Adult Onset Still ' s Disease : A Case Report and Review of Literature

o manifest a fever of ≥ 39.0 C. The highest temperatures are 7 seen in late afternoon or early evening. In the differential diagnosis of a patient with FUO (fever of unknown origin), maculopapular rashes, arthralgia and sore throat should raise 8-11 the suspicion of AOS. Febrile spikes are often accompanied by exacerbation of other symptoms like rash, fatigue and 12 arthralgia. The classic rash is an evanescent, Salmon-pink, maculopapular eruption, which frequently appears during febrile attacks and is predominantly found on the proximal 13 limbs and trunk with rare involvement of face. Even though >90% patients in series reported from West have this characteristic rash, this has been less reported in studies from India, probably due to difficulty in identifying the rash in 14,15 people with dark skin. This rash can be induced by a minor trauma (Koebner’s phenomenon) and dermatographism is a frequently encountered phenomenon in patients with AOSD. Sore throat is known as a cardinal sign 16 of AOSD and may be associated with odynophagia. Arthralgias and arthritis occur in about 64% to 100% of the patients and flare up of joint symptoms occur during the 17 febrile spikes. The most common joints involved are the knees, wrists, ankles and elbows. Sacro-illiac involvement is uncommon. Destructive arthritis is found in 25% of cases. Joint fluid aspirate often discloses marked leucocytosis with a PMN predominance. Generalized myalgia is seen in many 18 patients and can be severe and coincide with fever spikes. Lymphadenopathy develops in 44% to 90% of patients with 19,20 AOSD, and may raise suspicion of lymphoma initially. Hepatosplenomegaly is common in early disease and reflects 21 tissue infiltration by inflammatory cells. Macrophage activation syndrome (MAS) is a life threatening condition, which is characterized by uncontrolled activation and proliferation of T-lymphocytes and macrophages in bone marrow, RES and CNS. MAS is a dreaded complication of rheumatic diseases, especially systemic onset Juvenile rheumatoid arthritis, has also been reported in AOSD and should be considered in patients with AOSD when it presents with acute febrile illness, hepatosplenomegaly, lymphadenopathy, pancytopenia and increased liver enzymes, coagulopathy, CNS, pulmonary and renal involve22 ment. The reactive hemophagocytic syndrome (RHS) is a term describing a condition similar to MAS from clinical and also the laboratory stand-point in patients with AOSD. was normal. Her laboratory investigations revealed Hb of 2 10.6 gm/dl, TLC of 24.22/mm with 84% polymorphs, with high ESR of 65mm1st hour by Westergren's method. KFT was normal. LFT showed mild transaminitis with AST of 56 U/L and ALT of 82 U/L with proteins of 7.58gm/dl and albumin of 3.2gm/dl. ALP was normal. She was extensively worked up for infections. Her repeated blood culture (x4) came sterile. Her urine routine was normal, urine for culture sensitivity was normal. Chest X-ray was normal, USG abdomen was normal except mild splenomegaly. Her Montoux test was negative (<5mm). The trans-esophageal echocardiography(TEE) was normal. Bone marrow showed mild iron deficiency anaemia. Her ASO was negative, throat swab for culture sensitivity was sterile. The PBF for MP ,and viral serology (CMV, EBV, HBsAg and HIV) were negative. The CRP was positive,whileas ANA, anti dsDNA and RF were negative. After extensive workup, we made the diagnosis of “Adult Still's disease” as she was fulfilling most 5 of the criteria laid down by Yamaguchi. We sent her serum ferritin levels, which came markedly elevated, of the order of 3601mg/L. She was put on Naproxysn 500 mg TDS and showed marked response. Her fever, rash, arthralgias and myalgias subsided. Her leucocyte count decreased to baseline and was following our department regularly. The patient remained asymptomatic for around one year when in March 2011, she again presented with two weeks' history of high o grade fever (40 C), myalgias, arthralgias and evanescent rash. Her G.P. examination revealed mild pallor, and maculopapular rash on trunk and body which was transient in nature. Her laboratory investigations revealed TLC of 3 15.37/mm with 92% polymorphs. Platelet count of 3 413000/mm , ESR of 84mm1st hour(Westergren's method) Her septic screen was negative. Serum ferritin levels were slightly elevated (586mg/L). Her ANA, RF, Anti-dsDNA were negative. She was diagnosed as polycyclic Adult Still's disease. She did not respond well to Naprosyn 500mg TDS and was put on steroids (Predinsone 40mg/day) and she showed a marked response. Her symptoms, signs and lab. parameters improved markedly and is following our outpatient department.

