Clinical and Experimental 2008; 26: 933-937. CASE REPORT

Clinical, biological and Introduction exanthema, , hepat- sonographic response to Adult-onset Still’s disease (AOSD) is an osplenomegaly, and serositis), tender IL-1 blockade in adult-onset uncommon systemic infl ammatory dis- joint count (TJC), swollen joint count Still’s disease order of unknown etiology, character- (SJC), physician global assessment of ized by high-spiking , evanescent disease activity, patient assessment of R. Priori*, F. Ceccarelli*, salmon-pink rash, , hepatic ; DAS28 was calculated and ACR F. Barone, A. Iagnocco, dysfunction, polyserositis, lymphad- response considered (13). The follow- G. Valesini enopathy, splenomegaly, or ar- ing laboratory values were also collect- thralgias (1). Although its pathogenesis ed: haematological profi le, fi rst-hour Divisione e Cattedra di Reumatologia, remains unclear, abnormalities in cy- erythrocyte sedimentation rate (ESR), “Sapienza” Università di Roma, Italy. tokine serum levels documented a Th1 C-reactive protein (CRP), and serum *The fi rst two authors contributed equally predominance with high serum con- ferritin levels. Laboratory data and joint to this work. centration of IL-1, IL-6, TNF-α, IFN-γ scores before treatment are summarized Roberta Priori, MD and soluble IL-2 receptor, candidating in Table II. Fulvia Ceccarelli, MD AOSD as a Th1 mediated disease (2). US was performed in hand and wrist Francesca Barone, MD Several conventional treatments have bilaterally in the patients 1, 2 and 3; Annamaria Iagnocco, MD been used in AOSD, such as non-ster- in patient 1 joint was also stud- Guido Valesini, MD, Professor of oidal anti-infl ammatory drugs, often in ied. The joints evaluated were chosen Rheumatology combination with corticosteroids, and because they were involved in our pa- Please address correspondence to: immunosuppressive therapy (metho- tients. US was performed by an expe- Professor Guido Valesini, trexate, azathioprine, cyclosporine A, rienced rheumatologist sonographer, Divisione di Reumatologia, Policlinico Umberto I, lefl unomide, and cyclophosphamide) or using a Philips/HP Image Point HX Viale del Policlinico, intravenous gammaglobulins (3). More machine equipped with 10 and 14 MHz 00161 Roma, Italy. recently, anti- agents (anti- linear probes for knee and wrist/hand E-mail: [email protected] TNF-α anti-IL1, anti-IL6) have been respectively. Power Doppler (PD) was Received on October 29, 2007; accepted in sporadically used in refractory AOSD, also applied with the following settings: revised form on April 14, 2008. opening new avenues to the therapeutic frequency 7.5 MHz, PRF 700-1000Hz, © CopyrightCopyright CLINICAL AND approach of this disease, which, up to gain 18-40dB, low fi lter. The joints were EXPERIMENTAL RHEUMATOLOGY 2008.2008. now, remains empirical. The IL-1 recep- examined according to EULAR guide- tor antagonist (IL-1Ra) anakinra seems lines for ultrasonography in Rheuma- Key words: Adult-onset Still’s to be effective for AOSD (4-12) even tology and the presence of alterations disease, sonography, IL-1, anakinra, if neutralisation of IL-1 might be more within the joint and periarticular soft therapy. effective in patients with highly active tissues were considered to be present systemic disease than in patients with according to OMERACT defi nitions chronic arthritis, with no or less intense for ultrasonographic pathology related systemic symptoms (12) (Table I). to common pathological lesions seen We report three cases of AOSD with in patients with infl ammatory arthritis severe joint involvement resistant to (14, 15). The presence of infl ammation conventional treatment where anakinra was documented in joints and/or peri- administration resulted in sustained re- articular tissues (joint effusion, syno- mission. Moreover, the benefi t on arthri- vial proliferation, hyperaemia in the tits was confi rmed by musculoskeletal synovial tissue, tenosynovitis) together ultrasound (US). with the presence of permanent dam- age (bone erosions and cartilaginous Patients and methods abnormalities). For all the changes a Between 2000 and 2007, 18 patients semiquantitative score (0-3) was used with AOSD classifi ed according to for each structure examined, where 0 Yamaguchi criteria were seen in the De- indicated the absence of any change partment of Rheumatology, Sapienza and 1 to 3 the presence, respectively, Università di Roma. of slight, moderate, and severe chang- Among them, 3 were considered refrac- es. The subsequent summed total was tory to traditional treatment and, after used as an indicator of global change in obtaining informed consent, were treat- each joint (single-joint score). The sum ed with anakinra (100mg/subcutaneous- of the single-joint scores was used as ly daily). The patients were evaluated at an indicator of overall polyarticular in- baseline and after 3 months of anakinra volvement in each patient (total score) Competing interests: none declared. treatment for systemic symptoms (fever, (16).

