Headaches. Is this a migraine?

A 23-year-old woman who has recently graduated from university, has been applying for a job for 5 months but has not succeeded. She is depressed and according to her family has lost her self esteem. She presents to you with five episodes of headache during the past 2 months. Each episode begins with yawning, sensitivity to light, and a depressed mood that is followed by the gradual onset of neck pain that spreads to the occipital region and eventually to the retro-orbital region on the right side. The pain becomes incapacitating over a period of 1 to 2 hours and is associated with nausea and sensitivity to light and sound. With two of the episodes, she had jagged lines in her vision for 15 minutes as the neck pain was beginning; with all the episodes, she had severe fatigue and difficulty concentrating and finding words. The headache last approximately 24 hours, and, after resolution, she has several hours of residual neck soreness, fatigue, and depressed mood. How will you evaluate and treat this patient?

Sounds like migraine. She is the right age, gender and has depression and anxiety about getting a job. What else can this be associated with? Migraine may be associated with increased risks of several other disorders, including asthma, stroke, anxiety and depression, and other pain disorders. When she was 10 years old she suffered from nightmares, headaches with vomiting and her work at school suffered. She was withdrawn from school for 2 months, her paediatrician diagnosed anxiety, she was sent to visit her grandmother in the village. There, a faith healer prayed over her, her father encouraged her to ride horses at the farm and she gradually became better and returned home and joined school again. The headaches did not recur until now.

Plan of management.

Management should include establishing an accurate diagnosis, identifying and modifying potential exacerbating factors (including medications), developing a plan for the treatment of acute attacks, and determining whether preventive therapy is warranted.

A complete physical examination is warranted including a careful neurological examination. Since this is her initial presentation as an adult, examine the optic fundi and even though there are no indications that it anything but migraine do imaging studies for an intracranial  lesion. It is not necessary to do cranial imaging every time she has a headache unless a new neurological symptom or sign develops. Keep an eye on her blood pressure. Lab tests should include a complete blood picture, tests for renal and liver functions and blood sugars at least. These do not need to be repeated for every episode of headache.

Why isn’t migraine just a bad headache? A migraine may be associated with a stroke especially in the older patients and those with diabetes and hypertension hence needs to be distinguished as a migraine from a sentinel headache preceding a subarachnoid hemorrhage or a hemorrhagic stroke.

A variety of premonitory symptoms  may occur hours before the headache begins and postdromal symptoms  may last for hours after the headache ends. Yawning, mood change, light sensitivity, neck pain, and fatigue are common premonitory symptoms that may persist during and after the headache.

There may be an aura.

Aura symptoms may include visual disturbances (e.g., wavy lines or bright or dark spots), other sensory changes (e.g., numbness or tingling), language dysfunction, and vertigo.

Cutaneous allodynia (the experience of normal touch as uncomfortable) is also a common component of a migraine attack. Patients may not recognize or spontaneously report these symptoms, but when asked to record them, they can often identify the onset of an attack several hours before a headache occurs and realize that the disabling features of an attack often outlast the headache.

Some presumed triggers of migraine may be manifestations of the premonitory phase of a migraine attack; food, light, sound, and odor triggers that are identified by patients may in some cases be early symptoms of gastrointestinal and sensory sensitivity that are part of the attack.

What happens to the brain during a migraine attack?

The diverse and highly variable symptoms of migraine reflect complex alterations in the functioning of the nervous system. Changes in the activity of multiple brain regions during migraine attacks have been visualized with functional imaging techniques and quantified with the use of clinical electrophysiological techniques. These studies reveal activation of the hypothalamus, thalamus, brain stem, and cortex corresponding with various symptoms of a migraine attack, including those occurring before and after headache.

Although migraine is associated with intracranial vasodilation a cross sectional study was done and magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura was carried out. (The Lancet Neurology. Volume 12, Issue 5, May 2013, Pages 454-461) Migraine pain was not accompanied by extracranial arterial dilatation, and by only slight intracranial dilatation. It is now clear that constriction of blood vessels is not a required mechanism of therapies for migraine.12 Although migraine is associated with an increased relative risk of stroke and cardiovascular disease,14,15 the mechanisms underlying this association remain uncertain, and it is exceedingly rare for cerebral ischemia or infarction to occur during a migraine attack. Future migraine research should focus on the peripheral and central pain pathways rather than simple arterial dilatation.

Diagnosis of migraine. Don’t mistake a migraine for cervical pain or sinus infection.

 Migraine headache is characteristically severe, unilateral, and throbbing, it may also be moderate, bilateral, and constant in quality. The features of migraine other than headache, particularly sensitivity to light and sound, nausea, and interference with the ability to function, may be more useful in diagnosis than the character of the headache. Other common migraine symptoms, including aura, cognitive dysfunction, dizziness, and fatigue, may lead physicians to order brain imaging, yet this is generally unnecessary if symptoms have a gradual onset and are transient. Neck pain is another common symptom of migraine, but it is frequently misinterpreted as a manifestation of a disorder in the cervical spine, often leading to unnecessary scans of this region. Patients or physicians frequently believe that migraine is related to sinus disease, whereas the majority of patients who receive a diagnosis of “sinus headache” in fact have migraine.

Lifestyle changes which may help.

  • Don’t skip a meal.
  • Get regular sleep at your usual time.
  • Don’t drink too much caffeine.
  • Do regular exercises.
  • You may need extra medicines before, during and after menstrual periods.

Medicines which make a migraine worse.

Many medicines make migraines worse or trigger them. They include oral contraceptives, postmenopausal hormone therapy, nasal decongestants, selective serotonin-reuptake inhibitor antidepressants, and proton-pump inhibitors. In some patients, the frequency and severity of attacks can be dramatically reduced by adjusting or discontinuing these medications. In addition, regular use of analgesic medications, particularly opioids and barbiturate–caffeine–analgesic combinations, can increase migraine frequency and severity, even when taken only once or twice a week. This exacerbation cannot be explained simply by tolerance, dependence, or addiction but rather is a direct adverse effect on migraine. Withdrawing the frequently used medication can result in marked improvement, but this may require substantial time and effort, and in some patients, inpatient treatment is needed.

How will you abort an acute migraine attack?

  • Triptans such as almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan will provide relief by 2 hours and the patient is usually free of the headache in 24 hours. Nasal or subcutaneous delivery is more effective than oral. Don’t prescribe to any one with coronary artery disease.
  • Ergots also provide pain relief in 2 hours and can be used as a nasal spray or subcutaneous injection and is often used for refractory migraine.
  • Acetaminophen (paracetamol) will provide pain relief in 19% of patients. Use with an antiemetic like prochlorperazine (Stemetil) or chlorpromazine (Phenergan), metoclopramide (maxolon).
  • NSAIDs like aspirin, diclofenac, ibuprofen, ketorolac and naproxen will also provide relief in 2 hours in 20-40% of patients. Use with triptans.
  • Combinations of acetaminophen-aspirin and caffeine or naproxen and sumatriptan may also provide pain relief in 2 hours in 20% of patients.
  • Single pulse TMS (transcranial magnetic stimulation) through a handheld device will also work in about 20% of patients.
  • CGRP (calcitonin gene-related peptide) receptor antagonists are under investigation. These are remigepant, ubrogepant,
  • A review of three trials evaluating valproate products (divalproex sodium, sodium valproate, and valproic acid) at doses ranging from 500 to 1500 mg daily for migraine prevention found that valproate was significantly more effective than placebo as measured by the number of patients experiencing a ≥50 percent reduction in migraine frequency in adults.
  • Intravenous valproate. The utility of IV valproate for the treatment of acute migraine in children is not established, and the existing evidence is limited and retrospective
  • Anti-inflammatory drugs, and antiemetic agents individually or in combination) should be taken as early as possible after the onset of a migraine attack.
  • Preventive therapies (e.g., beta-blockers, candesartan, tricyclic antidepressants, and anticonvulsant agents as well as botulinum toxin for chronic migraine) should be considered on the basis of the frequency and severity of attacks, response to medications for acute migraine, and coexisting conditions.
  • Recent clinical trials support the efficacy of new therapies targeting calcitonin gene–related peptide (CGRP) for the treatment of acute migraine and for migraine prevention. The  CGRP is a therapeutic target in migraine because of its hypothesized role in mediating trigeminovascular pain transmission and the vasodilatory component of neurogenic inflammation. The US Food and Drug Administration (FDA) approved the CGRP  antagonists erenumab, fremanezumab, and galcanezumab in 2018 and eptinezumab in 2020 for migraine prevention.

In clinical practice, a substantial percentage of patients report dissatisfaction with triptans because of a slow or incomplete response. For some, the addition of a nonsteroidal antiinflammatory drug (NSAID) (including nonprescription preparations), or taking one of these medications independently, can be effective.

Multiple ergotamine preparations are available, and intravenous dihydroergotamine in particular is a mainstay of treatment for refractory migraine in urgent care or inpatient settings. Intranasal, subcutaneous injectable, rectal suppository, or other non-oral preparations of therapies for acute migraine may be able to achieve therapeutic levels more quickly than oral preparations and are indicated if nausea and vomiting are a feature of migraine attacks.

Be careful with triptans. The primary concern with frequent triptan use is not safety but rather the potential development of medication-overuse headache, which the ICHD, third edition, defines as more than 10 days per month of triptan use in a person who has 15 or more days of headache per month.

When are you going to initiate preventive therapy in a patient?

There is no evidence supporting a specific “threshold” migraine frequency for which preventive therapy is clearly warranted, although it is generally agreed that preventive therapy should be considered if migraine occurs at least once per week or on 4 or more days per month. Preventive therapy may also be tried in the following situations:

  • Frequent or long lasting migraine headaches
  • Migraine attacks that cause significant disability or diminished quality of life despite appropriate acute treatment
  • Contraindication to acute therapies
  • Failure of acute therapy
  • Serious adverse effects of acute therapies
  • Risk of medication overuse headache
  • Menstrual migraine

All currently available preventive medication therapies for migraine were initially developed for other indications and have been secondarily adopted as treatments for migraine. Antihypertensive agents (e.g., beta-adrenergic blockers and candesartan), anticonvulsant agents (e.g., topiramate and divalproex sodium), and tricyclic antidepressants (e.g., amitriptyline and nortriptyline) are standard preventive therapies for migraine. For some patients, these agents can be highly effective, although the average difference in headache days per month between preventive therapies and placebo has been small in clinical trials. Adverse effects are common for most of the preventive therapies, and patients often report an initial response that “wears off” despite increasing doses. Adherence to treatment is generally poor.

OnabotulinumtoxinA is a Food and Drug Administration (FDA)–approved therapy for the prevention of chronic migraine, defined as headache occurring on more than 15 days per month, with migraine features on at least 8 of those days. There is limited evidence to support the use of nonprescription agents — including coenzyme Q10, riboflavin, magnesium, melatonin, and petasites (Petasites are a genus of flowering plants in the sunflower family, Asteraceae) — but these agents are nonetheless widely used because of their acceptable side-effect profile.

Preventive migraine therapy also is indicated to reduce the risk of neurologic damage and/or impairment in the presence of uncommon migraine conditions including:

  • Hemiplegic migraine
  • Migraine with brainstem aura
  • Persistent aura without infarction
  • Migrainous infarction

Which preventive therapy to choose? For patients with hypertension, a beta-blocker or candesartan may be warranted; for those with insomnia, a tricyclic antidepressant may be considered; and for patients who are obese, topiramate may be appropriate.

How to use beta blockers.

  • Propranolol in two divided doses starting at 40 mg daily; dose range 40 to 160 mg daily
  • Metoprolol in two divided doses starting at 50 mg daily; dose range 50 to 200 mg daily
  • Nadolol starting at 20 mg once a day; dose range 20 to 240 mg daily
  • Atenolol starting at 25 mg daily; dose range 25 to 100 mg once daily

For calcium channel blockers verapamil appears to be popular, flunarizine, nimodipine and nifedipine are also used. Tolerance tends to develop.

Of the ACEi/ARBs lisinopril appears to be more effective.

The tricyclic antidepressants most commonly used for migraine prevention include amitriptyline, nortriptyline, doxepin, and protriptyline. Amitriptyline is the only tricyclic that has proven efficacy for migraine; there are insufficient data regarding the other tricyclics The tricyclic antidepressant amitriptyline (starting dose 10 mg at bedtime, dosage range 20 to 50 mg at bedtime) was effective for migraine prevention in four trials. In other trials, the serotonin-norepinephrine reuptake inhibitor venlafaxine (starting at 37.5 mg once a day, dosage range 75 to 150 mg once a day) was also effective as prevention for migraine.

A 2012 guideline from the AAN concluded that topiramate and sodium valproate are established as effective for migraine prevention, while evidence is insufficient to determine the effectiveness of gabapentin.

Topiramate — Several placebo-controlled studies, a systematic review, and a meta-analysis have found that topiramate is effective preventive therapy for migraine. Significant reductions in migraine frequency occurred within the first month at topiramate doses of 100 and 200 mg/day.

The young woman described in the vignette has migraine with and without aura. If her neurologic examination is normal, there is no indication for an imaging study, given that she has had multiple episodes of typical duration with complete resolution of symptoms between episodes and no “red flags,” such as an abrupt onset of symptoms, fever, concurrent clinically significant illness, or persistent headache between attacks. Many practitioners reflexively order an imaging study when attacks include neurologic symptoms in addition to headache, but such symptoms are characteristic of migraine. Current medications should be reviewed as possible exacerbating factors. Consistency of lifestyle factors (diet, caffeine intake, sleep, and exercise) should be encouraged, and a strategy for the treatment of acute attacks with triptans, NSAIDs, antiemetics, or a combination of these agents should be developed, with an emphasis on treating as early as possible after migraine onset. The frequency and severity of migraine attacks should be monitored to assess whether preventive therapy may be indicated; options include a beta-blocker, candesartan, a tricyclic antidepressant, an anticonvulsant (topiramate or divalproex sodium), or onabotulinumtoxinA (if headache occurs ≥15 days per month). This choice should be informed by coexisting conditions and potential adverse effects. Paper or electronic symptom diaries can be very helpful in assessing the clinical course of migraine and the response to therapies. If pharmacologic therapies are ineffective or have unacceptable side effects, neuromodulation approaches should be considered.

