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Morbo di Still

Adult Still’s disease

Autore: Lisa A Mandl, MD, MPH; John M Esdaile, MD
Data: 28/04/2006
Fonte: www.utdol.com

 

UpToDate performs a continuous review of over 350 journals and other resources. Updates are added as important new information is published. The literature review for version 14.1 is current through December 2005; this topic was last changed on May 13, 2005. The next version of UpToDate (14.2) will be released in June 2006.

 

INTRODUCTION — Adult Still’s disease (ASD) is an inflammatory disorder characterized by daily, spiking high fevers, arthritis, and an evanescent rash. First described in children by George Still in 1896, “Still’s disease” became the eponymous term for juvenile rheumatoid arthritis and is now called systemic onset juvenile rheumatoid arthritis [1]. (See “Clinical manifestation and diagnosis of systemic onset juvenile rheumatoid arthritis”). In 1971, ASD was used to describe a series of adult patients who did not fulfill criteria for classic rheumatoid arthritis but had features similar to the children with systemic onset juvenile rheumatoid arthritis [2].

 

ETIOLOGY — The etiology of ASD is unknown. A variety of infectious triggers have been suggested, including the following viruses: rubella, echovirus 7, mumps, Epstein-Barr, cytomegalovirus, parainfluenza, and parvovirus [3-6]. Suspected bacterial pathogens include Yersinia enterocolitica and Mycoplasma pneumoniae [5,7].
It has also been suggested that genetic factors may be important. In one series of 62 French patients, for example, HLA-B17, B18, B35, and DR2 were significantly associated with ASD [8]. However, other studies have not confirmed these findings [9]. Familial cases are very uncommon and there have been few reports of cases in twins [10].

 

EPIDEMIOLOGY — A retrospective French study estimated the incidence of ASD to be 0.16 cases per 100,000 persons per year with an equal sex distribution [11]. There is a bimodal age distribution, with one peak between the ages of 15 and 25 and the second between the ages of 36 and 46. However, occasional patients present with ASD after the age of 70 [12,13].

 

CLASSIFICATION CRITERIA — There is no specific test or combination of tests that can be used to establish the diagnosis of ASD. Thus, a number of different classification criteria have been proposed for the purpose of classification. To establish a diagnosis of ASD requires the presence of certain major or minor criteria or a combination of both and the absence of certain exclusions (show table 1) [14].
Major criteria — The proposed major criteria include:
Fever of at least 39ºC lasting one week or longer
Arthralgias or arthritis lasting two weeks or longer
Characteristic rash which is a macular or maculopapular, nonpruritic salmon-pink eruption, usually apparent over the trunk or extremities during febrile episodes Leukocytosis (10,000/µL or greater) with 80 percent or more granulocytes

 

Minor criteria — Minor criteria include:
Sore throat
The recent development of significant lymph node swelling
Hepatomegaly or splenomegaly
Abnormal liver function studies, particularly aminotransferases and lactate dehydrogenase
Negative tests for antinuclear antibody and rheumatoid factor

 

Exclusions — The following findings must not be present in ASD:
Infection, such as infectious mononucleosis or parvovirus B19
Malignancy, particularly lymphoma
Other rheumatic diseases such as polyarteritis nodosa, systemic lupus erythematosus, or rheumatoid vasculitis with extraarticular features

 

Six sets of criteria have now been proposed for establishing the diagnosis of ASD [15-20].
These sets are all similar, with the differences being the number of major and minor criteria required. A comparison of these six sets of criteria demonstrated that the Japanese criteria had the greatest sensitivity in establishing the diagnosis when applied to 65 clinically definite French cases of ASD (93 percent) [15]. The Japanese criteria require the presence of five features, with at least two being major diagnostic criteria.