933 CASE REPORT Anakinra in AOSD / R. Priori et al.

Table I. Anakinra therapy in AOSD. Principal studies published so far.

Authors Patients Concomitant therapy Follow-up Patients evaluation

Rudinskaya A et al. (2003)4 1 pt PDN, MTX 12 months ESR, CRP, ferritin, WBC

Aelion J et al (2004)6 2 pt Pt 1: PDN, MTX Not specifi ed ESR, ferritin, WBC Pt 2. no therapy

Haraoui B et al. (2004)7 3 Pt 1. PDN, Cy Pt 1: 6 months Only clinical response Pt 2: PDN, MTX, HCQ Pt 2: 4 months Pt 3: PDN, MTX Pt 3: 5 months

Fitzgerald AA et al. (2005) 9 4 pt Pt 1: PDN Pt1*: 12 months Pt 1: ferritin, CRP, WBC, IL18 Pt 2: PDN Pt 2**: 14 months Pt 2: ESR, WBC Pt 3: PDN, MTX Pt 3: 6 months Pt 3: CPR, WBC, ferritin Pt 4: PDN Pt 4: 12 months Pt 4: CPR, WBC, ESR, ferritin

Vasques Godinho FM et al. (2005) 5 1 pt PDN, MTX 18 months ESR, WBC

Kalliolias GD et al. (2007) 10 4 pt PDN 5-17 months Clinical evaluation, WBC ESR, CRP, ferritin

Kötter I et al. (2007) 11 4 pt Pt 1: PDN, LFN 12 months Clinical evaluation, ESR, CRP, IL-6, Pt 2: PDN, MTX TNF-α Pt 3: PDN, MTX Pt 4: PDN; MTX

Lequerrè T et al. (2007) 12 15 pt 12 pts: PDN 1-27 months ACR response, HAQ, clinical evaluation 10 pts: MTX 1 pt: MMF + col 1 pt: col

*On two different occasions the patients witheld anakinra with reactivation of the disease. She fi nally progressed to activation syndrome and cyclosporine was added. **On one occasion anakinra was stopped and successfully restarted. (MTX: methotrexate; PDN: prednisone; Cy: cyclophosphamide; MMF: mycophenolate mofetil; LFN: lefl unomide; HCQ: hydroxychloroquine; col: colchi- cine; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; WBC: white blood cell).

Table II. Laboratory parameters, joint clinical and sonographic scores before and after three months of treatment with anakinra.

Patient 1 Patient 2 Patient 3 Baseline After 12 weeks Baseline After 12 weeks Baseline After 12 weeks

ESR (mm/h) 18 4 8 9 68 8 CRP (mg/dl) 6 1 5 2 32 3 Ferritin (ng/ml) 1130 28.3 118 13.3 820 62.5 Tender joint 12 4 18 1 14 2 Swollen joint 10 1 8 0 6 0 Prednisone (mg/daily) 25 5 25 12.5* 25 7.5 VAS for activity disease of patient 76 20 64 5 72 10 VAS for activity disease of physician 78 46 58 5 70 5 DAS28 index 5.91 2.79 5.66 2.10 6.77 2.3 ACR response – ACR50 – ACR50 – ACR20 US score 18 4 48 12 22 6

*on alternate days.

PD evaluation was performed for the of wrists, hands and , intermittent trexate (MTX) in the last 2 months, oral analysis of vascularization of the syno- fever (up to 39°C), faringodynia and prednisone 25 mg/daily and indometa- vial membrane with a scoring system rash associated to increase in C-reac- cine) and even if biological markers of ranging from 0 to 3 (indicating respec- tive protein (CRP) level (60mg/liter), activity ameliorated, an invalidating tively absence of increased perfusion ESR 38 mm/h and ferritin (1030 ng/ hand, wrist and knee arthritis persisted. or minimal, moderate severe perfusion) ml). After the exclusion of infective, US, perfomed in the involved joints, (17). The single joint scores were added neoplastic and other rheumatic disor- showed wrists synovial proliferation to obtain a global US score. ders, AOSD was diagnosed. The pa- with erosions of radio-carpal bone sur- tients responded only partially to treat- face, tenosynovitis of left fl exor carpi Case 1 ment (methotrexate 15 mg/im weekly radialis and fl exor carpi ulnaris, syno- A 32-year-old north African woman for fi ve months, hydroxychloroquine vitis of second and third MCP and knee presented with symmetric poliarthritis (HCQ) 400 mg/daily added to metho- joint effusion. MTX was stopped and

