Rheumatologic manifestations of hemoglobinopathies

Introduction

Hemoglobinopathies are primarily inherited diseases that affect the structure and synthesis of haemoglobin. Two hemoglobinopathies are associated with major rheumatic manifestations, sickle cell disease and thalassemia, which will be the focus of this chapter.

Normal major adult hemoglobin (HbA) is a tetramer of two alpha and two beta globin chains α ₂ β ₂ , minor adult HbA2 is α ₂ δ ₂ , and fetal HbF is α ₂ γ ₂ . HbF synthesis begins at 11 weeks postconception and is the predominant hemoglobin of the fetus until week 38 when a switch to HbA begins. A small amount of HbF is synthesized postnatally; however, profound erythroid stresses can cause an increase of HbF levels as may occur in patients with hemoglobinopathies.

Sickle Cell Disease

Sickle cell disease (SCD) is a spectrum of diseases caused by a monogenic mutation on chromosome 11 causing the sixth amino acid on the β-globin chain, glutamic acid, to be replaced by valine. This substitution results in production of the pathologic hemoglobin HbS.

The HbS mutation increases polymerization of the hemoglobin in the deoxygenated state, causing aggregates of fibrous polymers. These polymers have reduced solubility, increased viscosity, and distort the structure of the erythrocyte into the eponymous sickle cell shape. HbS also has reduced pliability with increased adherence leading to recurrent vasoocclusion and chronic hemolysis. These vasoocclusive events occur mainly in small vessels and are the primary mechanism underpinning the rheumatologic complications of SCD ( Fig. 211.1 ).

Sickle cell anemia (SCA) is the most severe phenotype of SCD caused by the homozygous mutation HbSS. Patients with sickle cell trait carry one mutation, HbSA. However, there are also patients with composite heterozygote mutations that express the phenotype of both mutations. A patient with Hb S–β thalassemia genotype will express both features of thalassemia and sickle cell disease. Another example is HbSC (HbC also results from the substitution of the sixth amino acid, glutamic acid on the β-globin chain, however by lysine as opposed to valine in HbS). HbSS–SCA and HbSβ-thal ⁰ (β-thal ⁰ denotes no HbA) present with the most severe disease compared to the other heterozygous conditions such as Hb SC.

Mutations that are protective include α-thalassemia and hereditary persistence of fetal hemoglobin. Sickle cell trait is relatively benign; clinical manifestations only develop in states of severe hypoxia, dehydration, and extreme physical exertion.

Hemoglobinopathies provide protection from malarial infection and have therefore developed in areas where malaria was endemic. SCA has the highest incidence in patients with African descent. Nearly 30% have sickle trait in certain populations south of the Sahara. King Tutankhamun may have suffered rheumatologic complications of SCA such as juvenile osteonecrosis. The first case suspected to have SCA was published in 1846 and describes asplenism in an executed slave. Approximately 10% of African Americans are heterozygote carriers, and 1 in 400 are HbSS. Sickle cell disease has also been shown to be prevalent in Latin America, Middle East, the Mediterranean, and the Indian subcontinent ( Fig. 211.2 ).

SCA used to be considered a disease of children; up until the 1950s, the medium survival was less than 20 years old. Today SCA reduces life expectancy by approximately 30 years.

Clinical

The rheumatologic manifestations and complications of SCD include acute painful crises, dactylitis, avascular necrosis, bone infarction, osteomyelitis, septic arthritis, vertebral collapse, secondary osteoarthritis, and synovial effusions. The initial clinical presentation is often in childhood. Presence of HbF after birth initially protects against vasoocclusive events, thus patients do not usually present during the first 6 months of life. Risk factors for triggering an occlusive event include cold exposure, intense physical effort, hypoxia, dehydration, infections, and general trauma. There have been reports suggesting that steroid treatment may trigger a vasoocclusive event; however, this is based solely on retrospective studies and case reports. Treatment of patients with concomitant SCD and rheumatologic disease need to be carefully considered under the coordinated care of both the rheumatologist and hematologist.

Acute painful crisis

The most common clinical manifestation is acute painful crisis resulting from vasoocclusion, tissue ischemia, inflammation, and nociception. Classically, patients experience 1–2 days of prodromal numbness and aching that subsequently develops into severe pain within the joints, extremities, lower back, chest, and abdomen. The pain is often continuous and throbbing. It may be localized or involve multiple sites in an additive or migratory pattern. After around 7 days the intensity of the pain usually begins to decline. Persistence of pain for longer than 2 weeks often indicates the development of complications such as osteonecrosis and osteomyelitis. Acute painful crises are commonly accompanied with increased red cell distribution width, reticulocytes, leukocytes, and a relative thrombocytopenia. These laboratory changes begin to resolve as the pain declines. Increased frequency of acute painful crises is associated with increased mortality. Chronic pain without obvious pathology has also been described in patients with SCD.

Dactylitis

Dactylitis may also be a presenting feature seen in children with SCD and is associated with hand–foot syndrome. This causes painful swelling of the hands and feet. Unlike dactylitis of psoriatic arthritis, the pathophysiology in SCD is due to microvascular occlusions in the diaphysis marrow of the small bones of the hands and feet. The bone marrow of children is very vascular “red marrow” and later becomes substituted with a less vascular fatty marrow “yellow marrow.” This explains why dactylitis is not seen after the age of 5–6 years. Hand–foot syndrome is often accompanied by fever and may be complicated with osteomyelitis or osteonecrosis. Imaging can help differentiate the diagnosis. Magnetic resonance imaging (MRI) is the most sensitive imagery and may demonstrate signs of bone infarction or osteomyelitis. Osteonecrosis associated with hand–foot syndrome can lead to destruction of the phalanges or metacarpal bones, culminating in deformity and shortening of the involved digits. Other pediatric complications include short stature, poor weight gain, and delayed puberty likely due to malnutrition, endocrine abnormalities, and long-term effects of anemia ( Fig. 211.3 ).

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