 

 

 

Rheumatoid arthritis and Psoriatic arthritis

Rheumatoid arthritis is a common autoimmune disease that is associated with progressive disability, systemic complications, early death, and socioeconomic costs. The cause of rheumatoid arthritis is unknown, and the prognosis is guarded. However, advances in understanding the pathogenesis of the disease have fostered the development of new therapeutics, with improved outcomes. The current treatment strategy, which reflects this progress, is to initiate aggressive therapy soon after diagnosis and to escalate the therapy, guided by an assessment of disease activity, in pursuit of clinical remission. The mortality rate is higher among patients with rheumatoid arthritis than among healthy persons, and cardiovascular (myocardial infarction, heart failure and stroke) and other systemic complications remain a major challenge. These increased rates are not explained by traditional risk factors, use of glucocorticoids or nonsteroidal antiinflammatory drugs, or shared genetic features. Inflammation in rheumatoid arthritis also affects the brain (fatigue and reduced cognitive function), liver (elevated acute-phase response and anemia of chronic disease), lungs (inflammatory and fibrotic disease), exocrine glands (secondary Sjögren’s syndrome), muscles (sarcopenia), and bones (osteoporosis).

Rheumatoid arthritis is characterized by synovial inflammation and hyperplasia (“swelling”), autoantibody production (rheumatoid factor and anti–citrullinated protein antibody [ACPA]), cartilage and bone destruction (“deformity”), and systemic features, including cardiovascular, pulmonary, psychological, and skeletal disorders.

Infectious agents (e.g., Epstein–Barr virus, cytomegalovirus, proteus species, and Escherichia coli) and their products (e.g., heat-shock proteins) have long been linked with rheumatoid arthritis, and although unifying mechanisms remain elusive, some form of molecular mimicry is postulated has been postulated in rheumatoid arthritis. Increased T cell senescence may contribute to molecular mimicry.

Smoking and other forms of bronchial stress (e.g., exposure to silica) increase the risk of rheumatoid arthritis among persons with susceptibility HLA–DR4 alleles.

Why are women more susceptible to rheumatoid arthritis? Molecular explanations for such phenomena are emerging from animal models of inflammation, which show a link between the hypothalamic–pituitary–adrenal axis and cytokine production.

Why the systemic loss of tolerance is linked to a localized onset of inflammation in the joint is still unclear (transitional phase of rheumatoid arthritis).  Autoantibodies, such as rheumatoid factor and ACPA, are often (but not always) detected in patients before the development of arthritis (pre-articular phase of rheumatoid arthritis); in some series, autoantibody levels have increased and there has been evidence of epitope spreading as the onset of disease approaches.

Psoriasis begins as a relatively benign skin diseases but progresses to complicated skin disease and arthritis. Psoriatic arthritis is  chronic and inflammatory and involves the joints, entheses, bone, axial skeleton, and skin, with heterogeneous clinical features associated with substantial disability and reduced life expectancy. There is accumulating evidence that interleukin-17 is central to the pathogenesis of psoriatic arthritis and other spondyloarthritides, such as ankylosing spondylitis. In the management of psoriatic arthritis inhibition of interleukin-17 signaling by brodalumab induces significant clinical responses in patients with psoriasis. By contrast, efficacy has not been observed for brodalumab in clinical trials involving patients with rheumatoid arthritis or Crohn’s disease.

Five subtypes of  psoriatic arthritis have been described.

  • The oligoarticular subtype affects four or fewer joints and typically occurs in an asymmetric distribution.
  • The polyarticular subtype affects five or more joints; the involvement may be symmetric and resemble rheumatoid arthritis.
  • The distal subtype, which affects distal interphalangeal joints of the hands, feet, or both, usually occurs with other subtypes, occurring alone in only 5% of patients.
  • Arthritis mutilans, a deforming and destructive subtype of arthritis that involves marked bone resorption or osteolysis, is characterized by telescoping and flail digits.
  • The axial or spondyloarthritis subtype primarily involves the spine and sacroiliac joints.

These patterns may change over time. Given below is the CASPAR classification for psoriatic arthritis.

The diagnosis of psoriatic arthritis is based on the recognition of clinical and imaging features, since there are no specific biomarkers. Involvement of at least five domains is possible; these include psoriasis, peripheral joint disease, axial disease, enthesitis, and dactylitis. Patients should be carefully assessed for these domains, with the understanding that various domain combinations may be present in an individual patient. The personal history and family history of psoriasis are often positive. Inflammatory arthritis, enthesitis, dactylitis, and joint distribution provide important clues, as do extraarticular features such as inflammatory bowel disease and uveitis. It is important to look for psoriatic skin lesions, particularly in the groin, umbilical area, hairline, ears, and natal (i.e., intergluteal) cleft. Nail lesions, including pits and onycholysis, as well as the presence of spinal disease, support the diagnosis.

Risk factors.

There are several environmental risk factors for psoriatic arthritis. These include obesity; severe psoriasis; scalp, genital, and inverse (or intertriginous) psoriasis; nail disease; and trauma or deep lesions at sites of trauma (Koebner’s phenomenon)

Differential diagnosis.

It is necessary to differentiate psoriatic arthritis from rheumatoid arthritis, osteoarthritis, gout, pseudogout, systemic lupus erythematosus, and other forms of spondyloarthritis.

Rheumatoid arthritis is characterized by proximal, symmetric involvement of the joints of the hands and feet, with sparing of the distal interphalangeal joints, whereas in more than 50% of patients with psoriatic arthritis, the distal joints are affected; the involvement tends to be characterized by a “ray” distribution, with all the joints of the same digit involved and other digits spared. This is noticeable both clinically and radiographically. At its onset, psoriatic arthritis tends to be oligoarticular and less symmetric than rheumatoid arthritis, although with time, psoriatic arthritis may become polyarticular and symmetric. The affected joints are less tender in psoriatic arthritis than in rheumatoid arthritis and may have a purplish discolorationSpinal involvement (sacroiliac joints or the lumbar, thoracic, or cervical spine) occurs in more than 40% of patients with psoriatic arthritis but is uncommon in patients with rheumatoid arthritis.

Psoriatic monoarthritis, particularly involving the toes, or dactylitis may be misdiagnosed as gout or pseudogout. The uric acid level may be elevated in patients with psoriatic arthritis, as well as in those with gout, making the differential diagnosis difficult, particularly if crystal analysis of joint fluid is negative or cannot be performed.

The distal-joint involvement that is characteristic of psoriatic arthritis is also observed in osteoarthritis. In psoriatic arthritis, palpation of distal joints reveals soft swelling due to inflammation, whereas in osteoarthritis, swelling arises from a bony osteophyte and is solid.

Ankylosing spondylitis typically begins late in the second decade of life or early in the third decade, whereas psoriatic spondyloarthritis is more likely to develop in the fourth decade of life. Psoriatic spondyloarthritis may be less severe than ankylosing spondylitis, with less pain and infrequent sacroiliac-joint ankylosis; an asymmetric distribution of syndesmophytes (bony growths originating inside a ligament of the spine) is more common in cases of psoriatic arthritis.

Bone erosions are observed in 47% of patients within the first 2 years, despite the use of traditional disease-modifying medications in more than half the patients. In an observational trial involving patients with psoriatic arthritis treated with anti–tumor necrosis factor (TNF) agents such as  adalimumab, etanercept, or infliximab, the rate of partial remission was 23%. However, relapse rates are high when biologic agents are discontinued.

Differential responses in patients with rheumatoid arthritis versus those with psoriatic arthritis provide further evidence that these diseases have different causal mechanisms. The observed clinical response to brodalumab among patients with psoriatic arthritis in this study (March 9, 2017 N Engl J Med 2017; 376:957-970
DOI: 10.1056/NEJMra1505557) supports the concept that interleukin-17 pathways are critical in the pathogenesis of psoriatic skin and joint disease. The clinical response of psoriatic skin disease to brodalumab has been established in previous studies among patients with psoriasis, including approximately 20% who also had psoriatic arthritis.

Genetic differences between rheumatoid arthritis and psoriatic arthritis.

Rheumatoid arthritis, is associated with class II major histocompatibility complex (MHC) alleles, psoriasis and psoriatic arthritis are associated with class I MHC alleles.

Psoriatic arthritis is a highly heritable polygenic disease. The recurrence risk ratio (defined as the risk of disease manifestation in siblings vs. the risk in the general population) is greater than 27, which is substantially higher than the recurrence risk ratio for psoriasis or rheumatoid arthritis. Most notably, HLA-C*06 is a major risk factor for psoriasis but not for psoriatic arthritis. In psoriatic arthritis, frequencies of HLA-B*08, B*27, B*38, and B*39 have been observed, with specific subtypes of those alleles linked to subphenotypes, including symmetric or asymmetric axial disease, enthesitis, dactylitis, and synovitis. It has been shown consistently that T cells are important in psoriasis and psoriatic arthritis.

A central role for CD8+ T cells in disease pathogenesis is supported by the association with HLA class I alleles, oligoclonal CD8+ T-cell expansion, and the association of psoriatic arthritis with human immunodeficiency virus disease.

When should a diagnosis of rheumatoid arthritis be made?

  • Inflammation of three or more joints.
    • Arthritis is typically present in the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the hands. The wrists are also commonly involved, as are the metatarsophalangeal (MTP) joints in the feet, but any upper or lower extremity joint may be affected. Symmetric polyarthritis, particularly of the MCP, MTP, and/or PIP joints, strongly suggests RA.
    • Although distal interphalangeal (DIP) joint disease can occur in patients with RA, DIP involvement strongly suggests a diagnosis of osteoarthritis or psoriatic arthritis
  • Positive rheumatoid factor (RF) and/or anti-citrullinated peptide/protein antibody (such as anti-cyclic citrullinated peptide [CCP])) testing.
  • Elevated levels of C-reactive protein (CRP) or the erythrocyte sedimentation rate (ESR).
  • Diseases with similar clinical features have been excluded, particularly psoriatic arthritis, acute viral polyarthritis, polyarticular gout or calcium pyrophosphate deposition disease, and systemic lupus erythematosus (SLE).
  • The duration of symptoms is more than six weeks.
  • Serology: RFs occur in 70 to 80 percent of patients with RA. Their diagnostic utility is limited by their relatively poor specificity, since they are found in 5 to 10 percent of healthy individuals, 20 to 30 percent of people with SLE, virtually all patients with mixed cryoglobulinemia (usually caused by hepatitis C virus [HCV] infections).
  • Anti-citrullinated peptide antibodies.  The specificity of ACPA for RA is relatively high, usually over 90 percent. ACPA can occur in other diseases, including several autoimmune rheumatic diseases, tuberculosis, and sometimes chronic lung disease.
  • Other factors such as genetic factors, tissue factors, epitopes and acute phase reactants such as IL-6 have not found to correlate with disease activity or prevention of bone destruction.

2013 Update of the EULAR recommendations (the table of 2010 recommendations can be seen in the online supplement or the original publication). The 2020 EULAR has been cancelled because of COVID-19 pandemic.

 

 

 

Diabetes in pregnancy.

Why is there insulin resistance in pregnancy? The placenta secretes  diabetogenic hormones which include growth hormone, corticotropin-releasing hormone, placental lactogen (chorionic somatomammotropin), prolactin, and progesterone. These and other metabolic changes ensure that the fetus has an ample supply of nutrients.

Why does gestational diabetes develop?

Gestational diabetes mellitus develops during pregnancy in women whose pancreatic function is insufficient to overcome the insulin resistance associated with the pregnant state. Among the main consequences are increased risks of preeclampsia, macrosomia, and cesarean delivery, and their associated morbidities.

What is the likelihood if a pregnant woman has an abnormally high blood sugar?

  • A woman may have type 1 or type 2 pre-existing diabetes at the time of conception.
  • Develop transient hyperglycemia caused by placental hormones and transient pancreatic insufficiency: gestational diabetes.
  • Undiagnosed type 2 diabetes in reproductive-age women related to the ongoing epidemic of obesity. There has been an attempt to distinguish women with probable preexisting diabetes that is first recognized during early pregnancy. These women will need to be followed up and treated for Type 2 diabetes after the pregnancy is over. This is different from those whose disease is a transient manifestation of pregnancy-related insulin resistance and diagnosed in the late second or the third trimester.
  • The oral glucose tolerance test is no longer recommended for the diagnosis of diabetes except in gestational diabetes.
  • One-step and two-step approaches to OGTT for gestational diabetes.

    • Two-step approach – The two-step approach is the most widely used approach for identifying pregnant women with gestational diabetes mellitus in the United States. The first step is a 50 gram one-hour glucose challenge test (GCT) without regard to time of day/previous meals. Screen-positive patients go on to the second step, a 100 gram, three-hour oral glucose tolerance test (GTT), which is the diagnostic test for gestational diabetes mellitus.

    • One-step approach – The one-step approach omits the screening test and simplifies diagnostic testing by performing only a 75 gram, two-hour oral GTT but requires an overnight fast. The following thresholds have been proposed to define a positive screen: ≥130 mg/dL, ≥135 mg/dL, or ≥140 mg/dL (7.2 mmol/L, 7.5 mmol/L, or 7.8 mmol/L).

    • The positive predictive value (PPV) of this test varies depending on the prevalence of gestational diabetes mellitus in the population tested and the GTT criteria used for diagnosis of gestational diabetes mellitus. A 50 gram one-hour plasma glucose >182 mg/dL (10.1 mmol/L) had >95 percent probability of gestational diabetes mellitus. At glucose levels ≥200 mg/dL (11.1 mmol/L), others have reported PPVs of 47 to 80 percent for an abnormal GTT.
Range of diagnostic criteria for gestational diabetes mellitus
Approach Criteria Fasting mg/dL One-hour mg/dL Two-hour mg/dL Three-hour mg/dL
Two step (100-gram load) Carpenter and Coustan 95 (5.3 mmol/L) 180 (10.0 mmol/L) 155 (8.6 mmol/L) 140 (7.8 mmol/L)
Two step (75-gram load) CDA 95 (5.3 mmol/L) 191 (10.6 mmol/L) 160 (8.9 mmol/L)
One step (75-gram load) WHO 92 to 125 (5.1 to 6.9 mmol/L) 180 (10.0 mmol/L) 153 to 199 (8.5 to 11 mmol/L)
IADPSG 92 to 125 (5.1 to 6.9 mmol/L) 180 (10.0 mmol/L) 153 (8.5 mmol/L)

Why worry about gestational diabetes or hyperglycemia in a pregnant woman? Here is a list of complications likely to arise.

  • Preeclampsia, gestational hypertension
  • Polyhydramnios
  • Macrosomia and large for gestational age infant
  • Maternal and infant birth trauma
  • Operative delivery (cesarean, instrumental)
  • Perinatal mortality
  • Fetal/neonatal hypertrophic cardiomyopathy
  • Neonatal respiratory problems and metabolic complications (hypoglycemia, hyperbilirubinemia, hypocalcemia, polycythemia)

Diagnosis of Diabetes in non-pregnant patients.

