Haemoglobinopathies

Inherited abnormalities of the globin genes are the commonest single-gene disorders in the world and fall into two main groups: thalassaemias and sickle cell disease. Thalassaemias are due to quantitative defects in globin chain synthesis which cause variable anaemia and ineffective erythropoiesis. Thalassaemia was initially thought to be a disease of the bones due to uncontrolled bone marrow expansion causing bony distortion, although this is now unusual with appropriate blood transfusions. Osteopenia, often severe, is a feature of most patients with thalassaemia major and intermedia, caused by bone marrow expansion, iron overload, endocrinopathy, and iron chelation. Treatment with bisphosphonates is generally recommended. Other rheumatological manifestations include arthropathy associated with the use of the iron chelator deferiprone. Sickle cell disease involves a group of conditions caused by polymerization of the abnormal -globin chain, resulting in abnormal erythrocytes which cause vaso-occlusion, vasculopathy, and ischaemic tissue damage. The characteristic symptom is acute bone pain caused by vaso-occlusion; typical episodes require treatment with opiate analgesia and resolve spontaneously by 5 days with no lasting bone damage. The frequency of acute episodes varies widely between patients. The incidence of osteomyelitis is increased, particularly with salmonella, although it is much rarer than acute vaso-occlusion. Avascular necrosis can affect the hips, and less commonly the shoulders and knees. Coincidental rheumatological disease sometimes complicates the condition, particularly systemic lupus erythematosus (SLE) which is more prevalent in populations at increased risk of sickle cell disease.

Multicentric reticulohistiocytosis

Multicentric reticulohistiocytosis (MRH) is a rare systemic disease characterized by the combination of typical papular and nodular skin lesions and a severe and destructive polyarthritis, although virtually any organ system of the body can be involved. MRH most commonly affects middle-aged white women; it is about three times more common in women with a mean age at onset in the fifth decade. MRH is a rare histiocytic proliferative disease of unknown aetiology, characterized by tissue infiltration by histiocytes and multinuclear giant cells. The stimulus for the histiocytic proliferation has not been fully elucidated, although there is an association with internal malignancies and abnormal immunological laboratory findings. The diagnosis is confirmed by skin or synovial biopsy. The disease often runs a waxing and waning course and sometimes stabilizes. Work-up for underlying malignancy cannot be overemphasized. The recommended treatment for MRH is oral methrotrexate plus prednisone tapered gradually over 3–4 months.

Sarcoidosis

Sarcoidosis is a systemic disease characterized by non-necrotizing granulomata and manifestations in almost any organ. Diagnosis relies on the exclusion of other granulomatous disorders and a compatible pattern of symptoms and clinical findings. Inflammatory lesions and granulomata may undergo spontaneous resolution or persist in chronic disease with eventual fibrosis and permanent organ damage. Immunological disease mechanisms are linked to severe derangements of the cytokine network. In systemic resolution or under prednisolone therapy of symptomatic disease pro-inflammatory cytokines are downregulated and histological lesions may completely vanish. Corticosteroid-resistant disease, however, requires treatment with an immunosuppressive regimen consisting of prednisolone and an immunosuppressive agent or anti-tumour necrosis factor (TNF) monoclonal antibodies.

Amyloidosis

Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited in the interstitial space as insoluble and remarkably stable fibrils that progressively disrupt tissue structure and function of organs throughout the body. Protein misfolding and aggregation have increasingly been recognized in the pathogenesis of various other diseases, but amyloidosis—the disease directly caused by extracellular amyloid deposition—is a precise term with critical implications for patients with a specific group of life-threatening disorders. Amyloidosis may be acquired or hereditary and the pattern of organ involvement varies within and between types, though clinical phenotypes overlap greatly. Virtually any tissue other than the brain may be directly involved. Although histology remains the diagnostic gold standard, developments in scintigraphy and MRI technology often produce pathognomonic findings. Systemic amyloidosis is usually fatal, but the prognosis has improved as the result of increasingly effective treatments for many of the conditions that underlie it, notably the use of biologic anti-inflammatory agents in patients with AA amyloidosis and new immunomodulatory agents in patients with AL type. Better supportive care, including dialysis and solid organ transplantation, have also influenced the prognosis favourably. A range of specific novel therapies are currently in clinical development, including RNA inhibitors that suppress production of amyloid precursor proteins, drugs that promote their normal soluble conformation in the plasma, and immunotherapy approaches that directly target the amyloid deposits.

Foot and ankle

Foot and ankle problems have been the subject of major advances in the rheumatology in recent years. This chapter reviews the anatomy of the foot and covers the manifestations of foot pathology for the major conditions: rheumatoid arthritis, osteoarthritis, spondyloarthritis, connective tissue disease, crystal diseases, and miscellaneous conditions including hypermobility syndrome. Relevant local conditions including plantar fasciitis, tendinopathy, and neuroma are addressed separately. The principles of assessing and treating the foot and ankle in rheumatology are covered, along with the relevant specific approaches best suited to dealing with problems associated with the major conditions.