Criteria that avoid the need to specifically exclude other potentially confounding disorders have also been proposed [21]. Major criteria include high spiking fever (39ºC or higher), arthralgia, transient erythematous rash, sore throat, predominance of polymorphonuclear cells (80 percent or more), and glycosylated ferritin of no more than 20 percent. Two minor criteria are a maculopapular rash and leukocytosis (10,000/mm3 or higher). The presence of four or more major criteria or three major and two minor criteria had an 81 percent sensitivity and 99 percent specificity when applied to a group of 207 patients in whom the diagnosis of ASD was considered probable. In this retrospective study 72 patients were felt to have ASD and 130 another disorder and all had been selected because the glycosylated ferritin test had been performed. The reported sensitivity and specificity are encouraging. Further study of this diagnostic approach in other populations is needed but will depend upon the availability of the assay for glycosylated ferritin, a test that is not currently performed in most clinical laboratories.

 

CLINICAL FEATURES — The diagnostic criteria define the major clinical features of ASD (show table 2).
Fever — The fever of ASD is usually quotidian or “double-quotidian” with a brief peak in the late afternoon or early evening. Temperature swings can be dramatic, with changes of 4ºC occurring in four hours [1,16]. In approximately 20 percent of cases, fever persists between spikes [8]. In one study of 130 Turkish adults with FUO, ASD ranked second among identifiable causes of fever; only occult infection was a more common cause [22].

Rash — The classic rash of ASD is described as an evanescent salmon-pink, macular or maculopapular eruption which is apparent with fever, particularly in the evenings. The rash predominantly involves the trunk and extremities, but can also involve the palms and soles, and occasionally the face. It can exhibit the Koebner phenomenon, ie, precipitation by rubbing or hot water. As a result, the rash should be sought in areas subject to tight clothing, such as the waist or beneath the breasts. The rash is frequently misdiagnosed as a drug reaction, especially when the febrile illness has been treated with antibiotics.
Skin biopsy shows mild perivascular inflammation of the superficial dermis, consisting primarily of lymphocytes and histiocytes, and dermal edema (show histology).
Immunofluorescence of the skin biopsy may show slight deposition of C3 in the blood vessel walls [23]. Skin biopsy may help differentiate ASD from vasculitis or Sweet’s syndrome. Musculoskeletal — Arthralgia, arthritis, and myalgias are universal features of ASD. Initially, the arthritis may be mild, transient, and oligoarticular. These manifestations may evolve over a period of months into a more severe, destructive, polyarticular pattern [23].

The most commonly involved joints, in descending order, are the knees, wrists, ankles, elbows, proximal interphalangeal joints and shoulders. The synovial fluid is usually inflammatory, with a mean leukocyte count of 13,000 cells/µL but a range from 100 to 48,200 cells/µL. Synovial biopsy reveals a chronic synovitis with slight cell proliferation in the synovial lining layers, moderate vascular engorgement, and a mononuclear cell infiltrate [8,17].

Myalgias can be severe and debilitating and coincide with fever spikes. Muscle weakness is not present but the serum creatinine kinase and aldolase concentrations can be slightly elevated [8]. Electromyographic studies and muscle biopsy are usually normal or show a nonspecific inflammatory myopathy.
Pharyngitis — A severe, nonsuppurative pharyngitis occurs frequently. One review of 341 cases noted sore throat, which can recur with disease relapses, in 69 percent [24]. Liver disease — Serum transaminases and alkaline phosphatase are often modestly elevated. These changes may antedate the use of nonsteroidal antiinflammatory drugs (NSAIDs) and improve as the disease responds [25].
Eight cases of fulminant liver failure in association with ASD have been described, with four fatalities [8,26]. All patients had been treated with NSAIDs or aspirin. Lymphadenopathy and splenomegaly — Slightly tender, enlarged cervical lymph nodes and splenomegaly are seen in about one-half of patients with ASD. Because of the frequent presence of fever and leukocytosis, there may be diagnostic confusion with lymphoma. Lymph node biopsy in ASD typically shows intense, paracortical immunoblastic hyperplasia, which is distinct from the changes observed with rheumatoid arthritis, systemic lupus erythematosus, or Sjögren’s syndrome [27]. These light microscopic changes may resemble lymphoma. However, immunohistochemistry reveals a benign, polyclonal B-cell hyperplasia, which distinguishes ASD from lymphoma [28,29].

