Adult onset Still’s disease: a study of 14 cases

Clin Rheumatol (2008) 27:35–39 DOI 10.1007/s10067-007-0648-4 ORIGINAL ARTICLE Adult onset Still’s disease: a study of 14 cases S. Singh & R. Samant & V. R. Joshi Received: 25 June 2006 / Revised: 25 March 2007 / Accepted: 1 May 2007 / Published online: 15 August 2007 # Clinical Rheumatology 2007 Abstract We studied the clinical profile, laboratory parameters, disease course, and outcomes of patients with adult onset Still’s disease (AOSD). A retrospective analysis of adult patients with Still’s disease diagnosed from 2000 to 2004 was carried out. Their clinical features and laboratory findings at presentation, disease course, and outcomes were analyzed. Data of 14 patients with Still’s disease were analyzed. The age at disease onset ranged from 16 to 59 years with a mean of 29.85, the male to female ratio being 9:5. The mean duration of illness from onset of symptoms to presentation was 14.5 months (range). The most common clinical manifestations were fever (n=14), articular symptoms (n=14), rash (n=8), weight loss (n=12), and sore throat (n=5). Elevated ESR was present in all patients with a mean of 98.3 mm at 1 h. Hepatic enzymes were elevated in seven patients at disease onset. The mean duration of follow up was 19.14 months (range). Three patients progressed to chronic arthropathy. Cyclosporine led to dramatic recovery in five patients. Macrophage activation syndrome (MAS) was present in two patients, one after sulfasalazine therapy. One patient with MAS died. Still’s disease, although uncommon, has characteristic constellation of clinical and laboratory features and should be considered in the differential diagnosis of fever of unknown origin. Nonsteroidal anti-inflammatory drugs, steroids, and methotrexate may not be always effective, and cyclosporine is an effective drug in resistant cases. Sulfasalazine should be avoided in cases of AOSD. S. Singh : R. Samant (*) : V. R. Joshi Department of Rheumatology, P.D. Hinduja National Hospital & Medical Research Center, V.S Marg, Mahim (w), Mumbai-16, India e-mail: [email protected] Keywords Adult onset Still’s disease . Arthropathy . Cyclosporine . Macrophage activation syndrome . Sulfasalazine Introduction Still’s disease is a systemic inflammatory disorder of unknown etiology, and pathogenesis characterized by high spiking fever, arthralgia or arthritis, sore throat, transient maculopapular rash, lymphadenopathy, hepatosplenomegaly, and serositis. Although more common in children, cases are seen in adult practice also. Nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids are useful for acute disease; however, relapses are common, and chronic disease requires immunosuppressive therapy. However, data on the disease course and ultimate outcome of adult onset Still’s disease (AOSD) from India are limited. We analyzed the clinical manifestations, laboratory parameters, disease course, and outcomes of patients with Still’s disease at our institution. Materials and methods This is a retrospective analysis of 14 patients with AOSD. All patients were seen at the rheumatology clinic from 2000 to 2004. Diagnosis was based on Yamaguchi’s criteria after exclusion of common infections, hematological and autoimmune diseases [1]. Following data were recorded: demographic features, duration of illness before diagnosis, clinical features, complete hemogram, erythrocyte sedimentation rate (ESR), liver function tests, renal function tests, urine routine, 36 X-ray chest, rheumatoid factor (RF), antinuclear antibody (ANA) and serum ferritin levels, treatment, length of followup, disease course, outcome, and complication. Results Fourteen patients met the diagnostic criteria of AOSD. The age at onset ranged from 16 to 59 years with a mean of 29.85; the male to female ratio was 9:5. The mean duration of illness before diagnosis was 14.5 months (range 0.5–72 months). Fever was the presenting symptom in all the patients. Polyarticular joint involvement was present in 10 patients, while four had pauciarticular large joints