Adult-onset Still’s disease (AoSD) is the adult counterpart of a paediatric disorder named systemic-onset juvenile idiopathic arthritis (SoJIA). The frequency of the disease is very low, estimated between one case per 100,000 to one case per 1,000,000 adults. AoSD mainly affects young adults and there is no familial aggregation reported so far, i.e., no other cases amongst the close relatives of the patients.
AoSD is characterized by intense systemic inflammation but no signs of auto-immunity, i.e., of serum antibodies directed against self-antigens. The very few immunological investigations conducted so far identified a key role for interleukin 1 and inflammasome dysregulation, which are responsible for strong overproduction of other inflammation mediators, such as interleukin-6 or -18. Based on these elements, AoSD has been classified among the non-hereditary – i.e., non-familial – systemic autoinflammatory disorders.
AoSD is traditionally characterized by four cardinal symptoms, with many other manifestations possibly associated (Figure 2)2,8.
The 4 cardinal symptoms are :
- Fever, superior to 39°C, occurring repeatedly every evening for more than 1 week,
- Joint pain or swelling (arthritis), which may damage the joints in the absence of adequate treatment;
- Skin rashes, salmon-pink-colored macular or close to urticaria, occurring concomitantly to fever episodes;
- Increase in white blood cell counts above 10,000 /mm3 with more than 80% of neutrophil polymorphonuclear, associated with intense biologic inflammation, i.e., substantial increase of C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR).
Many other clinical or biologic signs are possible in addition to the 4 above, none of them being quite specific of AoSD diagnosis. This makes the disease quite difficult to diagnose for non-expert physicians.
To facilitate physician task, several classification criteria sets have been developed and may be used to estimate the probability of AoSD diagnosis (Table 1).
|Yamaguchi set (Yamaguchi 1992)||Fautrel set (Fautrel 2002)|
|At least 5 criteria, including 2 major criteria
and No exclusion criteria
|4 major criteria or 3 major criteria
and 2 minor criteria
The AoSD natural history is quite heterogeneous: some patients have only one intense flare without any relapse in the following years (10 to 30% of the patients depending on the study), some others experience recurrent flares of several weeks or months several years apart with long remission periods in between (10 to 40% of the patients depending on the study), finally some patients develop chronic disease with persistence of inflammatory signs on the long term (30 to 50% of the patients depending on the study).
To date, there are no predictors of AoSD long term evolution, which is often difficult to accept for patients.
Therapeutic strategies for AoSD
For many years, high dose corticosteroids were the key treatment for AoSD patients. Although quite efficient, steroids are responsible for significant side effects and alternative options are needed.
Conventional immunomodulatory agents such as methotrexate or ciclosporin A have been proposed and were shown helpful for patients with refractory and corticosteroid-dependent disease. However, these treatments rarely replaced steroids.
More recently, targeted therapies have been developed, specifically directed against interleukin-1 or -6, and have shown dramatic efficacy in the majority of AoSD patients. These molecules are summarized in Table 2. Recent guidelines for daily clinical practice proposed to introduce these treatments rapidly after disease onset in order to reduce the exposure to high dose steroids.
Recurrent pericarditis is manifested by the recurrence of the symptoms of acute pericarditis (pleuritic type chest pain, pericardial friction rub, widespread saddle-shaped or concave upward ST segment elevation on the ECG, and pericardial effusion), along with one or more signs of inflammation (fever, cardiac MRI evidence of inflammation of the pericardium, and/or an elevation in the white blood cell count, erythrocyte sedimentation rate, or C-reactive protein).
This recurrence appears after an initial documented episode of acute pericarditis with an intervening symptom-free interval of ≥4-6 weeks (typically within 18 months).After an initial episode of acute pericarditis, one or more recurrences arise in 15% to 30% of patients. These attacks can repeat and may lead to substantial disability. Cardiac tamponade is a rare, life-threatening complication.
Neutrophilic dermatoses (ND) are inflammatory skin conditions characterized by a sterile infiltrate of normal white blood (polymorphonuclear leukocytes) in the skin. Sterile means that this inflammation is not due to any microbe infection such as bacteria, fungi, virus or parasites. It is highly important to rule out any infection to confirm the diagnosis of ND. Clinical signs may be urticaria like symptoms (sweet syndrome, Figure 1), ulcerated wounds with pus (pyoderma gangrenousm, Figure 2) or pustular lesions. Diagnosis will be performed by well-trained dermatologists and will require a skin biopsy with careful histological analysis.