  • Early screening and diagnosis allow for the identification of at-risk persons (so that preventive measures, primarily lifestyle changes, may be undertaken) and those with early disease (so that treatment can be initiated).
  • The diagnostic cutoff point for diabetes is a fasting plasma glucose level of 126 mg per deciliter (7.0 mmol per liter) or more or a glycated hemoglobin level of 6.5% or more; the diagnosis requires confirmation by the same or the other test.
  • A fasting glucose level of 100 to 125 mg per deciliter (5.6 to 6.9 mmol per liter) is consistent with prediabetes; the range of glycated hemoglobin levels that are diagnostic of prediabetes is controversial, but the American Diabetes Association recommends a range of 5.7 to 6.4%.
  • Hemoglobinopathies and conditions of altered red-cell turnover can give spurious results for glycated hemoglobin; racial and ethnic differences in glycated hemoglobin levels have been reported for given ambient glucose levels.
  • Testing of glycated hemoglobin or fasting plasma glucose appears to identify different groups of patients with diabetes and prediabetes, yet both tests identify patients at similar risk for adverse sequelae.
  • Approximately one-quarter of women with A1C 5.7 to 6.4 percent ([39 to 46 mmol/mol] suggestive of impaired glucose intolerance) in early pregnancy develop gestational diabetes mellitus when screened and tested later in pregnancy compared with <10 percent of those with A1C <5.7 percent (39 mmol/mol).
  • A two-step testing approach at 24 to 28 weeks of gestation, is recommended by the American College of Obstetrician and Gynecologists (ACOG) guidelines (50 gram oral glucose challenge test followed by the 100 gram three-hour oral glucose tolerance test [GTT] in screen-positive women)

When is glycated Hb unreliable?

Depending on the assay, spuriously low values may occur in patients with certain hemoglobinopathies (e.g., sickle cell disease and thalassemia) or who have increased red-cell turnover (e.g., hemolytic anemia and spherocytosis) or stage 4 or 5 chronic kidney disease, especially if the patient is receiving erythropoietin. In contrast, falsely high glycated hemoglobin levels have been reported in association with iron deficiency and other states of decreased red-cell turnover.

Obesity is associated with an increased risk of adverse pregnancy outcomes. Lifestyle-intervention studies have not shown improved outcomes. Metformin improves insulin sensitivity and in pregnant patients with gestational diabetes it leads to less weight gain than occurs in those who do not take metformin.

 

 

Systemic Lupus Erythematosus.

Recognized initially as a disease of the skin, it was named “lupus” or latin for wolf, red or erythematosus because of its inflammatory tendency and systemic was added when it was realized that it is a disease which affects most organs. Here is a diagram of which organs it affects and the probable mechanism of why it occurs.

How does lupus present to a physician?

The skin manifestation is a malar rash as given in this picture. This is an acute manifestation of cutaneous lupus.

Image

Discoid lesions on the face of patients. Scarring occurs as well as marked photosensitivity in both these lesions. The picture on the right the lesions have become chronic.

Discoid lupus erythematosus      Discoid lupus erythematosus, Swinfen Charitable Trust

Discoid lupus erythematosus

Alopecia areata in the scalp.

Image

A discoid lesion on the pinna of a patient is seen in this picture.

Discoid lupus erythematosus

Chilblain like lesions on the toes.

Cutaneous lupus erythematosus (cutaneous LE) includes three subsets of LE-specific skin diseases:

  • acute cutaneous lupus erythematosus (ACLE)
    • Localized ACLE (ie, malar rash, butterfly rash)

    • Generalized ACLE

    • Toxic epidermal necrolysis-like ACLE

  • subacute cutaneous lupus erythematosus (SCLE)
    • Annular SCLE

    • Papulosquamous SCLE

    • Drug-induced SCLE

    • Less common variants: erythrodermic, poikilodermatous, erythema multiforme-like (Rowell syndrome), and vesiculobullous annular SCLE

  • chronic cutaneous lupus erythematosus (CCLE) which includes:
    • discoid lupus erythematosus (DLE), which may be generalised, localised or hypertrophic.
    • lupus erythematosus tumidus (LE tumidus),
    • lupus profundus (also known as lupus panniculitis),
    • chilblain lupus erythematosus (chilblain LE), and
    • lichenoid cutaneous lupus erythematosus-lichen planus overlap syndrome (LE-LP overlap syndrome).

Cutaneous disease is common in systemic lupus erythematosus (SLE); approximately 80 percent of patients develop skin disease at some point in their disease course. However, cutaneous LE frequently exists independently of SLE and may be two to three times more prevalent than SLE.

Always ask about the drugs that the patient is taking. Many classes of drugs have been implicated in SCLE, including antihypertensive drugs, lipid-lowering agents, proton pump inhibitors, antifungal agents, TNF-alpha inhibitors, and others. Drug-induced SCLE and idiopathic SCLE have similar clinical, histopathologic, and laboratory features and can be indistinguishable in the absence of a helpful medication history. Drug withdrawal often leads to improvement in drug-induced SCLE.

Mucosal manifestations of lupus are also commonly seen. These are ulcers and white plaques on the palate and inside the mouth. Do remember to examine the oral cavity. The oral ulcers are usually painless. Oral ulcers may be the first sign of SLE. There is no apparent association between the presence of oral ulcers and systemic activity.

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Cutaneous manifestations of vascular involvement in SLE include periungual erythema, livedo reticularis, telangiectasia, Raynaud phenomenon, and vasculitis. Cutaneous vascular abnormalities occur in approximately 50 percent of patients with SLE. Bullous cutaneous lupus erythematosus (bullous CLE) is a rare and distinct complication of SLE characterized by the development of autoantibodies against type VII collagen and subepidermal blistering. Affected patients develop a vesicular or bullous eruption that may affect any body site, including oral mucosa.

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Other than the mucocutaneous manifestations of systemic lupus patients commonly have constitutional symptoms such as fever (SLE should be part of the workup of pyrexia of unknown origin in a young woman of reproductive age), fatigue, weight loss, myalgia and arthralgia.

Cardiac disease among patients with SLE is common and can involve the pericardium, myocardium, valves, conduction system, and coronary arteries. Pericarditis, with or without an effusion, is the most common cardiac manifestation of SLE, occurring in approximately 25 percent of patients at some point during their disease course. Verrucous (Libman-Sacks) endocarditis is usually clinically silent, but it can produce valvular insufficiency and can serve as a source of emboli.

Raynaud phenomenon in SLE is a vasospastic process induced by cold that occurs in up to 50 percent of patients with SLE. Raynaud phenomenon is characterized by intermittent acral pallor followed by cyanosis and erythroderma. Cutaneous small-vessel vasculitis can manifest as palpable purpura, petechiae, papulonodular lesions, livedo reticularis, panniculitis, splinter hemorrhages, and superficial ulcerations.

Renal involvement is clinically apparent in approximately 50 percent of SLE patients and is a significant cause of morbidity and mortality. Several forms of glomerulonephritis can occur, and renal biopsy is useful to define the type and extent of renal involvement.

SLE-related gastrointestinal abnormalities can involve almost any organ along the gastrointestinal tract and include esophagitis, intestinal pseudo-obstruction, protein-losing enteropathy, lupus hepatitis, acute pancreatitis, mesenteric vasculitis or ischemia, and peritonitis. Symptoms may also be related to treatment and medication.

Pulmonary manifestations of SLE include pleuritis (with or without effusion), pneumonitis, interstitial lung disease, pulmonary hypertension, shrinking lung syndrome, and alveolar hemorrhage. Respiratory symptoms must also be distinguished from infection, particularly in patients on immunosuppressive therapy. The risk of thromboembolic involvement is increased in those with antiphospholipid antibodies or with lupus anticoagulant.

Neuropsychiatric involvement of SLE consists of a broad range of neurologic and psychiatric manifestations, including cognitive dysfunction, organic brain syndromes, delirium, psychosis, seizures, headache, and/or peripheral neuropathies. Other less common problems are movement disorders, cranial neuropathies, myelitis, and meningitis.

Lymph node enlargement commonly occurs in association with active SLE and usually involves the cervical, axillary, and inguinal regions. Splenomegaly can also be observed among SLE patients, particularly with active disease. Leukopenia can be due to lymphopenia and/or secondary neutropenia and generally correlates with clinically active disease. Neutropenia may also result from toxicity due to immunosuppressive medications. Mild thrombocytopenia is also a common hematologic abnormality. Rarely, severe thrombocytopenia can occur and requires treatment. Autoimmune hemolytic anemia is also relatively rare but can be severe, requiring immediate therapy.

Genetic factors in the causation of SLE.

SLE commonly results from the combined effect of variants in a large number of genes. In rare cases SLE may be associated with the deficiency of a single gene (e.g., the complement components C1q and C4). Lack of C4 has been linked to decreased elimination of self-reactive B cells (compromising negative selection), whereas lack of C1q leads to deficient elimination of necrotic (waste) material. Each allele contributes only minimally, and the cumulative effect of several genes is necessary to substantially increase the risk of SLE. Some genes have been associated with several autoimmune diseases (e.g., STAT4 and PTPN22 with rheumatoid arthritis and diabetes); others appear to increase the risk of SLE specifically.

Environmental factors.

Epigenetic changes such as DNA hypomethylation have been attributed to medications known to cause SLE. Hydralazine and procainamide inhibit DNA methylation and can induce manifestations of lupus in healthy persons. The regulatory regions of some genes known to be involved in the pathogenesis of the disease (ITGAL, CD40LG, CD70, and PPP2CA) have been reported to be hypomethylated in SLE. Smoking and exposure to ultraviolet light have been implicated in epidemiologic studies. The possibility that viruses may trigger SLE has been considered during the past 40 years. The faster seroconversion to Epstein–Barr virus (EBV) infection and higher viral load in patients with SLE than in normal subjects, the molecular similarity between EBV nuclear antigen 1 and the common lupus autoantigen Ro, and the inability of CD8+ T cells to control EBV-infected B cells suggest that viruses may contribute to the expression of lupus.

Female hormones and sex.

Hormones contribute through unknown mechanisms to the increased prevalence of SLE among women. The X chromosome may contribute independently from hormones because in castrated female and male mice that have been genetically manipulated to express XX, XO (female), XY, or XXY (male) combinations, the presence of two X chromosomes increases the severity of SLE. Among the genes known to contribute to the pathogenesis of SLE is CD40, which is located on chromosome X. Pregnancy may aggravate SLE, and although it is not clear whether rising levels of estradiol or progesterone play a role, a link between pregnancy outcome and the status of the disease at conception has been noted; in fact, the levels of these hormones are lower during the second and third trimesters in patients with SLE than in healthy pregnant women. Treatment with dehydroepiandrosterone has shown some clinical benefit.

Immune cells and cytokines.

Antigen receptor–mediated activation is altered in T and B cells from patients with SLE, and early signaling events are amplified. The T-cell receptor–CD3 complex, which recognizes and binds antigen and autoantigen and sends activation signals to the interior of the cell, is “rewired” in T cells, with the CD3-ζ chain replaced by the FcR-γ common chain. In relaying the signal intracellularly, the spleen tyrosine kinase (Syk) is used rather than the canonical 70-kD ζ-associated protein (ZAP-70).27 Lipid rafts, cholesterol-rich scaffolds that contain signaling proteins on the surface membrane of cells, are present in aggregates that are metabolically active, and their inhibition in lupus-prone mice results in a change in disease expression.  Limited amounts of interleukin-2, in turn, result in poor activity of cytotoxic T cells and thus an increased risk of infection, which is a major cause of illness and death in patients with SLE. Lack of interleukin-2 also results in the suppression of activation-induced cell death and, therefore, increased longevity of autoreactive T cells in patients with SLE. Interleukin-17 is produced mainly by activated T cells and plays an important role in the immune response against certain bacteria and fungi.

In active SLE, a marked disease activity–dependent reduction in the number of naive B cells is observed, and the number of plasma cells is increased in the peripheral blood. All B-cell subgroups (B1 and B2 cells in both the follicular and marginal zones) contribute to the production of autoantibodies. B cells are central to the expression of the disease.

Antibody responses overall are lower than normal after immunization of patients with SLE against tetanus toxoid or hemophilus influenza, but the majority of patients have protective responses. Low responses are associated with SLE itself and with immunosuppressive drug treatment. Patients with SLE should always be vaccinated (but only with killed vaccines) to gain all possible protection against infections. 

How does SLE cause tissue injury?

Immune complexes are central players in the tissue injury in SLE. They are formed in large amounts as antinuclear antibodies bind to the abundant nuclear material in blood and tissues, and they are not cleared promptly because the Fc and complement receptors are numerically and functionally deficient. In addition to activating complement, immune complexes may alter the function of Fc receptors.

In the kidney, immune complexes accumulate in the subendothelial and mesangial areas first, followed by deposition in the basement membrane and subepithelial areas. Immune complexes containing cationic anti-DNA antibodies and antibodies against the collagen-like region of C1q have an increased propensity to accumulate in the kidney. Anti-DNA and anti-nucleosome antibodies contribute to lupus nephritis, and anti-chromatin–chromatin immune complexes are present in the mesangium of patients with lupus nephritis.

Although the spectrum of autoantibody specificities in SLE is extensive, only a few have been shown to contribute to disease-related tissue injury.

  • Anti–blood-cell antibodies that activate complement and cause cytopenias are typical.
  • Anti–T-cell (CD3 and T-cell receptor) antibodies suppress interleukin-2 production.
  • Anti-Ro antibodies, which may alter the function of myocytes and cells of the conduction system, have been linked to neonatal lupus and specifically to congenital heart block. The presence of anti-Ro antibodies calls for special fetal monitoring (neonatal lupus develops in only 2% of fetuses of mothers who are positive for such antibodies) and treatment.
  • Some patients with SLE have antibodies against phospholipids and β2-glycoprotein 1. The presence of such antibodies is linked to thrombotic events and fetal loss in mice and is known as the antiphospholipid syndrome.
  • Antiphospholipid antibodies interfere with the coagulation system (especially protein C) and the function of endothelial cells.
  • Low doses of heparin (which has also been shown to inhibit complement activation) can reduce the risk of fetal loss in patients with the antiphospholipid syndrome.
  • Certain naturally occurring antibodies and autoantibodies (against DNA, phospholipids, histones, and ribonucleoprotein) may bind to ischemic tissues, activate complement, and cause damage. Such experimental findings may explain why some patients with SLE have disease flares after they experience a stressful event.