involvement. Sacroiliac involvement was present in one patient. Sore throat was present in five patients. Rash was present in eight patients, of which four had the typical transient rash, three had severe pruritis associated with the rash, while one patient had persistent rash over the palms. Twelve patients had significant weight loss at presentation. Lymphadenopathy was noted in 10, hepatomegaly in 8, and splenomegaly in 8 patients. Pericarditis was present in two patients and pleural effusion in one. Analysis of laboratory parameters revealed mean hemoglobin of 10.0 g/dl (range 7–13.3). ESR was elevated in all and ranged from 57 to130 mm at 1 h with a mean of 98.31. Thrombocytosis (range 4.5–7.45 lacs/mm3) was present in ten patients, while five patients had normal platelet count. RF, done in 10 patients, was absent in nine patients. One patient had weakly positive RF. ANA by immunofluoroscence was negative in all cases. Serum ferritin was estimated in eight patients. It was increased in seven of them (128–64,500 ng/ml). Hepatic dysfunction was present in seven (50.00%) patients at presentation, with elevated aspartate aminotransferase and alanine aminotransferase (range 61–442 U/l), while total bilirubin was increased (3.4 mg/dl) in only one patient. Renal function tests were normal in all cases. At a mean follow-up of 19.14 months (range 3–48), joint damage due to persistent arthritis was seen in three patients involving the wrists in all cases. The complications included macrophage activation syndrome (MAS) in two of whom one died. The first patient was diagnosed to have Still’s disease in December 2003 and was doing well on methotrexate and 5 mg of prednisolone. Sulfasalazine was started, as she was not tolerating methotrexate. A week later, she presented with exfoliative rash over the face, stomatitis, hematemesis, and jaundice. Investigations revealed the following: Hb 9 g/dl; total count 305,000; platelets 55, 000; international normalized ratio 4; serum ferritin 65,400 ng/ml; Clin Rheumatol (2008) 27:35–39 serum fibrinogen 10 mg/dl; triglycerides 450 mg/dl; serum glutamic oxaloacetic transaminase (SGOT) 2,323 U/l; Serum glutamic pyruvic transaminase (SGPT) 6,294 U/l; lactate dehydrogenase (LDH) 15,071 U/l; viral markers were negative. A diagnosis of possible MAS was made, and she was treated with cyclosporine 3 mg kg−1 day−1. She improved clinically, serum ferritin decreased to 354 ng/ml, and serum fibrinogen increased to 567 mg/dl. The second patient was admitted to our hospital with complaints of pyrexia of unknown origin, large joint pains, generalized pruritus, and weight loss since 3 months. On examination, she was febrile with a puffy face and pallor. BP was 94/60, pulse 100/min. She had bilateral knee effusions with right wrist swelling and a painful left shoulder. She had hepatosplenomegaly, hyperpigmentation over forehead, arms, and soles, and scratch marks all over. After admission, the investigations done on her showed Hb7.8 g/dl, white blood cell 19,890/ mm3, platelets 1.44 lacs/mm3, serum creatinine 1.2 mg/dl, total proteins 5.8 mg/dl, serum albumin 1.8 mg/dl, SGOT 66 U/l, SGPT 23 U/l, total bilirubin 0.7 mg/dl, serum alkaline phosphatase 455 IU/l, serum cortisol 14.3, RF+ve, hepatitis B surface antigen, human immunodeficiency virus, and ANA were negative. Repeat investigations 3 days later showed Hb 6.8 g/dl; total white blood count 340/mm3; platelets 73,000/mm3; SGPT 49 U/l; serum alkaline phosphatase 279 IU/l; LDH −2,328 U/l; total proteins 5.0 mg/dl; serum albumin 1.3 mg/dl; serum creatinine 2.2 mg/dl; uric acid 7.1 mg/dl; serum amylase was normal. Bone marrow revealed hemophagocytosis. During stay in ICU, her BP dropped suddenly, she developed bradycardia followed by asystole. She could not be revived despite all resuscitative measures. None of the patients with hepatic dysfunction progressed to chronic liver disease. Organ damage or vasculitis did not develop in any patient. Hemoglobin improved in all patients; however, the ESR remained elevated in five patients in spite