Sweet syndrome (SS) will manifest as acute, tender, red plaques with fever and sometimes joints pain. Blood screen shows high levels of polymorphonuclear leukocytes. Most of the time, SS is a reactive condition (after a viral infection) that will last a few days or a few weeks with spontaneous resolution. Chronic forms of SS (multiple relapses or long lasting disease) are very rare but may be a cutaneous marker of hematologic malignancies such as acute leukemia or myelodysplastic syndrome. Myeloid malignancies associated SS affect older people than reactive associated SS. First line treatments of SS are topical steroids or systemic steroids given orally.
Pyoderma gangrenosum (PG) may present as deep ulcers with necrotics lesions and pus that may cause pain and scarring. These wounds are often often misdiagnosed as bacterial cellulitis. Broad spectrum antibiotics are inefficient and surgical debridement will worsen the wounds. The worsening of PG in response to minor trauma or surgical debridement is called the “pathergy” phenomenom. PG may be idiopathic but may be the sign of an underlying systemic disease in half of the cases. Inflammatory bowel disease (Crohn’s disease and ulcerative colitis), rheumatoid arthritis, multiple myeloma and hematological malignancies have been associated with PG. PG treatments include topical steroids, oral steroids, ciclosporin and TNF alpha blockers such as infliximab.
Prevalence is unknown and about 150 cases have been reported, primarily in Europe. There is a slight male predominance and mean age of disease onset is 51 years. Time to diagnosis often exceeds 5 years. The first clinical sign is usually a mildly or non-pruritic skin rash. Elementary lesions are rose or red macules or slightly elevated plaques, which resolve within 24 hours. Lesions can occur on every body part, though involvement of face and extremities is rare. The frequency and duration of flares are variable. Almost all patients develop intermittent fever and body temperature can rise above 40°C. Fever is usually well tolerated and chills are rare. About 80% of patients experience bone and/or joint pain. Bone involvement is common, and 30 to 40% of patients show bone lesions on imaging studies. IgM levels can remain stable or progressively increase at a rate of about 0.5 to 1 g/L/year. Other signs include elevated erythrocyte sedimentation rate (ESR), inflammatory anemia sometimes with thrombocytosis (up to 50 % of cases), palpable lymph nodes (45%), and hepatic or splenic enlargement (30%). The monoclonal IgM component is a defining feature of the disease. Inflammatory AA amyloidosis may be a serious complication. The disease follows a chronic course. Etiology remains unclear but the syndrome is probably an acquired auto-inflammatory disorder. It shares many features with genetically determined auto-inflammatory diseases. Diagnosis is based on a combination of clinical, laboratory and radiological findings and on exclusion of another cause. Histopathological skin findings are noteworthy showing a neutrophilic infiltrate of the dermis, without vasculitis and without significant edema, characteristic of neutrophilic urticarial dermatosis. An immediate and marked response to anakinra treatment is supportive of the diagnosis. The initial work-up should include an examination of bone marrow, immunoelectrophoresis of serum and urinary proteins, and determination of immunoglobulin subtypes. The two latter examinations can then be used for follow-up on a biannual basis. Lymph nodes should be biopsied when they are enlarged. Differential diagnosis includes adult-onset Still's disease, hypocomplementic urticarial vasculitis, cryoglobulinemia, hyper IgD syndrome, and acquired C1 inhibitor deficiency (see these terms). Some treatments provide only incomplete and/or transient improvement or control of symptoms (steroids, non-steroidal anti-inflammatory drugs, colchicine, dapsone, peflacine, phototherapy) while others are mostly ineffective (anti-histamines, rituximab, intravenous immunoglobulins, TNF-blocking agents, immunosuppressive drugs). In contrast, the IL-1 receptor antagonist anakinra relieves all symptoms within hours after the first injection. Injection-site reactions are frequent with anakinra and sometimes severe, and can be a real concern. The neutrophil count must be monitored. The overall prognosis depends on the development of lymphoproliferative complications such as lymphoma, IgM myeloma or Waldenström's disease (see these terms). Although these complications have only been reported in about 20% of cases, their incidence may be higher since they generally develop more than 10 to 20 years after the first signs of the syndrome.