  • T cells infiltrate tissues, including the skin and the kidney, where they contribute to tissue damage.

  • In the skin, keratinocytes that are exposed to ultraviolet light become apoptotic and release nuclear material, which is not cleared efficiently in patients with SLE. This nuclear material may further stimulate the immune system.
  • Patients with C1q deficiency, which is rare, are particularly photosensitive.
  • The expression of additional organ-specific molecules is important in determining which organ or organs are damaged.
  • Expression of tumor necrosis factor receptor 1 is needed for the expression of skin disease, whereas it provides protection against kidney inflammation.
  • Atherosclerosis-attributed vascular events are significantly more frequent in patients with SLE than in matched healthy persons. Several factors contribute to this increased frequency, including antibodies to lipoproteins, oxidized lipoproteins, hypertension, and the metabolic syndrome.

How does all this information help in the treatment of SLE?

Patients with SLE are treated with nonsteroidal antiinflammatory drugs, antimalarial agents, glucocorticoids, and immunosuppressive drugs, including cyclophosphamide, azathioprine, methotrexate, and mycophenolate mofetil. The choice of the drug is determined largely by the severity of the disease and the function of the involved organ.

Cyclophosphamide pulses (intravenous infusions every month or bimonthly at lower doses) are effective in the treatment of lupus nephritis, although there are serious potential side effects, including bone marrow suppression, infections, and gonadal suppression. Mycophenolate mofetil has considerable therapeutic value with few side effects, but its long-term effects with respect to the preservation of kidney function are unproven.

Blockade of BLyS with an anti-BLyS antibody results in a small but significant beneficial clinical effect within the first year of treatment in patients with mild or moderate disease. This antibody (belimumab) is approved by the Food and Drug Administration for use in the treatment of lupus.

A monoclonal antibody against the interleukin-6 receptor (tocilizumab) was judged to be promising in a phase 1 clinical trial.

Complement activation is profoundly increased in patients with SLE, and inhibition of C5 with an antibody (eculizumab), which has proved efficacious in the treatment of paroxysmal nocturnal hemoglobinuria, is being considered.

A chimeric anti-CD20 antibody (rituximab) has shown initial promise in small studies and case series involving patients with SLE, but a trial of rituximab in patients with moderate-to-severe SLE failed to reach its primary end points.

Inhibitors of the nuclear factor of activated T cells (NFAT), such as tacrolimus, may benefit patients with SLE, as should dipyridamole, which along with its antiplatelet function inhibits calcineurin-mediated NFAT activity. The mammalian target of rapamycin (mTOR), which plays a role in several key metabolic pathways, is increased in T cells of patients with SLE, and treatment of cells with rapamycin (i.e., sirolimus) corrects the signaling process.

 

 

 

 

 

Salicylate Poisoning: recognizing and treating it.

Salicylates or “aspirin” have become so common that if you write it in your regular prescription you will have to give an explanation to your patient. Often the patient is told that it is being used as a blood thinner or that it is still the “painkiller” against which all the other NSAIDs are titrated against for efficacy. When used for the treatment of rheumatic fever what blood level should be maintained? Levels between 15 mg per deciliter [1.1 mmol per liter] and 30 mg per deciliter [2.2 mmol per liter] are considered to be therapeutic for inflammatory conditions).

Within 1 or 2 hours after a single salicylate ingestion, point plasma levels often exceed 40 or 50 mg per clinical manifestations of salicylate intoxication including tinnitus, vertigo, nausea, vomiting, and hyperpnea can occur.

Plasma levels between 50 mg per deciliter and 70 mg per deciliter (5.1 mmol per liter) indicate severe intoxication and can be associated with fever, sweating, listlessness, and incoordination.

At levels exceeding 75 mg per deciliter (5.4 mmol per liter), patients are at risk for hallucinations, seizures, cerebral edema, coma, noncardiogenic pulmonary edema, and cardiovascular collapse.

If salicylates are taken with ethanol or opioids blood levels build up slowly. When enteric coated preparations are ingested the blood levels may be low although toxicity is building up so frequent blood levels need to be measured.

The acute form of salicylate intoxication generally occurs in young adults who have a psychiatric history or who have had a previous overdose. Such persons tend to ingest salicylate alone or in combination with other drugs in a suicide attempt; when they present to the emergency department, they frequently volunteer that they have ingested salicylate or are found with partially filled containers of the drug, making the diagnosis straightforward.

A chronic form of intoxication may occur in patients who are ingesting acetylsalicylic acid therapeutically and then have an inadvertent overdose. Since the baseline tissue burden of the drug is high and pathways for salicylate elimination are nearly or fully saturated, additional intake of the drug may lead to substantial accumulation of free salicylate and extension of the normal half-life of 2 to 4 hours to as long as 20 hours. The plasma level of salicylate required to elicit symptoms tends to be lower in chronic than in acute salicylate poisoning, sometimes falling into the upper end of the therapeutic range, because of the large amount of drug previously distributed to and located within tissues, including the central nervous system (CNS). Do not rely overly on the serum levels which may not coincide the symptoms.  Serum (or plasma) levels should be used as an adjunctive consideration, along with the severity of the presenting symptoms, presence or absence of acid–base disorders, and overall clinical condition of the patient.

Chronic poisoning is more likely to occur in the elderly who are on multiple drugs some of which may contain contain salicylates; also in patients being cared for by several doctors with nobody coordinating the prescriptions. I once checked the prescription of a patient  who complained of taking too many pills. He was on 6 different vitamin B complex preparations, 3 calcium and vitamin D pills and 2 vitamin E pills and 11 painkillers for arthritis. He would see a new doctor who would give him a prescription and he would continue to take all the other drugs prescribed by his previous doctors. Fortunately his renal injury improved after stopping the NSAIDs and his frustration improved by stopping most of his vitamins and calcium. Salicylates are present in over the counter drugs such as Pepto Bismol, combination painkillers available over the counter, herbal medicines enhanced with salicylates, skin creams and ointments containing salicylic acid specially if applied to the skin and then heat is applied too. Ginger tea and mint tea are culprits too so do ask about home remedies. Heat induces skin pores to open and disperses the cream across a greater surface area, enhancing systemic absorption. If the cream comes in contact with irritated skin — or epithelium that has compromised integrity — systemic absorption is further enhanced. Naturally occurring foods and food additives contain salicylates; the highest concentration is found in herbs and spices. Administration of a drug that unbinds salicylate from protein, particularly in a patient with chronic kidney disease and hypoalbuminemia, can also increase the free salicylate level and lead to toxic effects.

Chronic salicylate poisoning is difficult to diagnose. The many conditions which may be mistaken for it are:

Encephalopathy of undetermined origin
Dementia or delirium
Viral encephalitis
Unexplained asterixis
Cardiopulmonary disease
Impending myocardial infarction
Pneumonia
Acute alcohol intoxication, alcohol withdrawal, or alcoholic ketoacidosis
Sepsis
Diabetic ketoacidosis
Unexplained decrease in capacity for self-care

Age-related decreases in hearing acuity may attenuate the perception of tinnitus or its cause. Tachypnea and rales on pulmonary examination may be attributed to preexisting lung and cardiac disease as opposed to salicylate-induced noncardiogenic pulmonary edema. Hyperpyrexia and altered mental status can be mistaken for sepsis, and metabolic acidosis accompanied by circulating ketone bodies may be ascribed to diabetic or alcoholic ketoacidosis.

Neurologic abnormalities, such as agitation, confusion, hallucinations, slurred speech, seizures, and coma, occur more frequently in patients with chronic salicylate poisoning than in those with acute intoxication. “Salicylate jag” refers to restlessness and mental aberrations that are reminiscent of alcohol intoxication. Even in the absence of a documented history of ingestion, plasma levels should be measured if salicylate intoxication is suspected.

How does the acid base disturbance cause the symptoms?

Why is there hyperventilation and respiratory alkalosis?

Toxic levels of salicylate exert a direct stimulatory effect on the respiratory center of the medulla, causing an increase in the rate and depth of respiration and the development of respiratory alkalosis as carbon dioxide , the source of carbonic acid, is breathed off.

As there is a compensatory increase in body catabolism and substrate breakdown is required to supply the energy needed for the increasingly inefficient production of ATP from ADP through glycolysis to which the muscles have shifted. This response is manifested by increased oxygen consumption, increased heat production (leading to hyperpyrexia, diaphoresis, and dehydration), depletion of liver glycogen, and increased metabolic production of carbon dioxide.

Occasionally neuromuscular irritability manifested as paratonia and extreme muscle rigidity can develop, further contributing to hyperthermia and increasing the risk of rhabdomyolysis.

The accumulation of ketoacids and other organic acids accounts for the majority of the increase in the anion gap. The contribution of salicylate is minor (<5 mmol per liter). Increased renal bicarbonate excretion in response to respiratory alkalosis decreases buffer capacity, potentially worsening the degree of acidosis as organic acids accumulate.

What acid base abnormality is likely to be seen?

An acid pH is more common in infants and young children because of an inappropriate adaptive respiratory response to the metabolic acidosis.

More than half of patients with salicylate poisoning have a mixed respiratory alkalosis and increased anion-gap metabolic acidosis.

A pure respiratory alkalosis occurs in 20 to 22% of patients. Although respiratory alkalosis facilitates the production of organic acids, it can ameliorate the toxic effects of salicylate on the CNS by slowing the entry of salicylate into tissues. 

Since salicylic acid has a pKa (negative logarithm of the acid dissociation constant) of 3, an alkaline blood pH ensures that more than 99% of the drug is in an ionized state, for which cell membranes are poorly permeable. The nonionized fraction of salicylic acid readily penetrates cells and will double in concentration if blood pH falls from 7.4 to 7.2. As a result, a greater amount of drug will leave the extracellular fluid, and intracellular concentrations will be increased in the brain, liver, and other organs.

Most affected adults who have ingested salicylates alone present with an alkaline pH, whereas coingestion of drugs that depress the CNS blunts the hypocapneic response. In one series, respiratory acidosis was present in 23% of patients who had ingested salicylates in combination with other drugs, as compared with only 2% of patients who had ingested salicylates alone.

Other fluid and electrolyte disturbances can develop in patients with salicylate poisoning.

  • Patients with severe intoxication may have fluid deficits of 4 to 6 liters.
  • Hypernatremia can develop as a result of accelerated, insensible water loss in the lung due to increased ventilation, and increased metabolism and heat production lead to cutaneous water loss from sweating.
  • Salicylate-induced emesis and urinary excretion of sodium organic acid salts cause the total-body sodium content to be reduced.
  • Excretion of these salts also causes renal potassium wasting and hypokalemia due to increased delivery of sodium to the distal nephron at a time when mineralocorticoid levels are increased.
  • High salicylate concentrations in the tubular lumen interfere with urate reabsorption in the proximal tubule, causing severe hypouricemia.
  • In the early stages of toxicity, transient or prolonged hyperglycemia can develop as a result of the combined effect of increased production of glucose and decreased use of glucose by tissues. However, depletion of glycogen stores and impaired gluconeogenic pathways confer a predisposition to hypoglycemia, particularly in patients with chronic intoxication or the later stages of acute intoxication
  • CNS hypoglycemia may be present even with normal peripheral-blood glucose levels.

Treatment

  1. Do a repeated neurological examination.
  2. Check blood pH, blood gases, bicarbonate, chloride, calculate the anion gap and blood sugar levels.
  3. Avoid intubation. The brief period of apnea associated with endotracheal intubation can lead to a rapid fall in pH, causing increased amounts of the drug to accumulate in the CNS through protonation of salicylate.
  4. Administer Lactated Ringer’s solution or isotonic saline at a rate of 10 to 20 ml per kilogram of body weight per hour for the first 2 hours, with subsequent adjustment to maintain a urine output of 1 to 1.5 ml per kilogram per hour.
  5. The goals of fluid therapy are to establish euvolemic and not force diuresis, which has been associated with an increased risk of pulmonary edema.
  6. Reduce gastric absorption of salicylate.
    1. Use activated charcoal for gastrointestinal decontamination at a dose pf 1-2/kg of body weight to a maximum of 100g in adults and 50 g in children.
    2. The dose of activated charcoal can be repeated every 4 hours until charcoal appears in the stool and clinical manifestations of salicylate intoxication resolve.
    3. Repeated doses may lower plasma salicylate levels and may be particularly useful in treating bezoars, which should be suspected when salicylate levels continue to rise or fail to decrease, despite appropriate management.
    4. In such cases, whole-bowel irrigation with polyethylene glycol may also be useful.
    5. A risk of aspiration (due to altered mental status or increasing somnolence), poor gastric motility, and salicylate-induced gastrointestinal hemorrhage are contraindications to the use of activated charcoal.
  7. Alkalinization of the urine to accelerate kidney clearance of salicylate is essential in the management of both acute and chronic intoxication.
  8. Hypokalemia is often present and can be made worse with an alkaline diuresis. If urine output is adequate and there is no evidence of acute kidney injury, 40 mmol of potassium can be added to each liter of solution to help correct the deficit. Deficits should be corrected, since hypokalemia increases the expression of hydrogen–potassium–ATPase in the collecting duct, making it more difficult to establish an alkaline urine.
  9. Hemodialysis is the most efficient way to remove salicylate from the body. The small size, low volume of distribution, and absence of tissue binding make salicylate an ideal substance for dialysis.
  10. A plasma salicylate level of more than 90 mg per deciliter (6.5 mmol per liter) is an indication for dialysis, regardless of signs and symptoms. This threshold for initiation of dialysis is particularly important in patients with acute poisoning after salicylate ingestion, since there may be few signs or symptoms in the first several hours after ingestion. Prompt removal of the drug at this stage can limit tissue accumulation and avert severe toxic effects.
  11. Continuous venovenous hemofiltration or hemodiafiltration can be used if the patient’s hemodynamic condition is unstable or if conventional hemodialysis is unavailable.

Membranoproliferative Glomerulonephritis.

Inflammatory diseases of the kidney present to us in a wide variety of ways. They can present as a nephrotic syndrome or with more active sediment in the urine and rapid loss of renal function known as the nephritic syndrome or they may present as gradual loss of renal function usually with some degree of proteinuria or the patient may already be in end stage renal disease with the need to go on dialysis and have a renal transplant. What is the way to distinguish between these entities? The gold standard is the renal biopsy though that too may be confusing as the proliferative component of many of the GNs may offer different diagnoses. I am going to be discussing membranoproliferative GN (MPGN) mostly.