arthralgia.The classic rash is an evanescent, Salmon-pink, maculopapular eruption, which frequently appears during febrile attacks and is predominantly found on the proximal 13 limbs and trunk with rare involvement of face.
Even though >90% patients in series reported from West have this characteristic rash, this has been less reported in studies from India, probably due to difficulty in identifying the rash in 14,15 people with dark skin.
This rash can be induced by a minor trauma (Koebner's phenomenon) and dermatographism is a frequently encountered phenomenon in patients with AOSD.Sore throat is known as a cardinal sign 16 of AOSD and may be associated with odynophagia.Arthralgias and arthritis occur in about 64% to 100% of the patients and flare up of joint symptoms occur during the 17 febrile spikes.The most common joints involved are the knees, wrists, ankles and elbows.Sacro-illiac involvement is uncommon.Destructive arthritis is found in 25% of cases.Joint fluid aspirate often discloses marked leucocytosis with a PMN predominance.Generalized myalgia is seen in many 18 patients and can be severe and coincide with fever spikes.Lymphadenopathy develops in 44% to 90% of patients with 19,20 AOSD, and may raise suspicion of lymphoma initially.Hepatosplenomegaly is common in early disease and reflects 21 tissue infiltration by inflammatory cells.Macrophage activation syndrome (MAS) is a life threatening condition, which is characterized by uncontrolled activation and proliferation of T-lymphocytes and macrophages in bone marrow, RES and CNS.MAS is a dreaded complication of rheumatic diseases, especially systemic onset Juvenile rheumatoid arthritis, has also been reported in AOSD and should be considered in patients with AOSD when it presents with acute febrile illness, hepatosplenomegaly, lymphadenopathy, pancytopenia and increased liver enzymes, coagulopathy, CNS, pulmonary and renal involve-22 ment.The reactive hemophagocytic syndrome (RHS) is a term describing a condition similar to MAS from clinical and also the laboratory stand-point in patients with AOSD.was normal.Her laboratory investigations revealed Hb of 2 10.6 gm/dl, TLC of 24.22/mm with 84% polymorphs, with high ESR of 65mm1st hour by Westergren's method.KFT was normal.LFT showed mild transaminitis with AST of 56 U/L and ALT of 82 U/L with proteins of 7.58gm/dl and albumin of 3.2gm/dl.ALP was normal.She was extensively worked up for infections.Her repeated blood culture (x4) came sterile.Her urine routine was normal, urine for culture sensitivity was normal.Chest X-ray was normal, USG abdomen was normal except mild splenomegaly.Her Montoux test was negative (<5mm).The trans-esophageal echocardiography(TEE) was normal.Bone marrow showed mild iron deficiency anaemia.Her ASO was negative, throat swab for culture sensitivity was sterile.The PBF for MP ,and viral serology (CMV, EBV, HBsAg and HIV) were negative.The CRP was positive,whileas ANA, anti dsDNA and RF were negative.After extensive workup, we made the diagnosis of "Adult Still's disease" as she was fulfilling most 5 of the criteria laid down by Yamaguchi.We sent her serum ferritin levels, which came markedly elevated, of the order of 3601mg/L.She was put on Naproxysn 500 mg TDS and showed marked response.Her fever, rash, arthralgias and myalgias subsided.Her leucocyte count decreased to baseline and was following our department regularly.The patient remained asymptomatic for around one year when in March 2011, she again presented with two weeks' history of high o grade fever (40 C), myalgias, arthralgias and evanescent rash.Her G.P. examination revealed mild pallor, and maculopapular rash on trunk and body which was transient in nature.Her laboratory investigations revealed TLC of 3 15.37/mm with 92% polymorphs.Platelet count of 3 413000/mm , ESR of 84mm1st hour(Westergren's method) Her septic screen was negative.Serum ferritin levels were slightly elevated (586mg/L).Her ANA, RF, Anti-dsDNA were negative.She was diagnosed as polycyclic Adult Still's disease.She did not respond well to Naprosyn 500mg TDS and was put on steroids (Predinsone 40mg/day) and she showed a marked response.Her symptoms, signs and lab.parameters improved markedly and is following our outpatient department.