934 Anakinra in AOSD / R. Priori et al. CASE REPORT anakinra started with a progressive im- taper prednisone. At baseline US evalu- synovial proliferation at the radio-car- provement of joint symptoms. By the ation of hand and wrist showed bilateral pal joints, mild intra-articular effusion end of the 8th week of treatment the pa- effusion in 2nd, 3 nd and 4 nd MCP and at the MCPs; tenosynovitis of the 2nd tient developed a diffuse itching rash wrist joints with synovial proliferation and 4nd fi nger fl exor tendons. Anakinra of the face, limbs and abdomen. Ana- and positive PD. Moreover, tenosynovi- 100 mg fl sc/daily was started with dra- kinra was discontinued and MTX was tis was present in fl exor tendons of 2nd, matic improvement; prednisone could reintroduced. US performed after ana- 3nd and 4nd fi ngers. Anakinra was started be tapered to 7.5 mg daily. US per- kinra discontinuation showed improve- and after three months, US performed formed after three months in the same ment of the synovitis in the second and in the same joints studied at baseline, joints showed the presence of bilateral third MCP, resolution of synovitis and demonstrated the resolution of teno- mild effusion in the radio-carpic joint tenosynovitis in the wrist and of joint synovitis of hand and wrist, with per- and 2nd and 3nd MCP joint. effusion in the knee. The patient, treat- sistence of mild effusion in 2nd and 3 nd ed with MTX 15 mg weekly and low MCP and wrist joints bilaterally. Pred- Results doses of oral corticosteroids, was still nisone could be was tapered up to 12.5 Table II shows laboratory parameters, in clinical remission 6 months after mg on alternate days. joint clinical and sonographic scores be- anakinra discontinuation. fore and after three months of treatment Case 3 with anakinra. A relevant improvement Case 2 A Caucasian women with Turner’s of joint involvement was recorded in A 32-year-old32-year-old CaucasianCaucasian womenwomen pre-pre- disease (mosaicism 90%XX; 10%XO) all the patients, in particular the mean sented fever up to 39°C, evanescent periodically treated with intravenous DAS28 reduced from 6.1 to 2.2; when macular rash, lymphadenopathy, ar- immunoglobulins because of selec- considering the ACR response criteria, thritis of hands and wrists, fatigue and tive IgG1 defi ciency was diagnosed 2 patients achieved ACR50 response myalgia. Laboratory evaluation showed with AOSD (wrist and hand arthritis, and one patient ACR20 response. US a white blood cell (WBC) count of remittent fever up to 39°C, maculo- evaluation demonstrated a good re- 15,530/μl, ESR 120mm/h, CRP 47mg/ papular rash, increase of ESR, CRP, sponse to treatment: mean US score dl and ferritin 993ng/ml. Other neoplas- ferritin and transaminases) at the age decrease from 29.3 to 6.6. (Fig. 1). The tic, infl ammatory and infective diseases of 16 and she was successfully treated mean dose of steroids could be reduced were excluded and AOSD diagnosed. with oral prednisone. At 22 years old, in all the patients. She was initially treated with MTX 15 there were new episodes of fever and mg im/weekly, HCQ 400 mg /daily, skin rash, hepatic involvement and se- Further follow-up prednisone 25 mg with disappearance vere hand and wrist arthritis; this last Two patients (cases 2 and 3) are cur- of fever, rash and lymphadenopathy, feature was resistant to HCQ 400 mg/ rently treated with anakinra, with mean amelioration of laboratory infl amma- daily and oral prednisone 25 mg/daily follow-up duration of 92 weeks. Patient tory markers but persistence of severe while other symptoms had subsided. 2 is still in remission after 29 months joint involvement. It was not possible to US showed intrarticular effusion with without side effects; patient 3 was in

Fig. 1. Longitudinal and transverse scan of superfi cialis and profundus fl exor tendon of the second fi nger before (A) and after therapy with anakinra in patient 2. (A): hypoechoic region (*) around fl exor tendon as from tenosynovitis; (B): disappearance of hypoecoic region, as from resolution of tenosynovitis.