Vasculitis (Kawasaki, Behcet, Takayasu):
Behçet's disease is a disease related to the inflammation of blood vessels. It is mainly manifested by mouth ulcers in the mouth or on the genitals, but also by damage to the eyes, skin, joints, nervous system and veins (occlusions) or arteries. Very pronounced fatigue is also present. Behçet's disease is more or less frequent depending on geographical origin. It is more frequent in patients from Turkey, North Africa or Japan (historically the "Silk Road"), while it is much rarer in Europe (except in the Mediterranean basin) or in the Nordic countries. Behçet's disease mainly affects young people between the ages of 15 and 45. It can affect both men and women. It is not a hereditary disease. There are rare family cases (5% of cases), suggesting that there is a genetic predisposition. In particular, a certain subtype of the HLA molecules (self-molecules present on the cells of the body that distinguish self-cells from those of another organism) HLA B51 is associated with disease. The cause of Behçet's disease is not known. However, patients have, for multiple reasons that are still imperfectly understood, a lack of regulation of their immune system, leading to the activation of certain white blood cells (lymphocytes) and the infiltration of vessels and organs by these cells are at the origin of the inflammation observed.
Takayasu arteritis is a very rare disease that belongs to the group of systemic vasculitis and affects large and medium sized blood vessels. The affected vessels are mainly the aorta (the main artery from the heart) and its first dividing branches, including arteries distributing blood to the brain, arms, abdomen and lower limbs. The exact cause of this disease is not known, and there is probably not only one. There may be an individual genetic susceptibility, but it is not a hereditary disease and it is not contagious. Takayasu arteritis mainly affects women (80-90% of cases). It is more frequent in Asia, and particularly in Japan. The first illness-related event usually occurs between the ages of 10 and 40. The first signs of the disease can be fever, excessive fatigue, involuntary weight loss, general weakness. Damage to the arteries can lead to coldness, cyanosis and/or pain in the hands and feet, linked to poor circulation of arterial blood. There are sometimes joint pains, muscle weakness, skin lesions, chest pain, shortness of breath upon exercise, a difference in blood pressure figures between arms, balance disorders, headaches, seizures and/or concentration or memory disorders. Visual disturbances can also occur. An increase in CRP is noted in more than half of the patients. Inflammation of the abdominal vessels can cause abdominal pain, diarrhea or even digestive bleeding. Inflammation of the coronary arteries can cause angina pectoris, i. e. chest pain during exercise, and sometimes even lead to myocardial infarction. Chest x-rays sometimes show abnormalities in the size of the aorta. However, blood vessels are much better analyzed by angiography (or arteriography), angio-MRI, angio-scanner and/or PET-scanner, which will better specify which vessels are affected. Takayasu arteritis is a chronic disease. Inflammation often persists indefinitely and therefore requires prolonged treatment, often for life. However, in some patients, the disease eventually "dies down" completely after a few months or years of treatment. The symptoms and inflammation then disappear. The basic treatment for Takayasu arteritis is based on corticosteroids, to stop the progression of the disease and reduce inflammation of the vessels. However, this treatment alone is sufficient in only half of the patients. Another treatment (an immunosuppressant) should be prescribed in combination with corticosteroids to reduce inflammation and control symptoms.
can be defined as fever (>38C) or symptomatic systemic inflammation lasting for more than 3 weeks where the underlying causes has not been identified despite thorough and appropriate medical work up. We know that most cases of fever of unknown origin turn out to be due to infection, malignancy or rheumatological disease. In IMMUNAID we are particularly interested in the small group of patients where the fever is due to autoinflammatory processes and whether we could identify these diseases earlier so avoiding unnecessary and unhelpful tests.