Membranoproliferative glomerulonephritis (MPGN), also termed mesangiocapillary glomerulonephritis, is diagnosed on the basis of a glomerular-injury pattern that is common to a heterogeneous group of diseases. MPGN accounts for approximately 7 to 10% of all cases of biopsy-confirmed glomerulonephritis and ranks as the third or fourth leading cause of end-stage renal disease among the primary glomerulonephritides. Although some diseases associated with MPGN are well known, recent advances have identified additional MPGN-associated conditions.

MPGN usually presents in childhood but can present at any age. Its course varies from a benign slowly progressive disease to a rapid progression to dialysis dependent disease.  The varied clinical presentation is caused by differences in the pathogenesis of the disorder and in the timing of the diagnostic biopsy relative to the clinical course. The degree of kidney impairment also varies, and hypertension may or may not be present. Patients who present early in the disease process, when the kidney biopsy shows proliferative lesions, are more likely to have a nephritic phenotype, and those with crescentic MPGN may present with a rapidly progressive glomerulonephritis. In contrast, patients with biopsies showing advanced changes that include both repair and sclerosis are more likely to have a nephrotic phenotype. Patients with classic MPGN often have features of both the acute nephritic syndrome and the nephrotic syndrome — termed the nephritic–nephrotic phenotype.

The typical features of MPGN on light microscopy include mesangial hypercellularity, endocapillary proliferation, and capillary-wall remodeling (with the formation of double contours) — all of which result in lobular accentuation of the glomerular tufts. At one time nephrologists tended to call the disease with evidence of capillary wall remodelling i.e. double contours, mesangioproliferative GN.

These changes result from the deposition of immunoglobulins, complement factors, or both in the glomerular mesangium and along the glomerular capillary walls. On the basis of the electron-microscopical findings, MPGN is traditionally classified as:

  • primary (idiopathic) MPGN type I (MPGN I),
  • type II (MPGN II),
  • type III (MPGN III) or secondary MPGN.

MPGN I, the most common form, is characterized by subendothelial deposits.

MPGN II is characterized by dense deposits in the glomerular basement membrane (“dense-deposit disease”).

Secondary MPGN, described by Rennke, is most often due to hepatitis C and other infections.

MPGN III has both subepithelial and subendothelial deposits.

As currently classified, MPGN I and MPGN III are likely to include cases of both immune-complex–mediated and complement-mediated MPGN. It is best to view each case as either immune-complex-mediated or complement mediated. Thus, immune-complex–mediated MPGN may occur when there are increased levels of circulating immune complexes, and complement-mediated MPGN may occur because of disorders associated with dysregulation of the alternative pathway of complement.

Here is a diagram taken from the NEJM review article https://www.nejm.org/doi/full/10.1056/NEJMra1108178.

Depicted above is the Normal Glomerular Capillary Wall and Immune-Complex–Mediated Membranoproliferative Glomerulonephritis (MPGN).

Because of persistent antigenemia, antigen-antibody immune complexes form as a result of chronic infections, elevated levels of circulating immune complexes may also be due to autoimmune diseases, or paraproteinemias caused by monoclonal gammopathies. The immune complexes trigger the activation of the classical pathway of complement and the deposition of complement factors of the classical pathway and terminal complement pathway in the mesangium and along the capillary walls. A kidney-biopsy specimen typically shows immunoglobulin and complement on immunofluorescence microscopy.

What infections can cause MPGN?

Chronic viral infections such as hepatitis C and hepatitis B, with or without circulating cryoglobulins, are an important cause of MPGN. Hepatitis C, which was recognized as a common cause of immune-complex–mediated MPGN in the 1990s, is now considered to be the main viral infection causing MPGN.

In addition to viral infections, chronic bacterial infections (e.g., endocarditis, shunt nephritis, and abscesses), fungal infections, and parasitic infections are associated with MPGN, particularly in the developing world. Bacteria associated with MPGN include staphylococcus, Mycobacterium tuberculosis, streptococci, Propionibacterium acnes, Mycoplasma pneumoniae, brucella, Coxiella burnetii, nocardia, and meningococcus. 

Which of the autoimmune diseases cause MPGN?

MPGN occurs in a number of autoimmune diseases. These include systemic lupus erythematosus and, occasionally, Sjögren’s syndrome, rheumatoid arthritis, and mixed connective-tissue disorders.

Monoclonal gammopathy.

Recent studies indicate that glomerular deposition of monoclonal immunoglobulin as a result of monoclonal gammopathy (also called dysproteinemia or plasma-cell dyscrasia), with or without cryoglobulins, is associated with MPGN.

Complement-Mediated MPGN. Can be acquired or genetic.

A schematic model of MPGN associated with dysregulation of the alternative pathway is shown. The injury phase develops because of the deposition of complement factors of the alternative pathway and terminal complement complex due to mutations and antibodies to complement-regulating proteins.

The complement cascade plays an important role in innate immunity. Complement factors can induce a potent inflammatory response that results in phagocyte chemotaxis, with opsonization and lysis of cells, including microorganisms. Complement activation occurs through the classical, lectin, or alternative pathways, all of which converge to form C3 convertase, which cleaves C3 into C3a and C3b. C3b, in the presence of factor B and factor D, associates with C3 convertase, generating even more C3 convertase and resulting in a potent amplification loop.

Dysregulation of the alternative pathway can occur because of mutations in or autoantibodies to complement-regulating proteins . For example, mutations in proteins that regulate the assembly and activity of C3 convertase and degradation of C3b, such as factors H, I, and B and factor H–related protein 5, result in dysregulation of the alternative pathway.

Acquired and Genetic Abnormalities Associated with Complement-Mediated MPGN.

Whatever the mechanism may be, dysregulation of the alternative pathway results in activated complement products, including C3b and terminal complement factors, which are delivered indiscriminately to endothelial surfaces, including glomeruli. The deposition of these complement products and debris in the mesangium and subendothelial region triggers glomerular inflammation and leads to MPGN. Immunoglobulins are not directly involved; thus, complement-mediated MPGN is typically immunoglobulin-negative but complement-positive on immunofluorescence studies.

Despite multiple genetic risk factors, MPGN due to complement abnormalities often develops relatively late in life, suggesting that additional insults or environmental factors are required.

The deposition of immunoglobulin, complement, or both in the mesangium and subendothelial region of the capillary wall triggers an acute injury, which is often followed by an inflammatory (cellular or proliferative) phase, with an influx of inflammatory cells. A subsequent reparative phase occurs, during which new mesangial matrix results in mesangial expansion, along with the generation of new glomerular basement membrane, which looks like a duplicated basement membrane (so-called tram tracks or double contours).

How to evaluate MPGN.

When a kidney-biopsy specimen from a patient with MPGN shows immunoglobulins,  evaluate for infections, autoimmune diseases, and monoclonal gammopathies.

Relevant tests for the detection of infections include:

  • blood cultures
  • polymerase-chain-reaction
  • serologic tests for viral, bacterial, and fungal infections.
  • Look for cryoglobulins.
  • Do tests for the detection of monoclonal gammopathy which include serum and urine electrophoresis, immunofixation studies, and free light-chain assays
  • If the results are positive results do bone marrow studies for a more precise diagnosis.
  • Positive screening tests for an autoimmune disease should be followed by specific tests for the autoimmune disease.

If the biopsy specimen from a patient with MPGN shows bright C3 immunostaining (with minimal or no immunoglobulin staining), an evaluation to detect abnormalities of the alternative pathway is indicated regardless of whether an electron microscopic examination shows dense-deposit disease or C3GN.

The initial evaluation of the alternative pathway should include:

  • measurement of serum complement levels
  • serum levels of the membrane-attack complex
  • an alternative pathway functional assay
  • hemolytic complement assays
  • followed by genetic analysis for mutations and allele variants of complement factors
  • assays for the presence of autoantibodies to complement-regulating proteins, including tests for the detection of C3 nephritic factor.

How to treat MPGN?

  1. Early studies (predating ACE-i and ARBs) used alternate day steroids. Retrospective studies showed no clear benefit from glucocorticoid therapy, but treatment was not as prolonged in adults as it was in children.
  2. Heparin and warfarin, frequently combined with glucocorticoids and cytotoxic agents, have not been confirmed in a prospective study.
  3. An early randomized, controlled trial showed that the combination of aspirin and dipyridamole slowed the decline in the glomerular filtration rate in adults with idiopathic MPGN, but there was no long-term benefit, suggesting that prolonged antiplatelet therapy is required for a sustained benefit.
  4. Limited uncontrolled data suggest that calcineurin inhibitors may reduce proteinuria in some patients with MPGN.
  5. In patients with a rapidly progressive course and crescents on renal biopsy, a few small, uncontrolled studies have suggested a benefit with high-dose “pulse” glucocorticoids, either as monotherapy or in combination with azathioprine, cyclophosphamide, or mycophenolate mofetil.
  6. The lack of randomized, controlled trials and the current understanding that multiple pathogenic processes lead to MPGN make it impossible to give strong treatment recommendations in this patient population.
  7. Patients with normal kidney function, no active urinary sediment, and non–nephrotic-range proteinuria can be treated conservatively with angiotensin II blockade to control blood pressure and reduce proteinuria, since the long-term outcome is relatively benign in this context. Follow-up is required to detect early deterioration in kidney function.
  8. Eculizumab, an anti-C5 monoclonal antibody that inhibits C5 activation, has been used successfully in patients with atypical hemolytic–uremic syndrome due to complement abnormalities in the alternative pathway. The role of such anticomplement agents in MPGN is not delineated but offers exciting possibilities for the future.
  9. MPGN often recurs in kidney-transplant recipients. Recurrence rates range from 27 to 65%,  depending on the study.

Two major pathophysiological factors — the deposition of immunoglobulin and the deposition of complement in the glomerular mesangium and capillary walls — may lead to MPGN. The presence of immune-complex–mediated MPGN necessitates evaluation for infections, autoimmune diseases, and monoclonal gammopathy. Complement-mediated MPGN is further subdivided into dense-deposit disease and C3GN, depending on the electron-microscopical findings; the presence of complement-mediated MPGN necessitates evaluation of the alternative pathway. Evaluation of MPGN according to the underlying pathophysiological processes may facilitate proper treatment.

Pregnancy in a woman with hypertension.

A 32-year-old woman, who has never been pregnant and who has a 5-year history of hypertension, wants to become pregnant. She has stopped using contraception. Her only medication is lisinopril at a dose of 10 mg per day. Her blood pressure is 124/68 mm Hg, and her body-mass index (the weight in kilograms divided by the square of the height in meters) is 27. She has a strong family history of hypertension with both parents suffering from hypertension and one older sibling also hypertensive. Her kidneys are normal in size and structure. She has no evidence of SLE, chronic kidney disease such as proteinuria or casts in her urine and her creatinine clearance is 80 ml/min. She has no cardiomegaly or signs of heart failure and is in sinus rhythm. She is not diabetic.  She has researched hypertension in pregnancy on the internet and has some questions for you. What would you advise?

Some of her questions are:

  • Is my pregnancy likely to be normal or complicated by preeclampsia or eclampsia or other complications of pregnancy?
  • Am I likely to carry the baby to term?
  • Babies are small in size at birth and are more likely to need an incubator and other assistance for breathing. Is that likely to happen?
  • Is the baby likely to suffer from congenital defects of the heart?
  • Is the baby likely to be born with defective kidneys?
  • Are my blood pressure medications likely to affect the baby?

This woman is suffering from chronic hypertension, which is defined as a blood pressure of at least 140 mm Hg systolic or 90 mm Hg diastolic pressure before pregnancy or, for women who first present for care during pregnancy, before 20 weeks of gestation.

The chances are good that this woman is likely to carry the pregnancy to term with a good outcome. Her blood pressure is well controlled and her renal function is in Stage 2 (creatinine clearance of 80 ml/min) so she has no end organ damage. The risk of an adverse outcome increases with the severity of hypertension and end-organ damage.

Her chance of getting a complication like eclampsia, preeclampsia, abruptio placenta, fetal growth restriction, preterm birth, and cesarean section are higher than in women who are normotensive. The risk of superimposed preeclampsia increases with an increasing duration of hypertension. Preeclampsia is a leading cause of preterm birth and cesarean delivery in this population.

In a study involving 861 women with chronic hypertension, preeclampsia developed in 22%, and the condition occurred in nearly half these women at less than 34 weeks of gestation, earlier than is typical in women without antecedent hypertension.

Definitions of hypertensive syndromes in pregnancy.

Preeclampsia refers to the new onset of hypertension and proteinuria or the new onset of hypertension and significant end-organ dysfunction with or without proteinuria after 20 weeks of gestation in a previously normotensive woman

Eclampsia refers to the occurrence of a grand mal seizure in a woman with preeclampsia in the absence of other neurologic conditions that could account for the seizure.

HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) probably represents a subtype of preeclampsia with severe features in which hemolysis, elevated liver enzymes, and thrombocytopenia are the predominant features rather than hypertension or central nervous system or renal dysfunction, although the latter do occur. The majority of patients, but not all, have hypertension (82 to 88 percent) and/or proteinuria (86 to 100 percent). 

Chronic hypertension – Chronic hypertension is defined as hypertension that precedes pregnancy or is present on at least two occasions before the 20th week of gestation or persists longer than 12 weeks postpartum. It can be primary or secondary to a variety of medical disorders.

Preeclampsia superimposed upon chronic hypertension – Preeclampsia is considered superimposed when it occurs in a woman with preexisting chronic hypertension. It is characterized by worsening or resistant hypertension (especially acutely), the new onset of proteinuria or a sudden increase in proteinuria, and/or significant new end-organ dysfunction after 20 weeks of gestation in a woman with chronic hypertension

Gestational hypertension – Gestational hypertension refers to hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) without proteinuria or other signs/symptoms of preeclampsia-related end-organ dysfunction that develops after 20 weeks of gestation. Development of proteinuria upgrades the diagnosis to preeclampsia.

The diagnosis of preeclampsia with severe features (formerly severe preeclampsia) is made in the subset of women with preeclampsia who have severe hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥110 mmHg) and/or specific signs or symptoms of significant end-organ dysfunction that signify the severe end of the preeclampsia spectrum.