Cardiopulmonary disease — Pericarditis, pleural effusions, and transient pulmonary infiltrates have been observed in 30 to 40 percent of patients with ASD. Affected patients may complain of a slight cough, pleuritic chest pain, or mild dyspnea. However, severe interstitial lung disease has been described [30]. Some patients progress to acute respiratory distress syndrome (ARDS), sometimes with a fatal result [31-33]. Myocarditis is a rare complication that can cause arrhythmias and heart failure [34].
Hematologic manifestations — While rare, pancytopenia may be indicative of the hemophagocytic (macrophage activation) syndrome and bone marrow aspiration reveals proliferation of histiocytes; hemophagocytosis is present in many, but not all, cases [35]. (See “Hemophagocytic lymphohistiocytosis” section on Macrophage activation syndrome). Pure red cell aplasia has also been reported [36].
Thrombotic thrombocytopenic purpura and/or the hemolytic uremic syndrome (TTP/HUS) has been reported rarely in association with ASD as a cause of renal failure and cerebral infarction or encephalopathy [37,38]. A relapsing course of TTP has been reported in one patient with ASD [39]. (See “Diagnosis of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults”).
Microangiopathic hemolytic anemia and thrombocytopenia may also occur if disseminated intravascular coagulation (DIC) develops. In this case there is depletion of fibrinogen, prolongation of the protime (PT) and activated partial thromboplastin time (aPTT) tests. A typical finding on blood smear is the presence of fragmented red cells (schistocytes). Thrombocytopenia and an elevated serum lactate dehydrogenase are also frequent laboratory features of this type of anemia. (See “Clinical features; diagnosis; and treatment of disseminated intravascular coagulation”).

 

LABORATORY FINDINGS — A number of laboratory findings are characteristically seen in patients with ASD. None is specific for ASD, but the constellation of the clinical features listed above plus the presence of these laboratory features should alert the clinician to the possibility of ASD (show table 3).
An elevated erythrocyte sedimentation rate (ESR) is seen in virtually all patients [8]. It is typically accompanied by a leukocytosis, with the peripheral white blood cell count exceeding 15,000 cells/µL. There is a predominance of granulocytes and the presence of immature forms, including bands, may suggest a septic process.
A normocytic, normochromic anemia with a hemoglobin less than or equal to 10 g/dL is seen in the majority of patients, and a reactive thrombocytosis is common.
Liver function studies — Elevations in the serum aminotransferases and lactate dehydrogenase are seen in 75 percent of patients with ASD. A wide range of values has been observed, from minimally abnormal to fulminant hepatic necrosis and death [8,26]. The liver biopsy findings are nonspecific [40].
Serum ferritin — ASD has been associated with markedly elevated serum ferritin concentrations in as many as 70 percent of patients [5]. This is probably an acute phase response since hepatocytes responding to inflammatory cytokines can increase ferritin synthesis [41]. The elevations correlate with disease activity, and have been suggested as a serologic marker to monitor the response to treatment [42-44].
Serum ferritin concentrations exceeding 3000 ng/mL (normal 40 to 200 ng/mL) have been observed in ASD, with some patients having values above 10,000 ng/mL [35,45]. It has been suggested that serum ferritin values above 3000 ng/mL, in a patient with compatible symptoms, should lead to suspicion of ASD in the absence of a bacterial or viral infection [35]. This degree of hyperferritinemia is not observed with other rheumatic diseases.
Glycosylation of ferritin also may help distinguish ASD from other rheumatic diseases, particularly in atypical presentations of the disease [46]. In one study, the percentage of glycosylated ferritin in patients with the ASD was markedly lower than in other inflammatory diseases (3.7 versus 30 percent) [43]. The percentage of glycosylated ferritin may remain low in both the active phase of disease and in remission [47].
Use of both the total serum ferritin and the glycosylated fraction may provide more diagnostic specificity for ASD than reliance upon either test alone. In one report, the combination of a five-fold or greater elevation of serum ferritin and a glycosylated fraction 20 percent had a modest sensitivity for ASD of 43 percent but a relatively high specificity of 93 percent [48].
Both marked hyperferritinemia and a low fraction of glycosylated serum ferritin also occur in hemophagocytic syndromes, such as those due to lymphoma and severe drug reactions [49,50]. This syndrome is characterized by activation of histiocytes with prominent hemophagocytosis in the reticuloendothelial system. It is associated with a variety of disorders, including viral infections, neoplasms and immune-mediated diseases Clinical features of the hemophagocytic syndrome include fever, rash, lymphadenopathy, hepatosplenomegaly, and pancytopenia. In contrast to ASD, arthritis is absent. (See “Hemophagocytic lymphohistiocytosis”).
Immunologic studies — As noted above, absence of antinuclear antibodies and rheumatoid factor is one of the minor criteria for ASD. However, a low titer of either test occurs in less than 10 percent of patients and may obscure the diagnosis [8].
Although nonspecific, elevated serum levels of interleukin-6, tumor necrosis factor-alpha, and interferon gamma are frequently present in patients with ASD [51]. By comparison, an increased serum concentration of interleukin-18 (IL-18), which is currently only available in the research setting, offers promise as a diagnostic test. In one study, the median serum level of IL-18 among 16 patients with ASD was more than two logs higher than that for 53 healthy individuals and for 149 patients with other systemic rheumatic or inflammatory diseases [52]. However, serum ferritin concentrations correlated very closely with the level of IL-18, suggesting that its measurement may add little to currently available laboratory testing.

