Misc Rheumatological Disorders

 

• Amyloidosis

  Aka systemic amyloidosis.

  Definition and epidemiology

  • Multi-system disease characterised by tissue deposition of amyloid, which are abnormally folded, misaggregated, insoluble, fibrous proteins.
  • UK prevalence: 1/1500.
  • There are also localised, organ-specific forms such as Alzheimer's disease and cutaneous amyloidosis.

  Types

  AL (primary) amyloidosis

  • Amyloid from monoclonal Light chains, due to plasma cell dyscrasia and sometimes a specific condition such as myeloma.
  • Can affect heart, lung, kidneys, liver, spleen, nerves, GI tract, skin, carpal tunnel.
  • Commonest and most lethal systemic amyloidosis. Median survival 2.5 yrs.

  AA (secondary) amyloidosis

  • Amyloid from serum amyloid A protein, an acute-phase reactant (like CRP) that accumulates in chronic inflammatory conditions.
  • Causes: RA, IBD, bronchiectasis, TB, familial Mediterranean fever, Castleman disease.
  • Most commonly affects kidneys, but also heart, liver, spleen, adrenals, and lymph nodes.

  Familial amyloidosis (FA)

  • Can result from inherited mutations in a range of proteins, including transthyretin (TTR) and apolipoprotein A-I (ApoAI).
  • TTR mutation is commonest, affecting heart, peripheral and autonomic nervous system, and carpal tunnel.

  Age-related (senile) systemic amyloidosis (SSA)

  • Amyloid from misfolded wild-type TTR.
  • Commonly affects heart and carpal tunnel.
  • Commonest in old, white men.

  Presentation

  Systemic symptoms: fatigue, weight loss, dizziness.

  Effects by system:

  • Skin and soft tissue: macroglossia (AL amyloid), easy bruising inc. periorbital (raccoon eyes), muscle infiltration inc. deltoid pseudohypertrophy.
  • Cardio: restrictive cardiomyopathy, arrhythmia, heart block.
  • Kidney: proteinuria and nephrotic syndrome.
  • GI: hepatosplenomegaly, dysmotility (exacerbated by autonomic dysfunction), bleeding
  • Neuro: peripheral neuropathy, autonomic neuropathy (orthostatic hypotension, sweating).
  • Respiratory: SOB, wheeze, haemoptysis.

  Investigations

  • Diagnosis: biopsy of unaffected site (e.g. subcutaneous fat) or affected organ (esp. if only limited disease). Congo red staining on microscopy shows green birefringence. Serum amyloid P (SAP) scintigraphy can also support the diagnosis.
  • Amyloid typing: immunohistochemistry (good for AA and TTR) or mass spectrometry (good for AL).
  • Look for underlying cause: protein electrophoresis, immunofixation, skeletal survey, and bone marrow biopsy for AL; genetic testing for FA.
  • Check for organ effects: bloods inc. FBC, U&E, LFT, BNP, plus urinalysis, ECG, echo, and nerve conduction tests if indicated.

  Management

  • Treat underlying cause if present e.g. chronic inflammatory disease.
  • Treat organ effects e.g. heart failure treatment, dialysis.
  • Chemotherapy for AL: {cyclophosphamide and dexamethasone} plus {bortezomib or thalidomide}.
  • Liver transplant for FA if protein produced by liver e.g. TTR, ApoAI.
  • Novel anti-TTR agents: patisiran, inotersen, tafamidis.

• Histiocytosis

  Definition and types

  • Range of conditions characterised by tissue dysfunction resulting from infiltration by monocytes, macrophages, and dendritic cells, and associated cytokine production.
  • Langerhans cell histiocytosis (aka histiocytosis X) is the commonest. Others include hemophagocytic lymphohistiocytosis and malignant histiocytosis.

  Langerhans cell histiocytosis (LCH)

  • Proliferation of cells which morphologically mimic (but do not derive from) Langerhans cells, dendritic cells of the skin and mucosal epithelium. Unclear if it is neoplastic, or a reactive, dysfunctional immune process.
  • Prevalence 1/50,000. Onset usually in childhood, but can affect any age.
  • 50% are single system (either uni- or multifocal), with an excellent prognosis, and 50% are multisystem, with 50% mortality.
  • Bone is the commonest organ affected (esp. skull in kids), with lytic lesions ('eosinophilic granulomas') that may be painful or painless, and may form palpable lumps.
  • Skin and oral mucosa is 2nd commonest, with purple papules or eczematous rash.
  • Other organs affected: lung (esp. adult smokers), bone marrow, lymph nodes, liver, spleen, pituitary (causing diabetes insipidus).

  Investigations of LCH

  • Bloods: FBC (cytopenia), ESR, LFTs.
  • XR: lytic lesions.
  • CXR/CT: nodules then cysts in the mid-upper zones.
  • Biopsy of affected tissue – e.g. skin, bone – for definitive diagnosis. Shows Birbeck granules on electron microscopy.

  Management of LCH

  • Bony lesions: excision if unifocal, NSAIDs or steroids if multifocal.
  • Skin lesions: topical steroids.
  • Chemotherapy for multisystem disease: prednisolone + vinblastine.

• Mastocytosis

  Pathophysiology and epidemiology

  • Proliferation and tissue infiltration of mast cells, which release histamine, leukotrienes, and other cytokines. A type of myeloproliferative disease.
  • Prevalence 1/10,000.

  Type and presentation

  • Cutaneous mastocytosis: urticaria pigmentosa, a diffuse maculopapular rash which becomes itchy and swollen on stroking (Darier sign).
  • Systemic mastocytosis: flushing, itch, anaphylactoid reactions, GI symptoms, hepatosplenomegaly, anaemia. Can be an indolent or aggressive form.
  • Other types: mast cell leukemia, mast cell sarcoma, extracutaneous mastocytoma.

  Investigations

  • ↑Tryptase (if systemic).
  • Skin and bone marrow biopsy.

  Management

  • Antihistamines
  • Adrenaline autoinjector (EpiPen) for anaphylactoid reactions.
  • Interferon alfa-2b ± prednisolone for aggressive disease.

• Adult-onset Still's disease

  Pathophysiology and epidemiology

  • Idiopathic autoimmune disease.
  • Can be an episode lasting weeks to months, either one-off or recurrent, or a chronic disease.
  • Prevalence 1/15,000. Onset age usually 15-45 years.

  Presentation

  Classic triad:

  • Fever: high, once/twice daily.
  • Arthralgia/arthritis: may initially be oligoarticular and later polyarticular, most commonly affecting knees, wrists, and ankles.
  • Rash: salmon-coloured, non-pruritic, maculopapular, appearing with the fever.

  Other features:

  • Pharyngitis, hepatomegaly, lymphadenopathy, pericardial disease, DIC.
  • Commoner in episodic disease.

  Diagnosis

  • Largely a diagnosis of exclusion, with the classic triad plus ↑neutrophils and ↑ferritin (70%) supporting the diagnosis.
  • Autoantibodies – ANA, RF – are rare (<10%).

  Management

  • NSAIDs for milder disease.
  • Steroids, methotrexate, and/or anti-TNFα agents for moderate/severe disease.
  • Consider anakinra, an IL-1 inhibitor, for refractory disease.