Women with chronic hypertension with superimposed preeclampsia are at increased risk for giving birth to an infant who is small for gestational age and for placental abruption, as compared with women with chronic hypertension without superimposed preeclampsia. Even in the absence of superimposed preeclampsia, women with chronic hypertension have an increased risk of adverse outcomes. Fetal growth restriction (estimated or actual fetal weight, <10th percentile for population norms) complicates 10 to 20% of such pregnancies. In an analysis of the Danish National Birth Cohort, after adjustment for age, body-mass index, smoking status, parity, and diabetes, chronic hypertension was associated with approximately five times the risk of preterm birth and a 50% increase in the risk of giving birth to an infant who is small for gestational age.8 Women with hypertension have an increased risk for abruptio placentae and stillbirth.

Hypertension along with diabetes, obesity, SLE, thyroid disease and phenylketonuria is a risk factor for congenital heart disease in the fetus.

What happens to the blood pressure during pregnancy in women with chronic hypertension?

Most women with chronic hypertension have a decrease in blood pressure during pregnancy, similar to that observed in normotensive women; blood pressure falls toward the end of the first trimester and rises toward prepregnancy values during the third trimester.  As a result, antihypertensive medications can often be tapered during pregnancy. However, in addition to the subset of women with chronic hypertension in whom preeclampsia develops, another 7 to 20% of women have worsening of hypertension during pregnancy without the development of preeclampsia.

How should you evaluate a woman with chronic hypertension in pregnancy. Follow the JNC 7 guidelines. ( Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:25602572[Erratum, JAMA 2003;290:197.) Such recommendations include the use of electrocardiography and assessment of blood glucose, hematocrit, serum potassium, creatinine, calcium, and lipoprotein profile, as well as urinalysis. Given the increased risk of preeclampsia in women with chronic hypertension, evaluation before pregnancy should also include a 24-hour quantification of urine protein to facilitate the identification of subsequent superimposed preeclampsia. The presence of end-organ manifestations of hypertension may worsen the prognosis during pregnancy and should be taken into account in counseling. For example, the presence of proteinuria at baseline increases the risks of superimposed preeclampsia and growth restriction. Do not do any tests requiring radiation if the patient is already pregnant.

How to monitor preeclampsia?

Superimposed preeclampsia should always be considered when the blood pressure increases in pregnancy or when there is a new onset of or an increase in baseline proteinuria. An elevated uric acid level may help to distinguish the two conditions, although there is substantial overlap in levels. The presence of thrombocytopenia or elevated values on liver-function testing may also support a diagnosis of preeclampsia. Recently, serum and urinary angiogenic markers have been studied as possible aids in the diagnosis of superimposed preeclampsia, but data are currently insufficient to support their use in this population.

How to treat the hypertension?

Which antihypertensive drug to use in pregnancy?

Methyl dopa is the the drug with the best safety profile. Methyldopa is both an alpha-2-agonist and an amino acid decarboxylase enzyme inhibitor that blocks the transformation of DOPA to DA and NE, causing a net decrease in central monoamine neurotransmitter levels. α2 agonist: inhibits adenylyl cyclase activity, reduces brainstem vasomotor center-mediated CNS activation; used as antihypertensive, sedative & treatment of opiate dependence and alcohol withdrawal symptoms). Effect of alpha 2 receptor blockade: Common effects include: Suppression of release of norepinephrine (noradrenaline) by negative feedback. Transient hypertension (increase in blood pressure), followed by a sustained hypotension (decrease in blood pressure). This effect may be enhanced by the simultaneous use of labetolol as the alpha-2 blockade may kick in later so methyldopa will then stimulate the alpha-2 receptors. Either avoid or monitor carefully.

Methyldopa and beta-blockers may have additive hypotensive effects. In addition, potentiation of hypertensive rebound associated with withdrawal of methyldopa or beta-blockers may occur if both drugs are withdrawn at the same time. The proposed mechanism may involve increased catecholamine release after methyldopa and/or a beta-blocker are withdrawn, which may lead to unopposed alpha-adrenergic effects and vasoconstriction.

Methyldopa manufacturers recommend adjusting the beta blocker dose if methyldopa is added to therapy, and not exceeding a methyldopa dose of 500 mg/day when it is first added to therapy. Patients should be instructed to notify their doctor if they have a reduced heart rate, dizziness, fainting or headaches, chest pain or vision problems.

Long-acting calcium-channel blockers also appear to be safe in pregnancy, although experience is more limited than with labetalol.21 Nifedipine is listed as the preferred drug for the treatment of hypertension in pregnancy only the extended action form may be used. However the rapid release form may be used to control severe hypertension in eclampsia as a last resort.

Use of nifedipine in preterm labour. 

Nifedipine can be used in preterm labour to delay pregnancy by 48 hours to 7 days. It acts a tocolytic agent.

Diuretics were long considered contraindicated in pregnancy because of concern about volume depletion. However, a review of nine randomized trials showed no significant difference in pregnancy outcomes among women with hypertension who took diuretics and those who took no antihypertensive medication. Accordingly, some guidelines support the continuation of diuretic therapy during pregnancy in women with chronic hypertension who were previously treated with these agents.

Which anti-hypertensive drugs to avoid in pregnancy?

Angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) are contraindicated in pregnancy. All the angiotensin-converting-enzyme inhibitors like captopril, enalapril, lisinopril etc are to be withheld before the start of pregnancy and not used in pregnancy because they cause neonatal renal failure.Their use in the second half of pregnancy has been associated with oligohydramnios (probably resulting from impaired fetal renal function) and neonatal anuria, growth abnormalities, skull hypoplasia, and fetal death. 

Mineralocorticoid receptor antagonists (MRAs; eg, spironolactone, eplerenone) are another class of drugs that block the renin angiotensin aldosterone system. Spironolactone crosses the placenta and has never been proven to be safe in pregnancy. The anti-androgenic activity of spironolactone has always been a concern, particularly in male fetuses. Feminization of male rat fetuses has been reported after treatment of pregnant female rats with high doses of spironolactone. Whether eplerenone, an MRA without anti-androgenic properties introduced approximately 10 years ago, will be safe for human pregnancy is unknown. The epithelial sodium channel (ENaC) inhibitor amiloride has been used rarely to treat pregnant women with hyperaldosteronism or Liddle’s syndrome, and there are sporadic case reports with favorable outcomes. Its use cannot  be recommend at this time because of limited experience.

Nitroprusside — Limited clinical experience (22 pregnancies) and the possibility of fetal cyanide poisoning have restricted the use of nitroprusside in pregnancy. Nitroprusside (0.5 to 10 mcg/kg/min) is the agent of last resort for urgent control of refractory severe hypertension; its use should be limited to a short period of time in an emergency situation

Can we use any therapy to prevent eclampsia other than good control of blood pressure?

Since superimposed preeclampsia is the major adverse pregnancy outcome associated with chronic hypertension, many women ask whether any therapies can decrease this risk. Large, randomized, placebo-controlled trials have shown no significant reduction in the risk of preeclampsia associated with the use of low-dose aspirin, calcium supplementation, or antioxidant supplementation with vitamins C and E.

Fetal surveillance.

Efforts to monitor women and their fetuses for complications may include more frequent prenatal visits for women with chronic hypertension than for women without this condition. Such visits are intended to monitor women closely for complications of chronic hypertension by measuring blood pressure and urine protein.

Many obstetricians supplement regular evaluation of fundal height with ultrasonographic estimation of fetal weight, beginning in the early third trimester and continuing at intervals of 2 to 4 weeks, depending on maternal blood pressure, medications, complications, and findings on previous imaging. Although data from low-risk populations suggest that ultrasonography and evaluation of fundal height have shown similar results for the detection of growth restriction, ultrasonography also assesses amniotic-fluid volume and fetal movements and tone (biophysical profile), evaluations that may be useful with respect to the risks associated with chronic hypertension in pregnancy.

Testing may also include the evaluation of the pattern and variability of the fetal heart rate (nonstress testing). Maternal complications (e.g., preeclampsia or worsening hypertension), nonreassuring fetal-testing results, or concern about fetal growth restriction are often indications for early delivery.

 

 

 

 

 

 

 

 

 

IgA Nephropathy: commonest cause of kidney disease seen in young adults.

Case 1. A 19 year old college student developed severe sore throat along with fever, dry cough and breathlessness. He saw his doctor three days later. His temperature was 38.6 degrees C, blood pressure was 160/105 mmHg, the throat was congested but there were no pus points in the throat. He had rhonchi in his chest but no crepitations. There was no rash, arthralgia, urticaria. He said that his urine was red in colour. The rest of the examination was unremarkable. His white cell count was raised to 15000/mm squared. The Hb and PCV were normal and there was no eosinophilia. His urine showed ++ proteinuria, macroscopic hematuria which persisted in subsequent samples. His creatinine was 1.6 mg/dl, blood sugars were normal. Creatinine clearance was 28 ml/min. The 24 hour urinary proteins were 1.8 gm/L/1.73 square metre of body surface. Serum proteins were 4.2 gm/dl. His doctor arranged for a renal biopsy.

Case 2. A 34 year old man had been suffering from frequent upper respiratory tract infections in the past year. He developed severe bloody diarrhoea for 4 days and recovered with the administration of a quinolone antibiotic. He decided to see his doctor for a general medical check up. The significant finding was a blood pressure of 180/95 mmHg. He had no evidence of heart failure and neither of his kidneys was palpable. He had no edema, was not anemic, did not have a rash or urticaria, nor arthralgia or Raynaud’s phenomenon. Lymph nodes liver and spleen were not enlarged. He was not diabetic, did not have a history of chest pain on exertion and was still jogging for 2 kilometers daily. His urine showed proteinuria and microscopic hematuria. His serum creatinine was 1.9mg/dl. His 24 hour urinary proteins were 2.1 gm/L/1.73 sq m of body surface. Creatinine clearance was 35 ml/min. Serum proteins were 3 gm/L. The rest of the lab investigations were unremarkable.

What are they both likely to have? IgA nephropathy.

About 75% of children and young adults with IgA nephropathy present with macroscopic hematuria during an upper respiratory or gastrointestinal illness. Evidence of acute kidney injury may be present. Older adults usually present with proteinuria, microscopic hematuria, or hypertension, alone or in combination. Case 1 has the nephropathy with macroscopic hematuria following an upper respiratory infection. Case 2 has a GI infection which seems to be the trigger but the hematuria is microscopic in nature and he does not notice any urinary changes. He could have presented with the hypertension and microscopic hematuria without the GI infection. The nephrotic syndrome is uncommon at presentation, except in patients with the pathological features of minimal-change disease on kidney biopsy.

What is IgA nephropathy?

Figure 1. Pathological Characteristics of IgA Nephropathy.

  • Panel A (periodic acid–Schiff stain) shows mesangial hypercellularity, with four or more cells per mesangial area (arrow).
  • Panel B (periodic acid–Schiff stain) shows segmental endocapillary proliferation with occlusion of the capillary lumen (arrow).
  • Panel C (periodic acid–Schiff stain) shows segmental glomerulosclerosis and adhesion, with focal accumulation of hyaline and obliteration of the capillary lumen (arrow).
  • Panel D (trichrome stain) shows tubular atrophy and interstitial fibrosis, with severe interstitial scarring and loss of tubules (arrow).
  • Panel E (periodic acid–Schiff stain) shows a glomerular crescent; a circumferential layer of epithelial cells surrounds the glomerular tuft (arrow).
  • Panel F (immunofluorescence stain with fluorescein-conjugated anti-IgA antibodies) shows diffuse mesangial staining for IgA (arrow).
  • In Panel G, an electron micrograph of a glomerular capillary tuft in a specimen fixed in osmium tetroxide shows electron-dense material in the mesangial area (arrow), a finding that is consistent with the accumulation of immune complexes.

(Taken from  June 20, 2013
N Engl J Med 2013; 368:2402-2414
DOI: 10.1056/NEJMra1206793)

The diagnostic hallmark of IgA nephropathy is the predominance of IgA deposits, either alone or with IgG, IgM, or both, in the glomerular mesangium. The mesangial IgA is exclusively of the IgA1 subclass and is deficient in galactose, a biochemical feature of central importance in the pathogenesis of IgA nephropathy.

Complement C3 and properdin are almost always present. C4 or C4d, mannose-binding lectin,and terminal complement complex (C5b–C9) are frequently detected, whereas C1q is usually absent

The features of IgA nephropathy on light microscopy may vary greatly among patients and within the individual biopsy sample. An increase in mesangial matrix and hypercellularity are common; other glomerular lesions may include focal necrosis (affecting a minority of glomeruli), segmental scarring (affecting only a portion of a glomerulus), and crescents in Bowman’s space.

Electron microscopy usually shows electron-dense material corresponding to immune deposits on immunofluorescence microscopy. These are generally observed in mesangial and paramesangial areas but are occasionally present in subepithelial and subendothelial portions of glomerular basement membranes.

Renal histologic features of Henoch–Schönlein purpura nephritis are strikingly similar to those of IgA nephropathy. The diagnosis of Henoch–Schönlein purpura nephritis rests on the concurrent presence of palpable purpura due to leukocytoclastic vasculitis with IgA in the walls of dermal capillaries. 

IgA nephropathy appears to be a systemic disease in which the kidneys are damaged as innocent bystanders, because IgA nephropathy frequently recurs after transplantation. Conversely, IgA glomerular deposits in a kidney from a donor with subclinical IgA nephropathy were reported to clear within weeks after engraftment in a patient with a different kidney disease. Of primary importance is the glycosylation pattern of IgA1. In IgA nephropathy, an increased fraction of circulatory IgA1 has a galactose deficiency in some carbohydrate side chains (O-glycans) that are attached to the hinge-region segment of the heavy chain. As a consequence of the galactose deficiency, N-acetylgalactosamine in truncated IgA1 hinge-region glycans is exposed. Recognition of this IgA1 hinge-region neoepitope by naturally occurring IgG or IgA1 antibodies leads to the formation of immune complexes in the circulation or perhaps in situ after glomerular deposition of galactose-deficient IgA1

Do genes affect IgA nephropathy?

Genetic factors undoubtedly influence the pathogenesis of IgA nephropathy. About 5% of patients with IgA nephropathy have a relative with biopsy-confirmed IgA nephropathy, microscopic hematuria, or proteinuria. The mode of inheritance is usually autosomal dominant with incomplete penetrance, suggesting a major gene with a large effect.

The serum level of galactose-deficient IgA1 is a heritable trait in diverse racial or ethnic groups. About 75% of patients with IgA nephropathy have a serum galactose-deficient IgA1 level above the 90th percentile for healthy controls; moreover, about 30 to 40% of first-degree relatives have similarly high levels. A study involving Han Chinese and Europeans identified five susceptibility loci: three on chromosome 6p21 in the MHC, one on chromosome 1q32 in the cluster of genes encoding complement factor H (CFH), and one on chromosome 22q12.

