocytic panniculitis; CyA, cyclosporine A.

creased serum levels of tumor necrosis factor have been detected, ls,21 Both tumor necrosis factor and interleukins are known to cause fever, anemia, changes in lipid metabolism with hypertriglyceridemia, and weight loss. 43,44Therefore, it is likely that increased production of lymphokines from activated T helper cells, that stimulate macrophages to secrete tumor necro-

sis factor and other cytokines, are responsible for the systemic features of this disease. The mechanism of cyclosporine A in CHP remains speculative. The dramatic response of CHP to cyclosporine A and the immunohistologic evidence of a T helper cell infiltrate 16 support the hypothesis that T cell dysfunction is central to its pathogenesis. 8,29Because cyclospo-

412

OSTROV ET AL

rine A acts in part by altering lymphokinemacrophage interactions, it may decrease stimulation of macrophages thereby limiting the evolution to cytophagic histiocytes and ultimately blunting the systemic illness. Although our literature review suggests that cyclosporine A is very effective in severe CHP, it is retrospective, and some case selection bias exists. However, the presumed pathophysiology of CHP, the mechanisms of action of cyclosporine A, and the highly significant difference in survival with and without cyclosporine A treatment strongly suggest an important role for this

drug in the management of patients with CHP associated with severe systemic manifestations. CONCLUSION

In summary, cyclosporine A has been used to successfully treat CHP, a potentially severe, life-threatening illness. Based on this review, we believe that cyclosporine A is the medication of choice in individuals with severe CHP and should be considered in all such patients. ACKNOWLEDGMENTS The authors thank Christopher Gocke, MD, for his assistance in preparation of the photomicrograph of the cytophagic histiocyte (Fig 3).

REFERENCES 1. Crotty CP, Winkelmann RK: Cytophagic histiocytic panniculitis with fever, cytopenia, liver failure and terminal hemorrhagic diathesis. J Am Acad Dermatol 4:181-194, 1981 2. Alegre VA, Winkelmann RK: Cytophagic histiocytic panniculitis. J Am Acad Dermatol 20:177-185, 1989 3. Aronson IK, West DP, Variakojis D, et al: Fatal panniculitis. J Am Acad Dermatol 12:535-551, 1985 4. White JW, Winkelmann RK: Cytophagic histiocytic panniculitis is not always fatal. J Cut Pathol 16:137-144, 1989 5. Schuval SJ, Frances A, Valderrama E, et al: Panniculitis and fever. J Pediatr 122:372-378, 1993 6. Royle G, Blacklock H, Miller M: Treatment of eytophagic panniculitis with Cyclosporine A. Am J Med 92:704705, 1992 7. Usuki K, Kitamura K, Urabe A, et al: Successful treatment of Weber Christian disease by Cyclosporine A. Am J Med 85:276-278, 1988 8. Oyama Y, Amano T, Hirakawa S, et al: Hemophagocytic syndrome treated with Cyclosporine A: A T cell disorder? Br J Haematol 73:276-278, 1989 9. Willis Sin, Opal Sm, Fitzpatrick JE: Cytophagic histiocytic pannieulitis. Systemic histiocytosis presenting as chronic non-healing ulcerative skin lesions. Arch Dermatol 121:910913, 1985 10. Winkelmann RK, Bowie JW: Hemorrhagic diathesis associated with benign Cytopbagic histiocytic panniculitis and systemic histiocytosis. Arch Intern Med 140:1460-1463, 1980 11. Garcia CJ, Barrio MI, Fonseca E, et al: Cytophagic histiocytic panniculitis. Report of a case in a 12 year old girl. Eur J Pediatr 150:463-469, 1991 12. Forstrom L, Winkelmann RK: Acute generalized panniculitis with amylase and lipase in skin. Arch Dermatol 111:497-502, 1975 13. Yanagawa T, Yokoyama A, Noya K, et al: Cytophagic histiocytic panniculitis evolving into total lipodystrophy. South Med J 83:1323-1326, 1990 14. Hilton DA, O'Malley BP, Durrant STS: Cytophagic histiocytic panniculitis. Postgrad Med J 66:958-961, 1990 15. Pettersson T, Karinieni AL, Terronene S, et al:

