Page 856 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 60 Systemic Autoinflammatory Syndromes 827

of vision. In severely affected patients, arthropathy, with distinct
radiographic findings of premature patellar and epiphyseal long Mevalonate Kinase Deficiency
bone ossification and osseous overgrowth, develops early in life. Before the discovery of the underlying genetic defect in the
If left untreated, this leads to growth retardation, severe joint mevalonate kinase gene, two distinct autosomal recessive diseases
contractures, and persisting disability. were distinguished, which are now known to form two ends of
The duration of attacks is variable and ranges from hours to a continuous spectrum: HIDS at the less severe end and mevalonic
days. At the severe end of the spectrum, patients have continuous aciduria (MA) at the most severe end.
inflammation. Attacks may be triggered by exposure to cold, HIDS is characterized by recurrent fever attacks that last for
minor trauma, or emotional stress. 4–6 days, starting in early childhood. The inflammatory attacks
In the past, patients with severe CAPS often died in childhood. occur on average every 4–6 weeks. Attack frequency varies in a
This changed after the introduction of anti–interleukin-1 (IL-1) single patient and among patients and tends to decrease later in
therapy, which is very effective in treating CAPS. Overall, patients life. Attacks often start with chills, followed by a rapid rise in
without neurological involvement are now believed to have a temperature. Factors that can provoke an attack are infections,
normal life expectancy. trauma, vaccination, and both physical and emotional stress,
although a clear trigger is often absent. Characteristic for HIDS
Tumor Necrosis Factor Receptor–Associated is the first attack being triggered by childhood vaccination.
Periodic Syndrome Fever is accompanied by cervical lymphadenopathy and
TRAPS is inherited in an autosomal dominant fashion. Age of abdominal pain with vomiting and diarrhea. The skin may show
onset varies widely. Many patients become symptomatic within erythema, papules, urticarial rash, or exanthema. The majority
the first years of life, with a median age of onset of 3 years, but of patients suffer from large-joint arthralgia or arthritis. Oral or
adult onset is also possible. The usual duration of fever in TRAPS genital aphthous ulcers may be present during attacks. Hepato-
is considerably longer than in the other classic autoinflammatory splenomegaly has been reported. Patients with HIDS appear to
syndromes: attacks persist for a minimum of 3 days but can last have normal life expectancy and experience no complications.
for several weeks. The interval between attacks in a single patient MA is located at the severe end of the MKD spectrum. This
can vary substantially. severe disease is present from birth and is characterized by
Localized myalgia, a deep cramping, and often severely dis- psychomotor retardation, ataxia, failure to thrive, cataracts, and
abling pain in a single limb resulting from monocytic fasciitis facial dysmorphia. Episodic fever or inflammation are present
and associated with fever is found in virtually all patients. The in MA. Many patients die in early childhood.
affected limb may show local erythema, which may migrate to In recent years, it has become clear that the spectrum of
the distal part of the extremity (Fig. 60.1). Almost all patients MKD comprises more than only these two diseases. Muta-
have abdominal pain, often accompanied by vomiting, constipa- tions in MVK have been found in the absence of typical MKD
tion, and bowel obstruction. Arthralgia and monoarthritis features in patients with retinitis pigmentosa and early-onset
involving hips, knees, or ankles are present in 25% of patients ulcerative colitis. Mutations in MVK have also been found in
at some point. Chest pain is frequent and can be caused by patients with the skin diseases disseminated superficial actinic
pleuritis or may be musculoskeletal in origin. Ocular symptoms porokeratosis and porokeratosis of Mibelli, cyclic neutropenia,
range from conjunctivitis and periorbital pain to severe uveitis and macrophage activation syndrome, but there is no evidence of
8
and iritis. Periorbital edema with conjunctival injection is a decreased mevalonate kinase activity in these patients. Mutations
distinctive, but infrequent, feature of TRAPS. Other less frequently in these diseases may overlap with mutations that may cause
observed symptoms are pericarditis and lymphadenopathy. MA and HIDS.
Periodic Fever, Aphthous Stomatitis, Pharyngitis,
and Adenitis Syndrome
PFAPA is primarily a childhood disease with a usual onset before
the age of 5 years. Patients suffer from recurring episodes of
fever that generally last for 3–6 days and recur with great regular-
ity. Additional symptoms include pharyngitis, cervical adenitis,
and aphthous stomatitis. Other symptoms may include headache,
vomiting and mild abdominal pain, arthralgia, and myalgia.
Between fever episodes, patients are symptom-free. In most
patients, attacks cease after several years, often before or during
adolescence.
Schnitzler Syndrome
A typical feature of Schnitzler syndrome is its late onset, at a
median age of 51 years. Patients typically present with chronic
recurrent and mostly nonpruritic urticarial rash. This can be
accompanied by fever, arthralgia or arthritis, and bone pain (Table
60.2). Symptoms progress over years. The presence of monoclonal
paraproteinemia, typically of immunoglobulin M (IgM), is char-
FIG 60.1 Migratory erythematous macular rash during an inflam- acteristic for Schnitzler syndrome. Presence of monoclonal IgG
matory attack in a patient with tumor necrosis factor recep- is less common and is sometimes referred to as variant Schnitzler
tor–associated periodic syndrome (TRAPS). syndrome. Onset of symptoms can precede paraproteinemia for