Forearm, hand, and wrist

The forearm, hand, and wrist is a functionally vital part of the musculoskeletal system and in consequence, is highly sophisticated and complex in its anatomical development. Frequently, the hand and wrist may be the site of onset of symptoms of a polyarthropathy such as rheumatoid arthritis or of osteoarthritis, so that the physician should always seek to screen for such conditions before making a local diagnosis. Tenosynovitis, de Quervain’s disease, trigger digit, Dupuytren’s, and carpal tunnel syndrome are local soft tissue pathologies which can usually be discriminated on clinical grounds with or without the use of simple diagnostic tests and are satisfying to treat for the most part. Non-specific forearm pain is more complex, with much controversy surrounding not only its aetiopathogenesis but also its existence. It can be difficult to diagnose and difficult to treat.

Renal osteodystrophy

Renal osteodystrophy (ROD) is a term that encompasses the various consequences of chronic kidney disease (CKD) for the bone. It has been divided into several entities based on bone histomorphometry observations. ROD is accompanied by several abnormalities of mineral metabolism: abnormal levels of serum calcium, phosphorus, parathyroid hormone (PTH), vitamin D metabolites, alkaline phosphatases, fibroblast growth factor-23 (FGF-23) and klotho, which all have been identified as cardiovascular risk factors in patients with CKD. ROD can presently be schematically divided into three main types by histology: (1) osteitis fibrosa as the bony expression of secondary hyperparathyroidism (sHP), which is a high bone turnover disease developing early in CKD; (2) adynamic bone disease (ABD), the most frequent type of ROD in dialysis patients, which is at present most often observed in the absence of aluminium intoxication and develops mainly as a result of excessive PTH suppression; and (3) mixed ROD, a combination of osteitis fibrosa and osteomalacia whose prevalence has decreased in the last decade. Laboratory features include increased serum levels of PTH and bone turnover markers such as total and bone alkaline phosphatases, osteocalcin, and several products of type I collagen metabolism products. Serum phosphorus is increased only in CKD stages 4-5. Serum calcium levels are variable. They may be low initially, but hypercalcaemia develops in case of severe sHP. Serum 25-OH-vitamin D (25OHD) levels are generally below 30 ng/mL, indicating vitamin D insufficiency or deficiency. The international KDIGO guideline recommends serum PTH levels to be maintained in the range of approximately 2-9 times the upper normal normal limit of the assay and to intervene only in case of significant changes in PTH levels. It is generally recommended that calcium intake should be up to 2 g per day including intake with food and administration of calcium supplements or calcium-containing phosphate binders. Reduction of serum phosphorus towards the normal range in patients with endstage kidney failure is a major objective. Once sHP has developed, active vitamin D derivatives such as alfacalcidol or calcitriol are indicated in order to halt its progression.

Avascular necrosis

Avascular necrosis (AVN) represents an important disease process of the cartilage-bone complex, which can occur at any age. According to aetiology one may discriminate between rare idiopathic avascular necroses and more common forms that occur as an effect of the underlying disease or rather the therapy, the secondary avascular necroses. Pathophysiologically it is assumed that a circulatory disorder leads to an ischaemic necrosis of bone, bone marrow, and adjunct cartilage. Sites of the human skeleton with predilection to AVN are the femoral head, humeral head, femoral condyle, proximal tibia, and ossicles of the foot and hand. Clinical signs are unspecific, but in the region of the load-bearing lower extremities pain occurs usually early. Plain radiographs, MRI, and sometimes also skeletal scintigraphy are used for diagnosis and staging. Usually 4-5 stages are distinguished; there are extra classification systems for individual entities. Spontaneous healing in terms of a return to normal without further damage can be found in small, circumscribed areas, but the bigger and the nearer the joint the more unlikely this is. Depending on region, stage of disease, age of the patient, concomitant diseases and cause, several conservative and surgical therapies may be applied. Conservative treatments include exoneration and relief of the extremity, physiotherapy, and if necessary medical treatment. The need for surgical intervention becomes more likely as AVN increases in size and gets closer to the joint. Surgical therapies include core decompression, revascularizing techniques, vascular bone transplant, corrective/transposition osteotomy, arthrodesis/joint reinforcement, or joint replacement.

Paget’s disease of bone

Paget’s disease of bone (PDB) affects up to 1% of people of European origin aged 55 years and above. It is characterized by focal increases in disorganized bone remodelling which disrupt normal bone architecture, causing the affected bones to enlarge and become weakened. This can lead to various complications including pain, deformity, fracture, nerve compression syndromes, and osteoarthritis. Genetic factors play a key role in the pathogenesis of PDB. This is mediated by a combination of rare genetic variants which cause familial forms of the disease and common variants which have additive effects on disease susceptibility. Suggested environmental factors for PDB include viral infections, calcium and vitamin D deficiency, and excessive mechanical loading of affected bones. The diagnosis can be made by the characteristic changes seen on radiographs, but isotope bone scans are a more sensitive method of defining disease extent. Serum total alkaline phosphatase levels are usually raised in patients with metabolically active disease and are often used as a measure of disease activity. Bisphosphonates are the treatment of choice for PDB; they reduce the elevations in bone turnover that are characteristic of the disease and are an effective treatment for bone pain. Among the bisphosphonates, zoledronic acid is most likely to give a favourable pain response. Bisphosphonate treatment should not be given with the primary aim of normalizing elevated biochemical markers of bone turnover since there is no evidence that this is beneficial. Although potent bisphosphonates can normalize elevated bone turnover in many patients with PDB, it unclear as yet whether this prevents complications of the disease.