Cytophagic histiocytic panniculitis. Report of four cases. Br J Dermatol 127:635-640, 1992 16. Hytiroglou P, Phelps RG, Wattenberg DJ, et al: Cytophagic histiocytie panniculitis: Molecular evidence for a clonal T-cell disorder. J Am Aead Dermatol 27:333-336, 1992 17. Alegre VA, Fortea JM, Camps C, et al: Cytophagic histiocytic panniculitis. J Am Acad Dermatol 20:875-878, 1989 18. Csato M, Szekeres L, Frecska I, et al: Cytophagic histiocytic panniculitis. Hautarzt 32:370-371, 1981 19. March LM, Webb J, Eckstein RP: Cytophagic histiocytic panniculitis. Aust NZ J Med 16:397-401, 1986 20. Valentini F: Weber Christian disease with systemic manifestations. Minerva Med 76:865-872, 1985 21. Maury CPJ, Pettersson T: Detection of circulating TNF in systemic histiocytosis. Br J Haematol 71:293-295, 1989 22. Ichikawa H, Fujiwara S, Matsunaga E, et al: Follow-up study on Cytophagic histioeytic panniculitis with abnormal immunologic findings. Nippon Hifuka Gakkai Zasshi 99:45-52, 1989 23. Entzian P, Barth J, Monig H, et al: Treatment of Weber Christian panniculitis with Cyclosporine A. Rheumatol Int 7:181, 1987 24. Phelps RG: Panniculitis, in Difficult Diagnoses in Dermatology. New York, NY, Churchill Publications, 1987, pp 389-403 25. Patterson JW: Panniculitis. New findings in the third compartment. Arch Dermatol 123:1615-1618, 1987 26. Diaz-Jouanen E, DeHoratius RJ, Alarcon-Segovia D, et al: Systemic Lupus Erythematosus presenting as panniculitis (lupus profundus). Ann Intern Med 82:376-379, 1975 27. Smith KC, Pittelkow MR, Su WPD: Panniculitis associated with severe cd-antitrypsin deficiency. Arch Dermatol 123:1655-1661, 1987 28. Aronson IK, West DP, Variakojis D, et al: Panniculitis associated with cutaneous T-cell lymphoma and cytophagic histiocytes. Br J Dermatol 112:87-96, 1985 29. Kahan BD. Cyclosporine. New Engl J Med 321:17251738, 1989

CYCLOSPORINE A IN CHP

30. Miescher PA, Favre M J, Mihatsch MJ, et al: The place of Cyclosporine A in the treatment of connective tissue diseases. Transplant Proc 20:224-237, 1988 31. Tindall RSA, Rollins JA, Phillips JT, et al: Preliminary results of a double-blind, randomized placebo controlled trial of Cyclosporine A in Myasthenia Gravis. New Engl J Med 316:719-724, 1987 32. Pistoia V, Buoncompagni A, Scribanis R, et al: Cyclosporine A in treatment of juvenile chronic arthritis and childhood polymyositis-dermatomyositis. Results of a preliminary study. Clin Exp Rheum 11:203-208, 1993 33. Ellis CN, Fradin MS, Messana JM, et al: Cyclosporine A for Plaque-type Psoriasis. New Engl J Med 324:277284, 1991 34. Hyams JS, Ballow M, Leichtner AM: Cyclosporine A treatment of autoimmune chronic active hepatitis. Gastroenterology 93:890-893, 1987 35. Okuda M, Kurata N, Mizoguchi A, et al: Effect of low-dose Cyclosporine A on Systemic Lupus Erythematosus disease activity. Arthritis Rheum 37:551-558, 1994 36. Forte O, et al: Radiologic evidence of disease modification in Rheumatoid Arthritis treated with Cyclosporine A. Arthritis Rheum 37:1506-1512, 1994 37. Seip M, Vidnes J: Cyclosporine A in a case of

413

refractory severe aplastic anemia. Scand J Hematol 34:228230, 1985 38. Selleri C, Catalano L, Alfinito F, et al: Cyclosporine A in adult onset neutropenia. Br J Hematol 68:137-141, 1988 39. Deray G, Benhmida M, Le Hoang P, et al: Renal function and blood pressure in patients receiving long-term low dose Cyclosporine A therapy for idiopathic autoimmune uveitis. Ann Intern Med 117:578-583, 1992 40. Feutren G, Mihatsch MJ, et al: Risk factors for Cyclosporine A induced nephropathy in patients with autoimmune diseases. New Eng! J Med 326:1654-1660, 1992 41. Kahan BD: Cyclosporine. New Engl J Med 322:1531, 1990 42. Jaffe ES, Costa J, Fauci AS, et ai: Malignant lymphoma and erythrophagocytosis simulating malignant histiocytosis. Am J Med 75:741-749, 1983 43. Beutler B, Cerami A: TNF, cachexia, shock and inflammation: a common mediator. Ann Rev Biochem 57:505-518, 1988 44. Tracy KJ, Manogue KR, et al: Cachectin/TNF induces cachexia, anemia and inflammation. J Exp Med 167:1211-1227, 1988