of clinical improvement. Five patients had a monocyclic course, two had intermittent flare, while seven patients had a polycyclic course. All patients had received NSAIDs without much benefit and required additional therapy. Steroids, methotrexate, and chloroquine provided clinical improvement in seven patients (Table 1). In three patients, the disease was resistant to this treatment and was treated with cyclosporine. Two patients received cyclosporine as first-line immunosuppressive. Dramatic improvement in the form of decrease in joint symptoms and signs, reduction in ESR, and increase in hemoglobin was seen within 3 months of starting cyclosporine in four out of five patients (Table 2). Sulfasalazine worsened the disease in three patients including sudden increase in lymphadenopathy in two and MAS in one patient. There was one death due to MAS. Clin Rheumatol (2008) 27:35–39 37 Table 1 Clinical course, treatment, response, complications, and outcome Sr. no Treatment 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Steroids Methotrexate Chq Cyclo Sazo + + + + + + + + + – + + + + + – + + + + + – + – – + + + + – + + + + + – – – – + – + + – + – + – – – – – – + – – + + + – – – – – – + – + + Course Complications and outcome M M P P P IF P M P M P P M IF I MAS,died Chronic arthritis I on therapy Chronic arthritis I on therapy Sazo-worsened, I on therapy Sazo-worsened, I on therapy Mas on sazo, I I on therapy pericarditis, I on therapy chronic arthritis I I Chq Chloroquine, Cyclo cyclosporine, Sazo sulfasalazine, I improved, mas macrophage activation syndrome, M monocyclic, P polycyclic, IF intermittent flares Discussion “Still’s disease” refers to the systemic variant of juvenile arthritis first described by George F. Still in 1897. A similar syndrome was subsequently seen in adults and called AOSD [2]. Most of the studies have described a female preponderance. In our case series, the male to female ratio was 9:5. Larson [3] has reported a similar ratio. The clinical presentation of our patients had some important differences (Table 3). A prodromal sore throat is seen in more than 70% of AOSD patients and seems to associate with onset or flare of disease activity. This was seen in only five (31.25%) of our patients. Singh et al. [4] have reported similar data from India. While 92% of all patients demonstrate some cutaneous manifestation during their illness, the more specific Still’s rash is seen in 86% of patients with AOSD. Rash was seen in 57.14% of our patients, similar to the earlier studies from India [4, 5]. In more than 33% of patients, the rash is pruritic and was present in three of our patients. Polyarticular involvement was present in ten (75%) of our patients consistent with the literature. One of our patients had sacroiliac involvement. This is uncommon, but has been reported by Bywaters and Goldman et al. [6]. The association of AOSD with bony ankylosis of carpal and carpometacarpal articulations approaches 50% for most clinical series and is also prevalent among systemic onset juvenile arthritis patients [7]. In our study, joint damage leading to carpal ankylosis was seen in three patients involving the wrists in all cases. Lymph node biopsy was performed in six of the eight patients with significant lymphadenopathy. Four patients had reactive lymphadenitis, while the initial impression in two patients was suggestive of lymphoproliferative disorder. However, critical review of these two slides refuted the Table 2 Laboratory parameters of patients treated with cyclosporine Patient 1 2 3 4 5 Before cyclosporine After (3–6 months) cyclosporine Hb (g/dl) TC (mm3) Platelet (mm3) ESR (mm at 1 h) Hb (g/dl) TC (mm3) Platelets (mm3) ESR (mm at 1 h) 11 11.4 11.1 9.00 8.4 13,090 17,500 19,000 30,150 5,600 2.8 4.51 6.09 55,000 2.36 110 40 116 64 82 12.6 13.9 14.0 12.6 11.6 7,610 13,000 6,400 12,320 5,990 2.7 2.3 2.5 3.19 2.2 17 09 15 30 36 Hb hemoglobin, TC total white blood count 38 Clin Rheumatol (2008) 27:35–39 Table 3 Comparison of the features of Still’s disease in previous studies Number