 

Bone marrow examination — The presence of fever and leukocytosis often lead to examination of the bone marrow to assess for occult infection or evidence of a myeloproliferative disorder. In one series of 12 patients with ASD who had bone marrow examinations performed, hyperplasia of granulocytic precursors was present in all of the marrow samples [53]. Other features that were less frequent included: hypercellularity (75 percent), increased numbers of plasma cells (8 percent), increased histiocytes (25 percent), and the presence of hemophagocytosis (17 percent). (See “Evaluation of bone marrow aspirate smears”).

Radiographic findings — The classic radiographic finding of ASD is a nonerosive narrowing of the carpometacarpal and the inter carpal joint spaces of the wrist, which often progresses to bony ankylosis [54,55]. These changes are eventually seen in about 40 percent of patients [8]. Ankylosis of the cervical spine, tarsal joints, or the distal interphalangeal joints are less common findings. An unusual complication of ASD is the rapid destruction of the hip, and less commonly the knee, which can require total joint arthroplasty [1,8,15,56].

 

COURSE — The clinical course of ASD can be divided into three main patterns [8,57]. Approximately one-third of patients fall into each group [8]:
A self-limited or monophasic pattern usually lasts less than one year, with complete resolution of symptoms.
A polycyclic or intermittent course in which there are one or more flares of disease with complete remission between episodes. Although subsequent flares cannot be predicted, they tend to be less severe and of shorter duration.
A chronic course of ASD is characterized by persistently active disease, usually due to a chronic, destructive arthritis. Although some patients require total joint arthroplasty, about one-quarter of patients in this group eventually improve after many years.
Several predictors of chronic disease and an unfavorable outcome in ASD have been described: The development of a polyarthritis early in the course of ASD or a proximal joint arthritis [4,57,58]
Involvement of the root joints (shoulders or hips) [8]
The need for more than two years of systemic steroid therapy [57,58]
Functional status in ASD is generally very good. In one series of 62 patients with ASD, 36 percent had a chronic disease course but 90 percent were judged to be in ACR functional class I [8]. Only four and two patients were in functional class II and III, respectively. Joint arthroplasty has significantly improved the functional status of many of these individuals with a chronic, destructive arthritis [18].
Chronic active inflammation may lead to secondary (AA) amyloidosis [59,60]. It has been suggested that lymphoma and ASD may both be present in some patients [29,61]; however, we believe the presence of lymphoma should exclude the diagnosis of ASD. There is at present no firm epidemiologic evidence that the subsequent risk of lymphoproliferative disorders is increased in patients with ASD.