SAPHO syndrome/ Chronic recurrent multifocal osteomyelitis
SAPHO syndrome – an acronym standing for Synovitis-Acne-Pustulosis-Hyperostosis-Osteitis – is a rare condition affecting less than 1 person per 10.000 inhabitants. Initially proposed by a french group led by Marcel-Francis Kahn and Anne-Marie Chamot, more than 30 years ago, the concept of SAPHO syndrome has been subsequently widely accepted by the international community. In fact, previous descriptions of this disease did not consider both its common and variable features. Everyone now agrees that the cornerstone of the diagnosis is a peculiar form of chronic osteitis, leading to new bone formation, with frequently extensive periostitis. The association with palmoplantar pustulosis is more frequent in females, whereas severe forms of acne (acne conglobata, fulminans) are predominantly observed in males. The absence of any dermatosis is possible, in approximately 10% of patients, usually leading to a greater delay between the first rheumatological symptoms and the confirmation of the right diagnosis. There is slight female predominance for this disease.
Chronic recurrent multifocal osteomyelitis (CRMO) is often considered as a paediatric form of SAPHO syndrome, although dermatological symptoms are frequently lacking at initial presentation.
In adults, the main osteo-articular localisations are the anterior chest wall, the spine and the pelvis. In children, the osteitic lesions are mainly located in the lower limbs (knee, hip) and in the spine. The first clinical symptom is a continuous pain, mainly nocturnal, of the affected bones or joints. When the anterior chest wall is affected, the persisting inflammatory process results in a visible and painful hypertrophy of either the medial part of clavicles or the sterno-clavicular or manubrio-sternal joints. Besides palmoplantar pustulosis and acne, other types of dermatoses can occur in SAPHO syndrome, like psoriasis vulgaris and hidradenitis suppurativa. It must be underlined that the first cutaneous symptoms can precede the initial rheumatological complaints for more than 20 years. Conversely, CRMO can be subsequently complicated by cutaneous diseases, predominantly psoriasis vulgaris or palmoplantar pustulosis. Some follow-up studies have also pointed out the increased incidence of inflammatory bowel diseases (mainly Crohn’s disease) during SAPHO syndrome. Recently, it has been shown that, besides bones and joints, the entheses (i. e. the bone insertions of tendons) could also be affected in SAPHO syndrome. Altogether, these data strongly support the inclusion of SAPHO syndrome – at least the adult form - in the larger group of spondyloarthropathies, like psoriatic arthritis. The main difference is that the prevalence of HLA B27 haplotype is far less frequent in SAPHO syndrome than in ankylosing spondylitis.
The clinical diagnosis of SAPHO syndrome can be difficult, since this disease can remain invisible for a long time. Additionally, the medical community is still relatively unaware of this rare condition, although it is well described in various internet platforms, like Orphanet. The coexistence of cutaneous symptoms is clearly helpful, but these manifestations can be transient or even forgotten by the patient. Current biology usually indicates an aspecific inflammatory reaction, which can be weak or even absent. This underlines the importance of imaging. Whereas conventional radiographs are initially unhelpful, MRI and bone scintigraphy generally allow the physician to make the correct diagnosis, thereby eliminating other alarming diseases, such as bone infection or cancer.
Once the correct diagnosis has been made, the first therapeutic step consists in reassuring the patient, particularly if the preceding waiting phase has been long. Although some familial cases could suggest a genetic transmission, all available data on this topic are quite encouraging, failing to find any relevant predisposing gene, at least for the adult forms of SAPHO syndrome.
In order to rapidly alleviate the bone or joint pains, analgesics and anti-inflammatory drugs represent the first-choice treatment. In predominantly osseous forms of SAPHO syndrome, one can select the option of bisphosphonates, since many publications have demonstrated a rapid and positive effect of sequential cures of either pamidronate or zoledronate, administered intravenously, without significant adverse effects. When joints are mainly affected, or in the case of an inadequate response to bisphosphonates, immunomodulatory drugs can be prescribed, as for psoriatic arthritis. Synthetic drugs like methotrexate or leflunomide sometimes help, even in unclassical indications, like localisations to the anterior chest wall. Finally, various biologic agents, mainly targeting TNF, have been tested in SAPHO syndrome, with conflicting results, probably due to a relative heterogeneity of patients. New targeted and synthetic molecules, like anti-Janus kinase agents, could be helpful. For the cutaneous component of SAPHO syndrome, a tight cooperation with dermatologists is mandatory. One should avoid vitamin A derivates since these compounds can induce periostosis, like SAPHO syndrome per se. Finally, the psychological distress, frequently registered in patients suffering from SAPHO syndrome, needs to be considered and treated, as a probable cause of worsening of the physical illness.