of patients Age Women Fever Arthritis Rash Sore throat Hepatomegaly Splenomegaly Lymphadenopathy Anemia Raised ESR Elevated transaminases Chen et al. (Taiwan) [18] Mert et al. (Turkey) [19] Singh et al. (Indian) [4] Present study 82 16–35 59 100% 100% 87% 84% – – – – 90% – 20 16–65 12 100% 90% 85% 75% 40% 25% 15% 65% 100% 65% 27 17–65 7 100% 100% 85% 44% 48% 59% 81.5% 96% 100% – 14 16–59 5 100% 100% 57.14% 35.7% 57.14% 57.14% 71.42% 50% 100% 42.8% same and confirmed reactive lymphadenitis. Pleuritis (40%) and pericarditis (30%) are quite common when detected by pleuritic chest pain, auscultatory rub, or the demonstration of pleural or pericardial fluid by abnormal chest radiographs, ultrasonography, or echocardiogram. In our study, pericarditis was found in only two patients and pleural effusion in one. MAS was seen in two patients in our study. The first patient developed MAS after receiving sulfasalazine for a week and was successfully treated with cyclosporine. Ravelli’s group has identified features that correlate best with the diagnosis of MAS. These include elevated serum ferritin (>10,000 mg/ml), triglycerides (>160 mg/dl), fibrinogen (<250 mg/dl), low platelet count, and bone marrow, spleen, or lymph node showing evidence of hemophagocytosis [8]. These characteristic features were present in our patient. The second patient had a fulminant course and the diagnosis of MAS was made postmortem. MAS is a fatal complication and warrants a high index of suspicion for diagnosis followed by aggressive treatment. Elevations in the hepatic enzymes were seen in seven of our patients. Serious hepatic failure and chronic liver disease have also been described; however, none of our patients progressed to these complications [9, 10]. Hyperferritinemia with values between 4,000 and 30,000 mg/ml have often been reported in association with the onset and/or flare of disease activity [11, 12]. Serum ferritin levels were available for eight patients and ranged from 128–64,500 mg/ml, the highest being in patient with MAS. Although very elevated ferritin levels are associated with AOSD, lower levels do not rule out the disease and are not part of the diagnostic criteria. Recently, glycosylated ferritin have been suggested for diagnosis and also incorporated into the diagnostic criteria [13]. However, this was not done in any of our patient due to nonavailability. Treatment of Still’s disease is largely empirical in the absence of randomized clinical trials because of the rarity of the disease. Nonsteroidal anti-inflammatory drugs are rarely sufficient, and around 80% of the patients require corticosteroids. Among the disease-modifying drugs, methotrexate still remains the most effective [14]. Cyclosporine has been advocated by some as a second-line agent in the treatment of refractory AOSD [15]. In our study, all patients required steroids for acute control of the disease. Methotrexate and chloroquine together were effective in seven patients, while three of these progressed to chronic arthropathy. However, cyclosporine provided dramatic benefit in five patients. Three of these were resistant to methotrexate and chloroquine, while two received cyclosporine as first-line immunosuppressive. Sulfasalazine worsened the disease in three patients including sudden increase in lymphadenopathy in two and MAS in one patient. Sulfasalazine has been reported to have frequent severe side effects in AOSD, ranging from mild ones like abdominal pain, nausea, and vomiting to severe ones like hypotension, severe myelosuppression, and fulminant hepatitis [16, 17]. This should be considered while treating patients with chronic arthritis and systemic symptoms. In this study of 14 patients with Still’s disease, we have highlighted that Still’s disease has a characteristic constellation of symptoms and signs and laboratory features. Fatal complications can occur rarely and should be anticipated. Patients can progress to joint damage even on treatment, commonly involving the wrist joint. 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