 

TREATMENT — Therapeutic decisions should be based upon the organ involvement and the severity of the disease. The choices are nonsteroidal antiinflammatory drug (NSAIDs) and aspirin, glucocorticoids, and immunomodulating drugs.
NSAIDs and aspirin — NSAIDs (including aspirin) are generally used as first-line therapy for ASD, leading to improvement in musculoskeletal symptoms and fever [8,18]. It may be helpful to monitor serum salicylate concentrations since high therapeutic levels (between 15 and 25 mg/dL) are often required [57]. Why such high levels of salicylates are needed in ASD compared with other rheumatic diseases is unknown. Aspirin or an NSAID should be continued for one to three months following disease remission.
As noted above, the rare complication of severe liver failure always occurred in conjunction with NSAID therapy [8,26]. Although a causality has not been proven, close monitoring of liver function tests, particularly early in the course of the disease, is recommended.
Glucocorticoids — Patients with very high fever spikes, debilitating joint symptoms, or internal organ involvement may require glucocorticoid therapy [57]. The usual prednisone dose is 0.5 to 1.0 mg/kg per day. Pulse methylprednisolone is used for life-threatening disease due to severe hepatic involvement, cardiac tamponade, disseminated intravascular coagulation, or other complications.
Immunomodulating drugs — There are no controlled trials assessing the efficacy of any of the immunomodulating drugs in ASD. Intramuscular gold salts have been given, with mixed results, to treat the arthritis of ASD [62]. Other approaches that have been tried include hydroxychloroquine, azathioprine, cyclophosphamide, cyclosporine, sulfasalazine, intravenous immune globulin, anti-tumor necrosis factor-alpha (anti-TNF-alpha) agents, and anakinra [8,62-66].
Cyclosporine — There is limited evidence of the efficacy of cyclosporine. There have been some case reports of successful use [67,68] and one small uncontrolled series of six patients treated with this agent [69]. Among these latter six patients, remissions were reported in four cases and improvement in the other two.
Sulfasalazine — Use of sulfasalazine in patients with ASD may be more likely to produce serious adverse effects than when used in patients with RA. This was the conclusion of a retrospective series of 41 patients with ASD, ten of whom were treated with sulfasalazine [70]. Sixty percent had some side-effect that was attributed to the drug. In contrast, only 15 percent of non-sulfasalazine treated patients had adverse effects.
Methotrexate — Methotrexate has been given to control the systemic disease and as a steroid sparing agent [71-73]. In one series of 13 patients, methotrexate was administered as a first-line agent in a dose of up to 20 mg per week; improvement was noted in eight [73]. Five of the eight responders were HLA-DR4 positive, while all nonresponders were HLA-DR2 positive.
Intravenous immunoglobulin — Intravenous immunoglobulin (IVIG) infusions were reported to result in good responses in five of seven French patients treated every four weeks in one uncontrolled series [74]. One relapse occurred. A total of four to six infusions were given. A critically ill patient also had an excellent response to IVIG combined with mycophenolate mofetil [75].
Anti-tumor necrosis factor agents — Experience with these anticytokine agents is limited. Promising results have been reported with infliximab and etanercept, including the following observations:
Two case reports of successful use of infliximab [76,77].
A small observational series of six patients treated with infliximab (3 to 5 mg/kg, intravenously, repeated at two weeks, six weeks and at intervals of six to eight weeks thereafter) reported resolution of fever, rash, hepatosplenomegaly, arthralgia and myalgia after the first series of infusions [78]. Glucocorticoid doses were reduced and follow up of from 5 to 28 months indicated continued effectiveness of the infliximab infusions. Four patients not responsive to glucocorticoids or glucocorticoids and methotrexate had complete remission of their disease after receiving infliximab [79].
An observational series of 12 patients treated with etanercept reported improvement in 7 of 12 after six months of treatment (ACR 20, 50, and 70 responses noted in seven, four, and two patients, respectively) [80]. Only one of the three patients with systemic features (fever and rash) had improvement in these manifestations of ASD.
An observational series of 20 patients with disease refractory to methotrexate treated with etanercept (10 patients), infliximab (15 patients), or both agents, sequentially (5 patients) noted complete remissions in five patients (1 with etanercept; 4 with infliximab) and partial responses in 11 ( 6 etanercept; 5 infliximab) [81]. However, anti-TNF was not continued in 17 of 20 patients due to loss of efficacy or adverse effects.
Thalidomide — Two case reports suggests that thalidomide may be effective in refractory cases of Still’s disease, possibly by inhibiting production of tumor necrosis factor (TNF) [82,83].
Anakinra — Anakinra (100 mg subcutaneous daily) appeared to control disease activity in two patients with ASD who were refractory to treatment with glucocorticoids and methotrexate and two others with disease refractory to glucocorticoids, methotrexate, and etanercept [64]. One patient, who had been asymptomatic for three months on anakinra, had recurrent symptoms shortly after stopping treatment, and improved when anakinra was reinstituted. Another patient treated previously with an inadequate response to several DMARDS, and to the combination of infliximab plus methotrexate, improved sufficiently on anakinra to maintain a clinical remission while glucocorticoids were tapered and discontinued [84].
Other — Autologous stem cell transplantation following high-dose cyclophosphamide conditioning and T cell depletion was reported to produce an initial remission [85]. However, recurrent synovitis was noted 15 months after the stem cell transplant.