Discussion
The diagnosis of Adult Still's disease is possible only by recognizing the striking constellation of clinical and labora-6 tory abnormalities.Moreover, it is a diagnosis of exclusion.One needs to exclude infections and other rheumatological or blood disorders before arriving at the diagnosis of Adult Still's disease.The infective, rheumatological and blood disorders like lymphoproliferative disorder or multiple myeloma were ruled in our patient.Our patient under discussion shared most of the features as laid down for The laboratory investigations reflect an exaggerated inflammatory response as evidenced by an elevated ESR and leucocytosis >15000/mL with ≥ 80% PMN, anaemia of chronic disease, hypoalbuminemia and thrombocytosis.Pancytopenia has been described in AOSD associated with 26 hemophagocytic syndrome (HS).Rheumatoid factor and antinuclear antibody tests are generally negative and if 27 positive, these are of low titers.High levels of ferritin seem to be characteristic of AOSD.Nearly 70% of patients have hyper-ferritinemia.Ferritin levels in AOSD are usually higher than those found in other autoimmune or inflamma-28-30 tory diseases.
Several cytokines like IL-Ib, IL-18, TNF-a and IL-6 seem to have some role in increasing the production of ferritin.A more specific diagnostic marker may be drop in glycosylated ferritin.In AOSD, decreased glycosylated ferritin, an isoform of ferritin was noted in comparison with other inflammatory diseases.In healthy individuals 50-80% ferritin is glycosylated, while in inflammatory diseases, it 31 drops to 20%-50% and in AOSD less than 20%.Hyperferritinemia with a value between 4,000 and 30,000mg/dl has 32 been reported in associated with onset and disease activity.
The disease may have a monocyclic (25-30%), polycyclic (25-30%) or chronic course (30-50%).In those with monocyclic course, the disease remits within a year, never to appear again.Those with polycyclic course have intermittent disease and characteristically the intensity tends to be less severe and the duration shorter in the subsequent episodes in comparison to first.Chronic disease is the most disabling, leading to chronic disabling arthritis.
Aspirin or NSAIDS are recommended as the initial treatment in AOSD, but the response rate is as low as 20% to 33 25%.Liver enzymes should be closely monitored in patients 34 in whom NSAIDS are used.Since response to NSAID monotherapy is not enough, most patients are treated with corticosteroids in the course of their disease, with an efficacy of upto 95%.Predinisolone should be used for the patients who do not respond to NSAIDS and also for patients suffering from persistent anaemia, peri-carditis, serositis, and 35 marked elevation of liver enzymes.Steroids are started with dose of 0.5 to 1mg/Kg and once the symptoms improve, they are tapered to lowest minimal dose.Relapses and flares may occur once steroids are tapered or stopped, however, they are treated with similar doses and usually respond well.Disease modifying antirheumatic drugs (DMARD) such as Methotrexate (MTX), Azathioprine, cyclophosphamide, and cyclosporine have been used for maintenance therapy and 36 control of disease.Biological therapies such as anti-TNF-α antibody infliximab, etnercept an anti TFN-α receptor blocker, and others have been reported to be effective in AOSD patients who do not respond to corticosteroids or 37,38 DMARD.Rituximab (anti-CD20; monoclonal antibody) is a new option in treatment; there are some case 39 reports about its usefulness in AOSD.In a few care reports, the efficacy of leflunomide was shown in the treatment of 40 AOSD.
Tocilizumab, a humanized anti IL-6 receptor monoclonal antibody of the IgG subclass has been addressed 41 in 2 case reports as being effective for AOSD.
The need to recognize Adult Still's disease as a separate clinical entity has been repeatedly stressed.AOSD, an important cause of FUO, remains a diagnosis of exclusion in the absence of one or more classical features.It is, therefore necessary for physicians to appreciate that AOSD is syndrome that affects adults.