Common genetic variants influence the risk of IgA nephropathy across ethnically diverse populations and implicate adaptive immunity in the pathogenesis.

Biomarkers for IgA nephropathy.

Although the serum level of galactose-deficient IgA1 is frequently elevated in patients with IgA nephropathy, the sensitivity and specificity of this laboratory finding are insufficient for the test to replace kidney biopsy as the diagnostic standard. The serum level of glycan-specific IgG antibodies is correlated with the level of urinary protein excretion and the risk of progression to end-stage renal disease (ESRD) or death. This biomarker may prove useful for monitoring disease progression or the response to therapy.

Many urinary markers like epidermal growth factors, podocytes, mannose binding lectins, are available for differentiating this disease from other kidney diseases and for prognosis but are not sufficiently specific for generalized clinical use in making a definite diagnosis.

How prevalent is IgA nephropathy?

The prevalence of IgA nephropathy relative to other glomerular diseases is generally inferred from the proportion of cases in biopsy series, but the true prevalence of IgA nephropathy is unknown because diagnosis requires kidney biopsy. The prevalence of clinically silent IgA nephropathy may be surprisingly high; in a Japanese study, 16% of donor kidneys had glomerular IgA deposits and nearly 2% exhibited mesangioproliferative changes with C3 deposits characteristic of IgA nephropathy.

What is going to be the clinical outcome?

The likelihood of dialysis or death was recently estimated with the use of three risk factors that are documented at biopsy:

  • urinary protein excretion of more than 1 g per day,
  • hypertension (>140/90 mm Hg), and
  • severe histologic lesions on the basis of glomerular, vascular, tubular, and interstitial features.

The 20-year predicted survival without the need for dialysis was 96% among patients with no risk factors versus 36% among those with three factors. The 10-year renal survival rate is about 90% among adults and children with normal renal function at diagnosis.

An impaired GFR, sustained hypertension, and substantial proteinuria independently predict a poor clinical course. In the Oxford classification three histologic features showed an independent value for predicting the outcome of renal function, even after clinical indicators at the time of biopsy and during follow-up observation were taken into account:

  • mesangial hypercellularity
  • segmental glomerulosclerosis or adhesion
  • tubular atrophy and interstitial fibrosis
  • A fourth histologic feature, endocapillary proliferation, showed an interaction with glucocorticoid or immunosuppressive therapy that suggested benefit from treatment

How should IgA nephropathy be treated?

Despite a better understanding of pathogenic mechanisms, there is no disease-targeted treatment for IgA nephropathy.

Control proteinuria and blood pressure by suppression of angiotensin II with an ACE inhibitor or angiotensin II–receptor blocker (ARB). The target systolic blood pressure is less than 130 mm with urinary protein excretion of less than 1 g per day but less than 125 mm Hg when the initial urinary protein excretion is more than 1 g per day. 

Intensive immunosuppression (glucocorticoids with cyclophosphamide or azathioprine) is reserved for patients with crescents in more than half the glomeruli and a rapid decline in renal function.

The KDIGO guidelines do not support the use of mycophenolate mofetil or antiplatelet drugs.

Tonsillectomy has been recommended by some centers, particularly in Japan, but this approach was not included in the KDIGO guidelines because of the lack of data from randomized, controlled trials.

Patients presenting with mild disease (normal blood pressure, normal estimated GFR, and a urinary protein-to-creatinine ratio consistently <0.20) do not require treatment. 

IgA nephropathy is a common glomerular disease and an important cause of kidney failure. Because of the critical interaction between an intrinsic antigen (galactose-deficient IgA1) and circulating anti-glycan antibodies, IgA nephropathy can be considered an autoimmune disease.

 

 

 

 

 

Membranous nephropathy: treatment in the light of the Membranous Nephropathy Trial of Rituximab (MENTOR)

A 56 year old man presented to his doctor with swelling of the feet, tiredness and breathlessness of three weeks duration. He had developed hypertension; BP of 160/100 mmHg about three months back and was on a beta blocker for its control. He was not diabetic, did not have arthralgia or arthritis, a rash or photosensitivity or Raynaud’s phenomenon. His optic fundi showed mild early hypertensive nephropathy with silver wiring of the vessels. He had pitting edema up to midcalf, abdominal wall edema with a suspicion of ascites and small bilateral pleural effusions. There was no cardiomegaly, AF, or hepatomegaly.  He had a good appetite and had not lost weight in the past 3 months. He was on no other drugs not even aspirin or lipid lowering therapy.

He was a lawyer by profession and spent long hours standing on his feet. Meals were irregular and often consisted of fast food bought at the canteen. He did not have a family history of diabetes or hypertension in his parents or grandparents and was the first of five siblings who were all healthy. He was affluent and lived in upper class suburbia in physical comfort. His urine dipstick was +++ for protein in the doctor’s office.

The significant finding was 8gm/L of proteins in his 24 hour urine. Serum proteins were 2.4 gm/L. Serum creatinine was .9 mg/dl. The serology for autoimmune diseases was negative, blood sugar levels did not indicate diabetes, triglycerides and lipids were just above normal. So he has proteinuria, edema, ascites and pleural effusion with significant proteinuria and hypoproteinemia and lipidemia.

His doctor tells him he has a nephrotic syndrome and he asks about the prognosis. What should he be told?

  • He needs to have a biopsy of the kidney to determine what kind of nephropathy he has.
  • If the biopsy shows that he has membranous nephropathy which is the commonest type of glomerulopathy expected in older adults spontaneous remission occurs in approximately 30% of affected patients, and among patients who continue to have nephrotic syndrome, end-stage renal disease develops in 40 to 50% over a period of 10 years.
  • What you should know: MN is seen in all ethnic and racial groups and in both sexes, but idiopathic MN is more common in white males over the age of 40 years. MN in young women should raise the suspicion of lupus. MN is less commonly seen in children, in whom it is often associated with hepatitis B or, less commonly, autoimmune or thyroid disease.
  • Why does this disease occur? A total of 70 to 80% of patients with membranous nephropathy have circulating autoantibodies to the phospholipase A2 receptor (PLA2R), and 1 to 3% have circulating antibodies to thrombospondin type-1 domain-containing 7A (THSD7A). In the remaining patients, the target antigen is unknown. In patients with anti-PLA2R antibodies, there is a tight correlation between antibody levels and disease activity, which suggests a causal relationship.
  • Is treatment available? Yes for 3 months a trial of diuretics, fluid restriction, lipid lowering drugs and an ACE-I like captopril or enalapril will be given, A reduction of more than 25% of the proteinuria will be considered a response.
  • Immunosuppressive therapy.
    • Ponticelli’s regime:  Controlled trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Engl J Med 1984;310:946950. (A high incidence of incidental infection specially TB in third world countries made this unpopular)
    • Jha VGanguli ASaha TK, et al. A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy. J Am Soc Nephrol 2007;18:18991904. The side effects of this are, though the regime is effective in 60 to 70% of patients, hyperglycemia, myelosuppression, infections, infertility, and cancer.
    • Alfaadhel TCattran D. Management of membranous nephropathy in Western countries. Kidney Dis (Basel) 2015;1:126137. Calcineurin inhibitors, including cyclosporine, are effective and are the preferred treatment for membranous nephropathy.
    • More-selective B-cell depletion with rituximab, therefore, appears to be a promising approach.
      • Ruggenenti PCravedi PChianca A, et al. Rituximab in idiopathic membranous nephropathy. J Am Soc Nephrol 2012;23:14161425.
      • Ruggenenti PFervenza FCRemuzzi G. Treatment of membranous nephropathy: time for a paradigm shift. Nat Rev Nephrol 2017;13:563579.
      • Fervenza FCAbraham RSErickson SB, et al. Rituximab therapy in idiopathic membranous nephropathy: a 2-year study. Clin J Am Soc Nephrol 2010;5:21882198.

How specific is the anti-PLA2R antibody to membranous glomerulopathy?

Anti-PLA2R antibodies have been identified in up to 82 percent of patients with primary MN in six additional cohorts from Europe and China. In one study, anti-PLA2R strongly correlated with clinical status; in another study, lower anti-PLA2R titers were associated with a higher rate of spontaneous remission, and, in two other studies, a decline in anti-PLA2R predicted the clinical response to immunosuppressive therapy. A fifth study found that higher anti-PLA2R titers within two years of diagnosis predicted substantially greater progression of kidney function decline over the subsequent five years of follow-u. This indicates that these antibodies should be monitored especially when treating with calcineurin inhibitors. 

What drugs are likely to cause membranous nephropathy?

Many drugs, primarily used to treat rheumatoid arthritis have been implicated in the development of MN, including nonsteroidal antiinflammatory drugs (NSAIDs), penicillamine, parenteral gold salts, bucillamine, alemtuzumab, mercurial salts, elemental mercury, and possibly anti-tumor necrosis factor (anti-TNF) agents (etanercept, infliximab, or adalimumab).

How was the MENTOR trial designed?

The Membranous Nephropathy Trial of Rituximab (MENTOR) to investigate whether rituximab would be noninferior to cyclosporine in inducing and maintaining remission of proteinuria, regardless of patients’ baseline anti-PLA2R status, for up to 24 months in patients with apparent primary membranous nephropathy. This investigator-initiated, open-label, randomized, multicenter, noninferiority trial was conducted at 22 sites in North America.

Who were the participants?

Patients with membranous nephropathy were eligible if their diagnosis was confirmed by renal biopsy, with the biopsy sample examined by light, immunofluorescence, and electron microscopy. Renal biopsy samples were centrally reviewed by the two principal investigators and two renal pathologists. Patients also had to be 18 to 80 years of age, have proteinuria of more than 5 g per 24 hours on average in two 24-hour urine samples obtained within 14 days, have a decline of less than 50% in proteinuria despite renin–angiotensin system blockade for at least 3 months before randomization, and have a stable quantified 24-hour creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area.

All patients received best-practice supportive care that included blockers of the renin–angiotensin system, blood-pressure management targeting a value of less than 130/80 mm Hg, dietary sodium restriction to less than 4 g per day, and dietary protein restriction to 0.8 to 1 g of protein per kilogram of body weight per day during at least the previous 3 months before randomization. Do remember that the restriction of proteins is not “no proteins in diet” but restriction of proteins. In underprivileged patients in the Third World .8 gm of proteins per kg per day is all the patients can afford so do take a careful dietary history and do not make further protein restrictions.

If proteinuria remained at a level of at least 5 g per 24 hours and the creatinine clearance was at least 40 ml per minute per 1.73 m2, patients were randomly assigned in a 1:1 ratio to receive rituximab or cyclosporine.

Intervention.

Patients who were assigned to the rituximab group received 1000 mg of intravenous medication (Rituxan, Genentech) on days 1 and 15. If proteinuria was reduced from baseline by at least 25% at 6 months but there was not complete remission, a second course of rituximab was administered regardless of the CD19+ B-cell count. If complete remission was observed at 6 months, no second course was given. If proteinuria was reduced by less than 25% by 6 months, the patient was considered to have treatment failure and no further rituximab was administered.

Patients who were assigned to the cyclosporine group received dose-adjusted cyclosporine (Neoral, Novartis), starting at an oral dose of 3.5 mg per kilogram per day, divided into two equal doses given at 12-hour intervals. Target trough blood levels of cyclosporine were 125 to 175 ng per milliliter. Blood levels were assessed every 2 weeks until the target trough level was reached. If complete remission was observed at 6 months, cyclosporine was tapered and discontinued over a 2-month period. If proteinuria was reduced from baseline by less than 25% at 6 months, the patient was considered to have treatment failure and cyclosporine was discontinued. If proteinuria was reduced by at least 25%, cyclosporine was continued for an additional 6 months. At the end of 12 months, cyclosporine was tapered by one third of the maintenance dose monthly and discontinued after 2 months. A persistent and otherwise unexplained increase in the serum creatinine level of more than 30% was managed by dose reduction as described previously. If the creatinine level did not fall to baseline values despite dose reductions, cyclosporine was discontinued and the patient was considered to have treatment failure.

Outcome and follow-up.

The primary clinical outcome was the composite of complete or partial remission at 24 months. Secondary clinical outcomes included the composite of complete or partial remission at 6, 12, and 18 months; complete remission at 6, 12, 18, and 24 months; time to treatment failure up to 24 months; end-stage renal disease; and adverse events. Continuous secondary outcomes, including anti-PLA2R levels, quality of life as assessed with the modified Kidney Disease Quality of Life Short Form (KDQOL-SF), version 1.3, proteinuria, and creatinine clearance, were systematically recorded only up to the occurrence of treatment failure.

Complete remission was defined as proteinuria of no more than 0.3 g per 24 hours and a serum albumin level of at least 3.5 g per deciliter. Partial remission was defined as a reduction in proteinuria of at least 50% from baseline plus final proteinuria between 0.3 g and 3.5 g per 24 hours regardless of creatinine clearance or the serum albumin level. We defined no response as no reduction in proteinuria of at least 25% from baseline. Relapse was defined as the development of proteinuria of more than 3.5 g per 24 hours after a complete or partial remission. End-stage renal disease was defined as a creatinine clearance of no more than 15 ml per minute, the initiation of dialysis, or renal transplantation.

Results.

The treatment effect of rituximab as compared with cyclosporine appeared to be consistent across subgroups defined according to age, proteinuria, anti-PLA2R antibody status, and history of immunosuppressive therapy at baseline. However, a test for interaction with sex indicated a more pronounced benefit of rituximab in women than in men (P<0.001 for interaction), which was probably due to baseline imbalances in anti-PLA2R levels. The interaction disappeared after adjustment for anti-PLA2R levels at baseline.

At 24 months, 23 patients (35%) in the rituximab group and none of the patients in the cyclosporine group had a complete remission (risk difference, 35 percentage points; 95% CI, 24 to 47). Of these patients, 18 were positive for anti-PLA2R antibodies at baseline and all were antibody-negative at 24 months.

A total of 26 patients (40%) in the rituximab group and 52 (80%) in the cyclosporine group had treatment failure by 24 months (hazard ratio, 0.34; 95% CI, 0.21 to 0.54).

At the end of the treatment period (12 months), 39 patients (60%) in the rituximab group and 34 (52%) in the cyclosporine group had a complete or partial remission (hazard ratio for response, 0.85; 95% CI, 0.55 to 1.32)

The decline in anti-PLA2R antibody levels was faster and of greater magnitude and duration in anti-PLA2R–positive patients in remission in the rituximab group than in those in the cyclosporine group and was accompanied by a greater decline in proteinuria.