 

SUMMARY AND RECOMMENDATIONS — Adult Still’s disease (ASD) is an inflammatory disorder characterized by daily, spiking high fevers, arthritis, and an evanescent rash. First described in children by George Still in 1896, “Still’s disease” became the eponymous term for juvenile rheumatoid arthritis and is now called systemic onset juvenile rheumatoid arthritis [1]. In 1971, ASD was used to describe a series of adult patients who did not fulfill criteria for classic rheumatoid arthritis but had features similar to the children with systemic onset juvenile rheumatoid arthritis [2]. It is a rare disorder with an incidence of approximately 2 per million per year, with an equal gender distribution, and bimodal age distribution with peaks between 15 and 25 years and another between ages 36 and 46.

 

Diagnosis — There is no specific diagnostic test for ASD. The diagnosis is made in the presence of suggestive clinical and laboratory features, but care must be taken to exclude, as far as is practicable, infectious diseases, other rheumatic diseases, vasculitis, and malignant disease (particularly lymphoma) that share symptoms, findings, and laboratory test abnormalities with ASD.
Major clinical characteristics that have been incorporated into classification criteria and that may be helpful in diagnosis include (show table 2): fever, arthralgia or arthritis, rash, and leukocytosis. Minor criteria, which are not diagnostic in and of themselves but may aid in the diagnosis include: sore throat, lymphadenopathy, hepatomegaly or splenomegaly, elevated serum aminotransferase enzymes, and negative tests for ANA and RF. Marked elevation of serum ferritin and a decreased fraction of glycosylated to total serum ferritin are not incorporated into any of the current classification schemes but may be valuable diagnostically. However, neither is specific for ASD.
Chronic disease may lead to joint destruction and, if left untreated, secondary amyloidosis. Life threatening visceral involvement is unusual but includes hepatic failure, pericarditis, acute respiratory distress syndrome, myocarditis with heart failure and arrhythmias, pancytopenia, TTP/HUS, and DIC.