935 CASE REPORT Anakinra in AOSD / R. Priori et al. remission up to 12 months of anakinra by anakinra, defi ning the response as our patient, resistant to MTX clinical treatment, when presented a fl are-up of a resolution of systemic symptoms response persisted after anakinra with- hand and wrist arthrits with improve- and an improvement of the ACR score. drawal for adverse effect and clinical ment after increase of steroid dosage. The response to anakinra after 3 and 6 remission was maintained with meth- months was rapid and sustained in most otrexate (previously ineffective) only, Discussion patients with AOSD and in a signifi cant supporting the role of this drug even Evidence-based medicine guidelines proportion of SoJIA patients: 11 of the in remission induction. Even if an as- for the management of AOSD are lack- 15 AOSD patients achieved at least a sociation between Turner’s syndrome ing and this disease still represents a 50% improvement for all disease mark- and infl ammatory arthritis have been therapeutic challenge. Recent advances ers (12) The authors suggest that anak- already described (26), the third case in AOSD pathogenesis advocate a key inra might be more effective in patients can be considered a peculiar one in that role for infl ammatory cytockines such with highly active systemic disease she had also a IgG1 defi ciency which as IL-1 and IL-18 in the disease patho- than in those with chronic arthritis. Al- was periodically treated with i.v. im- genesis, favouring the usage of block- though AOSD arthritis is known to be munoglobulins. Such treatment had no ing agents against these molecules in not progressive or deforming (25), in impact on AOSD systemic symptoms refractory AOSD treatment (18-20). our patients joint involvement and the nor on the arthritis which fi nally re- IL-1 is a potent pyrogen and hemato- consequent physical inability were the solved with anakinra. Of note, no side poietic growth factor and it is known most prominent clinical features, while effects were recorded in this case. to up-regulate, through IL-6 synthesis, systemic symptoms and laboratory ab- In conclusion, this observation sug- the expression of acute-phase reactants. normalities had partially responded to gests that anakinra might be useful for Moreover IL-1 appears to mediate the conventional treatment. High degree of AOSD with severe joint involvement disease also at articular level by inter- infl ammation was shown by US in the resistant to conventional treatment. acting with other cytockines such as affected joints, as demonstrated by the IL-18 and TNF-α (21). All these data presence of signs of synovitis, joint ef- References correlate with the biological effects fusion, hyperperfusion, tenosynovitis. 1. EFTHIMIOU P, PAIK PK, BIELORY L: Diag- nosis and management of adult onset Still’s observed in AOSD patient after anak- Over the last few years, US has become disease. Ann Rheum Dis 2006; 65: 564-72. inra administration, showing marked an established imaging technique in 2. CHOI JH, SUH CH, LEE YM et al.: Serum decrease in IL-1, IL-18, IL-6 levels, rheumatology because of its ability to cytokine profi les in patients with adult onset signifi cant clinical improvement with visualize soft tissue changes and it is Still‘s disease. J Rheumatol 2003; 30: 2422- 7. fever and leucocytosis disappearance nowadays considered a fi rst line tool 3. EFTHIMIOU P, GEORGY S: Pathogenesis and (22-25). for monitoring disease activity and re- management of adult-onset Still’s disease. Reports of anakinra use in AOSD are sponse to treatment also with biological Semin Arthritis Rheum 2006; 36: 144-52. limited. Rudinskaya et al. report the agents (16). 4. RUDINSKAYA A, TROCK DH: Successful Treatment of a patient with refractory adult- case of an adult patient with AOSD, As far as we know, US has never been onset Still disease with anakinra. J Clin previously refractory to conventional used to evaluate response to anakinra Rheumatol 22003;003; 99:: 3330-2.30-2. therapies, who dramatically responded in AOSD: with this tool we could docu- 5. 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Ann Rheum Dis 2004; 63 (Suppl.): 293-4. Recently, Kalliolias described 4 pa- late DAS 28 and ACR response. Even 8. AKRITIDIS N, PAPADOPOULOS A, PAPPAS G: tients who experienced a fast and safe if larger studies should be performed, Long-term follow-up of patients with adult- response to anakinra, with a steroid possibly with a longer follow-up, our onset Still’s disease. Scand J Rheumatol 2006; 3: 395-7. sparing effect (10). Kötter confi rmed report, strenghtened by the use of US, 9. FITZGERALD AA, LECLERCQ SA, YAN A, this result in 4 other patients, underly- suggests that anakinra might be useful HOMIK JE, DINARELLO CA: Rapid responses ing that IL-18 serum levels, CRP, ESR, in AOSD also in the presence of severe to anakinra in patients with refractory adult- liver enzymes, ferritin, and WBC, may arthritis. This observation is partially in onset Still’s disease. Arthritis Rheum 2005; 52: 1794-803. be helpful in assessing disease activity contrast to what previously reported by 10. 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936 Anakinra in AOSD / R. Priori et al. CASE REPORT

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