Adverse effects.

The incidence of adverse events was similar in the rituximab group and the cyclosporine group (71% and 78% of patients, respectively). The incidence of adverse events of grade 3 or higher was 52% in the rituximab group and 68% in the cyclosporine group, and the incidence of serious adverse events was 17% and 31%, respectively.

Rituximab was noninferior to cyclosporine in inducing proteinuria remission at 12 months and was superior in maintaining long-term proteinuria remission up to 24 months in patients with membranous nephropathy who were at high risk for progressive disease. The superiority of rituximab at 24 months appeared to be driven by the significantly lower incidence of relapse in the rituximab group than in the cyclosporine group during the observation period at months 13 to 24.

In conclusion, rituximab was noninferior to cyclosporine in inducing proteinuria remission at 12 months and was superior in maintaining long-term proteinuria remission up to 24 months in patients with membranous nephropathy who were at high risk for progressive disease.

Ref:

Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy

List of authors.

  • Fernando C. Fervenza, M.D., Ph.D.,
  • Gerald B. Appel, M.D.,
  • Sean J. Barbour, M.D.,
  • Brad H. Rovin, M.D.,
  • Richard A. Lafayette, M.D.,
  • Nabeel Aslam, M.D.,
  • Jonathan A. Jefferson, M.D.,
  • Patrick E. Gipson, M.D.,
  • Dana V. Rizk, M.D.,
  • John R. Sedor, M.D.,
  • James F. Simon, M.D.,
  • Ellen T. McCarthy, M.D.

July 4, 2019
N Engl J Med 2019; 381:36-46
DOI: 10.1056/NEJMoa1814427.

Managing gout.

The deposition of monosodium urate [MSU] crystal is characterized biochemically by extracellular fluid urate saturation, which is reflected in the blood by hyperuricemia, with serum or plasma urate concentrations exceeding 6.8 mg/dL (approximately 400 micromol/L); this level of urate is the approximate limit of urate solubility [1]. This produces the clinical manifestations of gout which may include:

  • Recurrent flares of inflammatory arthritis (gout flare)
  • A chronic arthropathy
  • Accumulation of urate crystals in the form of tophaceous deposits
  • Uric acid nephrolithiasis
  • A chronic nephropathy that, in gouty patients, is most often due to comorbid states

Hyperuricemia that is caused by the overproduction of urate or, more commonly, by renal urate underexcretion is necessary but not sufficient to cause gout. In one cohort study, gout developed in only 22% of subjects with urate levels of more than 9.0 mg per deciliter (535 μmol per liter) during a 5-year period. Gout tends to occur earlier in life in men, more often in post-menopausal women and is rare in childhood. In children gout occurs in instances of marked hyperuricemia due to urate overproduction, such as inherited defects in enzymes of purine metabolism or diseases with greatly increased rates of cell proliferation i,e glucose-6-phosphatase deficiency (glycogen storage disease, type I, myeloproliferative disorders, lymphoproliferative disorders, hemolytic disorders, psoriasis, obesity, Down’s syndrome, cytotoxic drugs or due to severely impaired renal uric acid clearance, as in familial juvenile hyperuricemic nephropathy.

In men, adult serum urate levels of 5 to 6 mg/dL are usually reached at puberty, with little increase thereafter due to age alone. The corresponding age-related course of serum urate levels differs in women, in whom serum urate concentrations average approximately 1.0 to 1.5 mg/dL lower than men of similar age; the lower levels result from higher urinary fractional excretion of urate during the childbearing period, which is mediated by estrogenic compounds. After menopause, the urate concentrations in women rise to levels comparable to those in adult men. It is usually not necessary  to check the uric acid level in a young woman because she has the onset of arthritis. If she does have a high level of uric acid then check out her renal function. She probably has impaired renal function. Pregnant women may have a rise in uric acid levels caused by placental insufficiency. They do not have gout and need their renal function checked as well. Increase in the incidence of gout is detectable in men by the fourth or fifth decades of life and in women by the sixth or seventh decades.

Gout has two clinical phases. The first phase is characterized by intermittent acute attacks that spontaneously resolve, typically over a period of 7 to 10 days, with asymptomatic periods between attacks. With inadequately treated hyperuricemia, transition to the second phase can occur, manifested as chronic tophaceous gout, which often involves polyarticular attacks, symptoms between attacks, and crystal deposition (tophi) in soft tissues or joints. Although the prevalence of tophaceous gout varies among populations, in one study, tophi were detected in three quarters of patients who had had untreated gout for 20 years or more. Recurrent attacks are common.

Who is likely to get gout?

The use of thiazide diuretics, cyclosporine, and low-dose aspirin (<1 g per day) can cause hyperuricemia, whereas high-dose aspirin (≥3 g per day) is uricosuric. Factors that are associated with hyperuricemia and gout include insulin resistance, the metabolic syndrome, obesity, renal insufficiency, hypertension, congestive heart failure, and organ transplantation. The uricosuric effects of glycosuria in diabetes may reduce the risk of gout. The risk of incident gout is increased in persons with an increased intake of dietary purines (particularly meat and seafood), ethanol (particularly beer and spirits), soft drinks, and fructose and is decreased in those with an increased intake of coffee, dairy products, and vitamin C (which lower urate levels). Triggers for recurrent flares include recent diuretic use, alcohol intake, hospitalization, and surgery. Urate-lowering therapy, which reduces the risk of gout attacks in the long term, can trigger attacks in the early period after its initiation, presumably as a result of mobilization of bodily urate stores.

What should we rely on to make a diagnosis of gout?

The diagnostic standard remains synovial fluid or tophus aspiration with identification of negatively birefringent monosodium urate crystals under polarizing microscopy. Crystals are detectable during attacks and also potentially between attacks, primarily in previously inflamed joints in patients with hyperuricemia. However, crystal evaluation is not performed routinely in clinical practiceHyperuricemia may not be present during acute gout attacks and therefore may not be a helpful criterion for diagnosis.

A typical presentation that is strongly suggestive of the diagnosis includes rapid development of severe pain (i.e., within 24 hours), erythema, and swelling in a characteristic joint distribution — for example, in the first metatarsophalangeal joint (podagra). In a population with a 0.5% prevalence of gout overall, a patient with hyperuricemia and this presentation has an 82% chance of having gout.

What can present as gout?

The differential diagnosis of acute gout includes:

  • other crystal-induced arthritides (e.g., calcium pyrophosphate dihydrate)
  • septic joint

Joint aspiration with Gram’s staining and culture must be performed if a septic joint is suspected, even if monosodium urate crystals are identified. Older adults, particularly women, may present with polyarticular involvement, which may be mistaken for rheumatoid arthritis; a tophus may be mistaken for a rheumatoid nodule. Tophaceous deposits that are not clinically apparent may be visualized by plain radiography or another imaging method. A diagnosis of gout should prompt evaluation for potentially modifiable risk factors (e.g., dietary habits) and associated coexisting illnesses (e.g., hypertension and hyperlipidemia) that may require intervention.

The American College of rheumatology has updated its recommendations for the management of gout in 2012. Each recommendation is rated as “strong” (supported by moderate- or high-certainty evidence) or “conditional” (benefits and risks are closely balanced, or only low-certainty evidence or no data are available).

(Allan S. Brett, MD reviewing FitzGerald JD et al. Arthritis Rheumatol 2020 June). Sponsoring Organization: American College of Rheumatology (ACR).

Key Points

  • Urate-lowering therapy (ULT) is strongly recommended for patients with two or more gout flares annually, or tophi, or gout-related radiographic damage.
  • ULT is conditionally recommended for patients who have had more than one flare but whose flares are infrequent (<2 annually).
  • ULT is not recommended routinely after a first gout flare but is conditionally recommended for a patient with a first flare if serum uric acid is >9 mg/dL or if the patient has stage ≥3 chronic kidney disease (CKD) or urolithiasis.
  • Allopurinol is the strongly recommended first-line ULT. To minimize adverse drug reactions, the starting dose should be ≤100 mg daily (≤50 mg daily for CKD patients), with titration for weeks to months until serum uric acid level <6 mg/dL is achieved. Indications for use of second-line agents (i.e., febuxostat, pegloticase, probenecid) are discussed in the guideline.
  • A 3- to 6-month course of concomitant anti-inflammatory therapy is strongly recommended when ULT is initiated and titrated.
  • Colchicine, nonsteroidal anti-inflammatory drugs, and glucocorticoids (systemic or intra-articular) all are appropriate first-line agents for acute gout flares. Adjuvant application of topical ice is also conditionally recommended.
  • Limiting intake of alcohol, purine, and high-fructose corn syrup is conditionally recommended.
  • For patients with hypertension, avoiding hydrochlorothiazide (which raises serum uric acid) and using losartan (which lowers serum uric acid) are conditionally recommended, if feasible.

Clinical management of gout.

Acute attack of gout.

The main aim of therapy for acute gout is rapid relief of pain and disability caused by intense inflammation. Options for managing acute attacks include the use of nonsteroidal antiinflammatory drugs (NSAIDs), colchicine, glucocorticoids, and possibly corticotropin. The choice of agent, dose, and duration of therapy is guided by consideration of coexisting illnesses that preclude the safe use of a particular regimen, as well as the severity of the gout. Adjunctive measures include applying ice to and resting the affected joint.

In a randomized trial, colchicine (at a dose of 1.2 mg at the onset of a flare, followed by 0.6 mg 1 hour later) was significantly more likely than placebo to result in a reduction in pain of 50% or more 24 hours later (rates, 37.8% and 15.5%, respectively). This regimen had efficacy similar to that of a high-dose regimen (1.2 mg, then 0.6 mg per hour for 6 hours), with fewer gastrointestinal side effects.

Monoarticular attacks are often managed with the use of intraarticular glucocorticoids. In two randomized, placebo-controlled trials of a 5-day course of oral prednisolone (one evaluating a dose of 30 mg daily and the other a dose of 35 mg daily), the efficacy of prednisolone was equivalent to that of standard regimens of indomethacin (vs. the 30-mg dose of prednisolone) and naproxen (vs. the 35-mg dose).

Clinical experience suggests that 7 to 10 days of treatment may be necessary to ensure the resolution of symptoms. Increased doses of antiinflammatory drugs are typically prescribed for the first few days, with a reduction in the dose once symptoms begin to improve. Flares should be treated without interruption of urate-lowering therapy. A “medications in the pocket” strategy should be considered for patients with established gout so that therapy can be started promptly at the onset of symptoms that are consistent with typical attacks.

There is evidence that attacks of gout are caused by the activation of the NLRP3 inflammasome by urate crystals, leading to the release of interleukin-1β33. For this reason, interleukin-1 antagonists are being studied as potential options for patients in whom other treatments are not feasible.34 In a randomized trial, the fully human monoclonal antibody canakinumab significantly reduced pain from acute gout, as compared with 40 mg of intramuscular triamcinolone acetonide, 72 hours after administration of the study drug.35 Anakinra and rilonacept improved acute and chronic gout symptoms, respectively, in two small, uncontrolled pilot studies; however, rilonacept did not significantly reduce pain, as compared with indomethacin, in a randomized trial.34,36,37

Three classes of drugs are approved for lowering urate levels: xanthine oxidase inhibitors, uricosuric agents, and uricase agents. Xanthine oxidase inhibitors block the synthesis of uric acid and can be used regardless of whether there is overproduction of urate. In this class of drugs, the one most commonly prescribed to lower urate levels is allopurinol, which is effective in decreasing flares and tophi, particularly among patients in whom target urate levels are achieved.22,39

Severe allopurinol hypersensitivity is not common but can be life-threatening. Allopurinol desensitization can be attempted in patients with mild cutaneous reactions, but its safety in those with more serious reactions is unknown.44 The majority of patients receive 300 mg of allopurinol daily, but this dose is often inadequate to achieve target urate levels. Daily doses up to 800 mg may be used in patients with normal renal function. The dose is typically reduced in patients with renal impairment, owing to concerns about an increased risk of hypersensitivity in such patients.

n 2009, another xanthine oxidase inhibitor, febuxostat, was approved by the FDA for the treatment of hyperuricemia in patients with gout. As compared with a daily dose of 300 mg of allopurinol, febuxostat at daily doses of 80 mg and 120 mg was 2.5 and 3 times as likely, respectively, to achieve serum urate levels of less than 6 mg per deciliter in a 52-week trial.22

Uricosuric drugs (including probenecid, sulfinpyrazone, and benzbromarone) block renal tubular urate reabsorption. Although these drugs can be used in patients with underexcretion of urate (accounting for up to 90% of patients with gout), they are used less frequently than xanthine oxidase inhibitors and are contraindicated in patients with a history of nephrolithiasis. Benzbromarone may be used in patients with mild-to-moderate renal insufficiency but is potentially hepatotoxic, whereas the other two drugs are generally ineffective in patients with renal impairment.

Uricase converts uric acid into soluble allantoin. Pegloticase, a polyethylene glycolated (pegylated) modified porcine recombinant uricase, was approved by the FDA in 2010 for chronic gout that is refractory to conventional treatments.

Pharmacological treatment of acute gout. Pegloticase must be administered intravenously, and infusion reactions are common.46 Rasburicase, which is approved for use in preventing the tumor lysis syndrome, is not appropriate for use in patients with gout because of its immunogenicity and short half-life.

Lifestyle, nutrition and adjunct therapy.

Patients are advised to avoid alcohol, meat, sea food, fructose containing drinks. The intake of milk and dairy products may help to reduce the uric acid levels in between attacks as does the intake of vitamin C 500mg daily. Losartan and fenofibrate also help lower the uric acid levels. Because rapid lowering of urate levels is associated with gout flares, with an increased risk associated with therapies that more effectively lower urate levels,22,46 prophylaxis against acute flares is advised during the initiation of urate-lowering therapy. Oral colchicine (at a dose of 0.6 mg twice daily for an average of 5.2 months) significantly reduced the likelihood of gout attacks and lessened the severity of flares that did occur, as compared with placebo.21 Diarrhea was common, resulting in a once-daily regimen of colchicine for many patients. Thus, the general recommendation for flare prophylaxis is to use colchicine at a dose of 0.6 mg once or twice daily, with dose adjustments as needed for renal impairment, potential drug interactions, or intolerance. For patients without tophi, prophylaxis should be continued for 6 months. 

I have copied the table for the pharma-therapy of gout. I have left the links in from the NEJM review article so that you can look them up yourself.