 

Treatment — Treatment depends upon the acuity and severity of illness. Mild disease with no life-threatening visceral involvement is best treated initially with NSAIDs or aspirin. Large doses of the latter may be needed and monitoring of salicylate concentration in the serum is useful to guide therapy. Salicylate levels of 15 to 25 mg/dL are the target range. Liver function testing is essential due to the risk of hepatitis and hepatic failure. Patients with very high fever, joint involvement that is disabling, or with potentially life-threatening visceral involvement are treated with glucocorticoids. A starting dose of 0.5 to 1.0 mg/kg per day is appropriate for most patients but intravenous high-dose methylprednisolone (eg, 250 mg QID for three days) may be used for severe hepatic, pulmonary, cardiac, hematologic, or other complications.
For the patient without life-threatening manifestations of ASD, whose symptoms become chronic and are not responsive to the above medications, we suggest medications with proven, long-term track records in inflammatory disease, such as methotrexate. Methotrexate has been used as a first line agent and in one study approximately two-thirds of the patients responded well to it [73]. Methotrexate is used in the same was as for rheumatoid arthritis. An initial dose of 7.5 mg per week can be increased up to 25 mg/week oral, subcutaneous or intramuscular dosing. (See “Use of methotrexate in the treatment of rheumatoid arthritis”, section on Dosing of MTX).
Monitoring of blood counts and serum aminotransferase enzyme levels is essential during treatment, and dose adjustment or discontinuation may be necessary for enzyme elevations above normal. Folic acid (1 to 5 mg daily) or folinic acid (leucovorin, 2.5 to 5 mg taken 8 to 12 hour after the methotrexate dose) may reduce the incidence of hepatotoxicity and myelosuppression. Liver enzymes should be monitored carefully, initially more frequently than is recommended for RA. These and other side effects are discussed elsewhere. (See “Major side effects of methotrexate”).
Disease refractory to glucocorticoids — Immunomodulating agents are used when ASD is not controlled with NSAIDs, aspirin, or glucocorticoids.
For the patient with one or more life-threatening manifestations of ASD who is not responding to high-dose glucocorticoids, the choice of treatment is more difficult, as there are no long-term, randomized controlled clinical trials to guide treatment. With this caveat regarding lack of proven therapies, we recommend a trial of one of the anti-TNF agents, despite their relatively short history of clinical use. Their parenteral or sub-cutaneous route of administration, rapid onset of action, and at least short term safety record lead to a recommendation to use them rather than the alternatives: azathioprine, cyclosporine, cyclophosphamide. These latter drugs appear to have equal or less efficacy than the anti-TNF agents with greater risk of serious adverse events. Infliximab may be more efficacious than etanercept, but further studies need to confirm early case reports. Care should be taken to ensure the patient does not have an occult infection, or history of untreated or inadequately treated tuberculosis.
Anakinra is an extremely promising therapy that may prove to the treatment of choice for ASD refractory to conventional treatment. Although we cannot advocate its routine use until there are more published data, it should be considered a viable option to other drugs such as azathioprine, cyclosporine and cyclophosphamide, given their adverse side effect profile and limited efficacy.
Difficulty weaning from glucocorticoids — Immunomodulating agents are also indicated for the patient who can not be successfully weaned from glucocorticoids. In this setting, in the absence of a life-threatening disease manifestation, use of oral agents with a slower onset of action is reasonable.
Hydroxychloroquine ( 6.5 mg/kg per day) is appropriate for arthralgia and arthritis, fever, and mild serositis.
Methotrexate (MTX) prescribed as above.
Cyclosporine at an initial dose of 2.5 mg/kg per day with an increase as tolerated to no higher than 5.0 mg/kg per day may be useful, particularly for patients with the hemophagocytic (macrophage activation) syndrome. Before cyclosporine is used, baseline blood pressure and renal function should be documented as impaired renal function is a frequent adverse effect of treatment. Calcium channel blocking drugs are preferred for treatment of hypertension when cyclosporine is being administered. (See “Cyclosporine and tacrolimus nephrotoxicity”).
Renal function is monitored carefully with appropriate adjustments in cyclosporine dose. Cyclosporine should be discontinuation in the event of significant changes in serum creatinine that do not respond promptly to dose adjustment. (See “Pharmacology and side effects of cyclosporine and tacrolimus” section on Strategies to minimize toxicity in rheumatic diseases).